ORCID Profile
0000-0003-0694-8743
Current Organisation
Monash University
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Enzymes | Cell Physiology | Biochemistry and Cell Biology | Cell Metabolism
Publisher: Wiley
Date: 04-2010
Publisher: Wiley
Date: 04-2006
Publisher: Springer Science and Business Media LLC
Date: 23-05-2009
DOI: 10.1007/S00125-009-1399-3
Abstract: Macrophage-mediated renal injury plays an important role in the development of diabetic nephropathy. Colony-stimulating factor (CSF)-1 is a cytokine that is produced in diabetic kidneys and promotes macrophage accumulation, activation and survival. CSF-1 acts exclusively through the c-fms receptor, which is only expressed on cells of the monocyte-macrophage lineage. Therefore, we used c-fms blockade as a strategy to selectively target macrophage-mediated injury during the progression of diabetic nephropathy. Obese, type 2 diabetic db/db BL/KS mice with established albuminuria were treated with a neutralising anti-c-fms monoclonal antibody (AFS98) or isotype matched control IgG from 12 to 18 weeks of age and examined for renal injury. Treatment with AFS98 did not affect obesity, hyperglycaemia, circulating monocyte levels or established albuminuria in db/db mice. However, AFS98 did prevent glomerular hyperfiltration and suppressed variables of inflammation in the diabetic kidney, including kidney macrophages (accumulation, activation and proliferation), chemokine CC motif ligand 2 levels (mRNA and urine protein), kidney activation of proinflammatory pathways (c-Jun amino-terminal kinase and activating transcription factor 2) and Tnf-alpha (also known as Tnf) mRNA levels. In addition, AFS98 decreased the tissue damage caused by macrophages including tubular injury (apoptosis and hypertrophy), interstitial damage (cell proliferation and myofibroblast accrual) and renal fibrosis (Tgf-beta1 [also known as Tgfb1] and Col4a1 mRNA). Blockade of c-fms can suppress the progression of established diabetic nephropathy in db/db mice by targeting macrophage-mediated injury.
Publisher: Elsevier BV
Date: 10-2005
Publisher: Wiley
Date: 21-03-2007
DOI: 10.1111/J.1464-5491.2007.02112.X
Abstract: The accuracy of measuring serum cystatin C levels for detecting various stages of chronic kidney disease (CKD) in diabetes is still unclear. In a cross-sectional study of 251 subjects, a reference glomerular filtration rate (GFR) was measured using (99c)Tc-DTPA plasma clearance (iGFR). Multivariate analysis was used to identify independent clinical and biochemical associations with serum cystatin C and iGFR levels. The diagnostic accuracy of cystatin C and commonly used creatinine-based methods of measuring renal function (serum creatinine, the MDRD four-variable and Cockcroft-Gault formulae) for detecting mild and moderate CKD was also compared. In the entire study population the same five variables, age, urinary albumin excretion rates, haemoglobin, history of macrovascular disease and triglyceride levels were independently associated with both cystatin C and iGFR levels. A serum cystatin C level cut-off > 82.1 nmol/l (1.10 mg/l) had the best test characteristics as a screening tool for detecting moderate CKD (< 60 ml/min per 1.73 m(2)) when compared with creatinine-based methods. At the upper threshold for mild CKD (< 90 ml/min per 1.73 m(2)), cystatin C also had greater diagnostic accuracy than creatinine, but had similar diagnostic accuracy when compared with creatinine-based formulae for predicting renal function. This study suggests that the clinical and biochemical parameters associated with serum cystatin C levels are closely linked to those associated with GFR and highlights the potential usefulness of screening for moderate or mild CKD in subjects with diabetes by simply measuring serum cystatin C levels.
Publisher: Wiley
Date: 04-2006
Publisher: Wiley
Date: 07-08-2018
DOI: 10.1111/DOM.13456
Abstract: To determine the effect of different stages of diabetic nephropathy (DN) and sex on the excess and absolute morbidity of coronary artery disease (CAD) and stroke in people with type 1 diabetes (T1D) in order to distinguish different cardiovascular disease (CVD) risk profiles in people with T1D. The study included 4410 people with T1D from the Finnish Diabetic Nephropathy Study (FinnDiane), ided by DN status, and a control population of 12 434 people without diabetes. CVD events were identified from the Finnish nationwide health registries. Cumulative incidences for CAD and stroke were calculated and standardized incidence ratios (SIRs) were estimated between participants with T1D and the control group, stratified by DN status and sex. There were 487 incident CADs and 290 strokes at the end of 2014 (median follow-up 12.9 years). The cumulative incidence rates of CAD and stroke were similar in men and women within different nephropathy groups. The SIR for CAD was 7.5 (95% confidence interval [CI] 6.9-8.2), 17.2 (95% CI 14.9-19.5) in women and 5.3 (95% CI 4.7-5.9) in men. The women-to-men ratio of SIR increased by nephropathy group: 3.3, 3.7, 5.3 and 6.8 in the normo-, micro- and macroalbuminuria and end-stage renal disease (ESRD) groups, respectively. The SIR for stroke was 5.0 (95% CI 4.3-5.5), similar in men and women. The women-to-men ratio of SIR for stroke was 0.8, 1.3, 1.6 and 1.7, in the normo-, micro- and macroalbuminuria and ESRD groups, respectively. The SIR in participants with normoalbuminuria and an estimated glomerular filtration rate ≥90 mL/min/1.73 m Although the excess CVD risk is several-fold greater in women compared to men, the absolute CVD risk in men and women was equal when nephropathy was taken into account. Even participants with normoalbuminuria and normal kidney function were found to have an excess CVD risk compared with the control group without diabetes.
Publisher: Informa Healthcare
Date: 12-07-2011
DOI: 10.1517/13543784.2011.591785
Abstract: In in iduals with diabetes, the presence and severity of kidney disease adversely affects their well-being, significantly contributes to burden of morbidity and increases their risk of a premature death. The efficiency of current management strategies for the treatment of diabetic nephropathy, even in optimal combination, is partial, at best. There remains an unmet need for additional renoprotective interventions in patients with diabetes. This review presents a comprehensive summary of some of the ?new contenders? for the treatment of diabetic nephropathy that have been tested or are being tested in randomised clinical trials in patients with diabetes with a predefined renal endpoint, but are not currently indicated for renoprotective therapy. Many of these drugs have been in clinical use for other indications, or initially developed for other purposes. Although substantial progress has been made towards understanding the pathogenesis of diabetic nephropathy, at present there are no new drugs that provide the solutions we want for our patients. Even when used in combination with standard medical care, current data indicate that renal complications are at best only modestly reduced, at the expense of additional pill burden and exposure to off-target effects. Given the ever-growing burden of diabetic kidney disease, there is a substantial opportunity for better and more targeted (?smarter?) therapeutic interventions in this context.
Publisher: American Diabetes Association
Date: 28-01-2016
DOI: 10.2337/DB15-0864
Abstract: Apoptosis-inducing factor (AIF) is a mitochondrial flavoprotein with dual roles in redox signaling and programmed cell death. Deficiency in AIF is known to result in defective oxidative phosphorylation (OXPHOS), via loss of complex I activity and assembly in other tissues. Because the kidney relies on OXPHOS for metabolic homeostasis, we hypothesized that a decrease in AIF would result in chronic kidney disease (CKD). Here, we report that partial knockdown of Aif in mice recapitulates many features of CKD, in association with a compensatory increase in the mitochondrial ATP pool via a shift toward mitochondrial fusion, excess mitochondrial reactive oxygen species production, and Nox4 upregulation. However, despite a 50% lower AIF protein content in the kidney cortex, there was no loss of complex I activity or assembly. When diabetes was superimposed onto Aif knockdown, there were extensive changes in mitochondrial function and networking, which augmented the renal lesion. Studies in patients with diabetic nephropathy showed a decrease in AIF within the renal tubular compartment and lower AIFM1 renal cortical gene expression, which correlated with declining glomerular filtration rate. Lentiviral overexpression of Aif1m rescued glucose-induced disruption of mitochondrial respiration in human primary proximal tubule cells. These studies demonstrate that AIF deficiency is a risk factor for the development of diabetic kidney disease.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2001
DOI: 10.1097/00007890-200110150-00024
Abstract: Hyperglycemia alters the inflammatory response to infection and ischemia. We hypothesize that perioperative glycemic control could also influence the risk for allograft rejection. Consecutive patients with established diabetes undergoing their first cadaveric renal transplantation and receiving steroid-sparing immunosuppression were identified (n=50). Records of capillary glucose observations over the first 100 hr following surgery and transplantation variables pertaining to graft function, acute rejection, and postoperative infection were identified and entered into multivariate analysis. Perioperative glycemic control was associated with an increased incidence of infection and acute rejection. Only 3 of 27 patients (11%) with optimal glycemic control during the 100 hr following surgery (mean 11.2 mmol/L). All patients with poor glycemic control experienced postoperative infection. This pilot study suggests that hyperglycemia may be associated with an increased risk of both allograft rejection and postoperative infection in patients with diabetes.
Publisher: Wiley
Date: 08-2009
DOI: 10.1111/J.1445-5994.2008.01821.X
Abstract: Intensive glycaemic control delays the onset and progression of diabetes-related complications, especially microvascular complications. However, only limited information is available regarding glucose-lowering treatment practices in Australian primary care. The aim of the study was to describe patterns of glycaemic control in subjects participating in the National Evaluation of the Frequency of Renal Impairment co-existing with Non-Insulin Dependent Diabetes Mellitus study. Expressions of interest were invited from all registered general practitioners in Australia, from which 500 investigators were randomly selected and asked to provide data on 10-15 consecutive adults with type 2 diabetes presenting to their practice. Just less than half of the 3893 enrolled patients had a haemoglobin (Hb)A(1c) or =8.0% (24.3%, 95%CI 22.9-25.9%. For patients using lifestyle alone, one or two oral glucose-lowering agents or insulin there was a progressive decline in the proportion achieving an HbA(1c) <7.0%, that is, 81, 55, 31 and 24%, respectively. There was a very good concordance between general practitioners' perception of optimal control (HbA(1c) <7.0%) and the actual glycaemic levels achieved in this study. Current targets for glycaemic control in type 2 diabetes have generally been followed in Australian general practice, but there is still a significant gap in the achievement of recommended glycaemic goals. A quarter of the patients clearly have poor glycaemic control. The immediate steps that can be taken to improve glycaemic control include the early use of combination oral glucose-lowering therapies and the increased use of insulin.
Publisher: Springer Science and Business Media LLC
Date: 12-2005
Abstract: Resistance to the actions of insulin is strongly associated with the microvascular complications of diabetes. To the extent that insulin resistance leads to hyperglycemia, dyslipidemia and hypertension, this association is not surprising. It is now clear that insulin also has direct actions in the microvasculature that influence the development and progression of microvascular disease. In the healthy state, insulin appears to have only minor effects on vascular function, because of the activation of opposing mediators such as nitric oxide and endothelin-1. Diabetes and obesity, however, are associated with selective insulin resistance in the phosphatidylinositol-3-kinase signaling pathway, which leads to reduced synthesis of nitric oxide, impaired metabolic control and compensatory hyperinsulinemia. By contrast, insulin signaling via extracellular signal-regulated kinase dependent pathways is relatively unaffected in diabetes, tipping the balance of insulin's actions so that they favor abnormal vasoreactivity, angiogenesis, and other pathways implicated in microvascular complications and hypertension. In addition, preferential impairment of nonoxidative glucose metabolism leads to increased intracellular formation of advanced glycation end products, oxidative stress and activation of other pathogenic mediators. Despite a strong temporal association, a causal link between pathway-selective insulin resistance and microvascular damage remains to be established. It is possible that this association reflects a common genotype or phenotype. Nonetheless, insulin resistance remains an important marker of risk and a key target for intervention, because those patients who achieve a greater improvement of insulin sensitivity achieve better microvascular outcomes.
Publisher: Springer Science and Business Media LLC
Date: 10-11-2016
Abstract: Chronic kidney disease (CKD) is a common comorbidity in patients with type 2 diabetes mellitus (T2DM) and both conditions are increasing in prevalence. CKD is estimated to affect ∼50% patients with T2DM globally, and its presence and severity markedly influences disease prognosis. CKD is more common in certain patient populations, including the elderly, those with youth-onset diabetes mellitus, those who are obese, certain ethnic groups, and disadvantaged populations. These same settings have also seen the greatest increase in the prevalence of T2DM, as exemplified by the increasing prevalence of T2DM in low-to- middle income countries. Patients from low-to-middle income countries are often the least able to deal with the burden of T2DM and CKD and the health-care facilities of these countries least able to deal with the demand for equitable access to renal replacement therapies. The increasing prevalence of younger in iduals with T2DM, in whom an accelerated course of complications can be observed, further adds to the global burden of CKD. Paradoxically, improvements in cardiovascular survival in patients with T2DM have contributed to patients surviving longer, allowing sufficient time to develop renal impairment. This Review explores how the changing epidemiology of T2DM has influenced the prevalence and incidence of associated CKD across different populations and clinical settings.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2013
Publisher: Bentham Science Publishers Ltd.
Date: 03-2010
DOI: 10.2174/187152910790780050
Abstract: Advanced glycation end-products (AGEs) are involved in mediating the effects of hyperglycaemia in diabetes. The most important receptor for AGEs is the receptor for advanced glycation end-products (RAGE). Binding of AGEs to RAGE converts transient cellular stimulation into sustained cellular dysfunction driven by long-term activation of the pro-inflammatory transcription factor NF-kB. Different splice variants of RAGE exist, including a soluble form that binds to AGEs but lacks the intracellular domain and thus fails to induce signal transduction. In this context, soluble RAGE may act as a therapeutic agent for AGE-induced effects. The balance between the synthesis of sRAGE and full-length RAGE may be an important determinant of AGE-induced dysfunction. An increasing amount of evidence suggests that AGEs either directly or via their interaction with RAGE play a pivotal role in the development and acceleration of atherosclerotic cardiovascular disease. These effects will be summarised in this review, together with the effects of therapeutic strategies targeting AGE/RAGE interactions. These treatments appear to have significant clinical potential, most likely in combination with currently used agents such as inhibitors of the renin-angiotensin system or statins, to reduce the major burden of diabetes, its associated cardiovascular disease.
Publisher: Figshare
Date: 2019
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2010
Publisher: American Physiological Society
Date: 06-2011
DOI: 10.1152/AJPRENAL.00015.2011
Abstract: Deficiency of the intrinsic lysosomal protein human scavenger receptor class B, member 2 (SCARB2 Limp-2 in mice) causes collapsing focal and segmental glomerular sclerosis (FSGS) and myoclonic epilepsy in humans, but patients with no apparent kidney damage have recently been described. We now demonstrate that these patients can develop tubular proteinuria. To determine the mechanism, mice deficient in Limp-2, the murine homolog of SCARB2, were studied. Most low-molecular-weight proteins filtered by the glomerulus are removed in the proximal convoluted tubule (PCT) by megalin/cubilin-dependent receptor-mediated endocytosis. Expression of megalin and cubilin was unchanged in Limp-2 −/− mice, however, and the initial uptake of injected Alexa Fluor 555-conjugated bovine serum albumin (Alexa-BSA) was similar to wild-type mice, indicating that megalin/cubilin-dependent, receptor-mediated endocytosis was unaffected. There was a defect in proteolysis of reabsorbed proteins in the Limp-2 −/− mice, demonstrated by the persistence of Alexa-BSA in the PCT compared with controls. This was associated with the failure of the lysosomal protease cathepsin B to colocalize with Alexa-BSA and endogenous retinol-binding protein in kidneys from Limp-2 −/− mice. The data suggest that tubular proteinuria in Limp-2 −/− mice is due to failure of endosomes containing reabsorbed proteins to fuse with lysosomes in the proximal tubule of the kidney. Failure of proteolysis is a novel mechanism for tubular proteinuria.
Publisher: Wiley
Date: 04-2006
Publisher: BMJ
Date: 13-08-2019
DOI: 10.1136/GUTJNL-2019-318512
Abstract: We evaluated the influence of the renin–angiotensin system (RAS) on intestinal inflammation and fibrosis. Cultured human colonic myofibroblast proliferation and collagen secretion were assessed following treatment with angiotensin (Ang) II and Ang (1–7), their receptor antagonists candesartan and A779, and the ACE inhibitor captopril. Circulating and intestinal RAS components were evaluated in patients with and without IBD. Disease outcomes in patients with IBD treated with ACE inhibitors and angiotensin receptor blockers (ARBs) were assessed in retrospective studies. Human colonic myofibroblast proliferation was reduced by Ang (1–7) in a dose-dependent manner (p .05). Ang II marginally but not significantly increased proliferation, an effect reversed by candesartan (p .001). Colonic myofibroblast collagen secretion was reduced by Ang (1–7) (p .05) and captopril (p .001), and was increased by Ang II (p .001). Patients with IBD had higher circulating renin (mean 25.4 vs 18.6 mIU/L, p=0.026) and ACE2:ACE ratio (mean 0.92 vs 0.69, p=0.015) than controls without IBD. RAS gene transcripts and peptides were identified in healthy and diseased bowels. Colonic mucosal Masson’s trichrome staining correlated with Ang II (r=0.346, p=0.010) and inversely with ACE2 activity (r=−0.373, p=0.006). Patients with IBD who required surgery (1/37 vs 12/75, p=0.034) and hospitalisation (0/34 vs 8/68, p=0.049) over 2 years were less often treated with ACE inhibitors and ARBs than patients not requiring surgery or hospitalisation. The RAS mediates fibrosis in human cell cultures, is expressed in the intestine and perturbed in intestinal inflammation, and agents targeting this system are associated with improved disease outcomes.
Publisher: Springer Science and Business Media LLC
Date: 2004
DOI: 10.1007/S00125-003-1256-8
Abstract: Diabetic renal disease has been postulated to progress as a result of an interaction between metabolic and haemodynamic pathways. Our aim was to assess the functional, structural, molecular and cellular aspects of renal disease in an experimental model of diabetes with associated hypertension. Streptozotocin-induced diabetic spontaneously hypertensive rats were randomised to no treatment, the ACE inhibitor, perindopril (2 mg/l), the AGE formation inhibitor, aminoguanidine (1 g/l) and a combination of both agents and were followed for 32 weeks. Diabetes was associated with a considerable increase in albumin excretion rate. Both aminoguanidine and perindopril retarded the increase in albuminuria, which was completely abrogated by combination therapy. Glomerulosclerosis and tubulointerstitial damage was reduced by both monotherapies with further renoprotection afforded by combination therapy in both cases. Combination therapy was also associated with a superior restoration in diabetes-induced nephrin protein depletion compared to either monotherapy. TGFbeta1 expression as assessed by in situ hybridisation was increased in the diabetic rats and reduced by perindopril and aminoguanidine. These findings indicate that in the context of diabetes-related renal injury, blocking both the renin-angiotensin and advanced glycation pathways offers superior renoprotection and could be considered as a therapeutic strategy in the prevention and retardation of progressive-diabetic renal injury.
Publisher: American Diabetes Association
Date: 15-10-2011
DOI: 10.2337/DB10-0892
Abstract: Progressive fibrosis in the diabetic kidney is driven and sustained by a erse range of profibrotic factors. This study examines the critical role of microRNAs (miRNAs) in the regulation of the key fibrotic mediators, TGF-β1 and TGF-β2. Rat proximal-tubular epithelial cells (NRK52E) were treated with TGF-β1 and TGF-β2 for 3 days, and expression of markers of epithelial-to-mesenchymal transition (EMT) and fibrogenesis were assessed by RT-PCR and Western blotting. The expression of miR-141 and miR-200a was also assessed, as was their role as translational repressors of TGF-β signaling. Finally, these pathways were explored in two different mouse models, representing early and advanced diabetic nephropathy. Both TGF-β1 and TGF-β2 induced EMT and fibrogenesis in NRK52E cells. TGF-β1 and TGF-β2 also downregulated expression of miR-200a. The importance of these changes was demonstrated by the finding that ectopic expression miR-200a downregulated smad-3 activity and the expression of matrix proteins and prevented TGF-β–dependent EMT. miR-200a also downregulated the expression of TGF-β2, via direct interaction with the 3′ untranslated region of TGF-β2. The renal expression of miR-141 and miR-200a was also reduced in mouse models representing early and advanced kidney disease. miR-200a and miR-141 significantly impact on the development and progression of TGF-β–dependent EMT and fibrosis in vitro and in vivo. These miRNAs appear to be intricately involved in fibrogenesis, both as downstream mediators of TGF-β signaling and as components of feedback regulation, and as such represent important new targets for the prevention of progressive kidney disease in the context of diabetes.
Publisher: Springer Science and Business Media LLC
Date: 2008
Publisher: Wiley
Date: 04-2006
Publisher: AMPCo
Date: 09-2006
DOI: 10.5694/J.1326-5377.2006.TB00556.X
Abstract: To examine factors influencing the identification of kidney impairment in patients with type 2 diabetes in Australian primary care. 348 general practitioner investigators were asked to estimate kidney function and its severity in 10-15 consecutively presenting patients with type 2 diabetes (n = 3893). They were then asked, for each patient, whether they routinely estimated kidney function. No instruction was provided on how kidney function should be estimated or categorised. Data were collected between April and September 2005. Kidney function estimated by the Cockcroft-Gault equation using clinical and laboratory data provided by the GP estimates of kidney function made by the GP. In 24% of the patients with type 2 diabetes, their GP routinely estimated kidney function. However, few of these patients had impaired kidney function or risk factors for kidney disease. There was a good statistical correlation between the estimates made by GPs and the data-derived estimates (R2 = 0.72). GPs identified patients with data-derived estimates of kidney function < 60 mL/min in over 83% of cases, with a specificity of 90%. Impaired kidney function was reported by GPs in 34.4% of men and 36.4% of women. These figures were discordant with function categorisation using both GP estimates and data-derived values, overlapping in half of the patients. Despite GPs' ability to assess creatinine clearance, "raw" (unstandardised) serum creatinine levels inappropriately influenced the perception of impairment of kidney function. GPs can accurately assess kidney function, without reporting of estimated glomerular filtration rate (eGFR). However, even in patients at increased risk of chronic kidney disease, routine estimates are seldom made. Our findings underline the value of the recent initiative recommending automatic reporting of eGFR in Australia.
Publisher: Wiley
Date: 23-06-2011
DOI: 10.1111/J.1365-2796.2011.02406.X
Abstract: Adiponectin is widely regarded as an anti-atherogenic, antioxidant and anti-inflammatory molecule. However, adiponectin concentration is paradoxically increased in in iduals with type 1 diabetes, in whom it is positively associated with adverse clinical outcomes. To explore the association between serum adiponectin concentration and mortality outcomes in adults with type 1 diabetes. Multicentre prospective cohort study. Primary and tertiary care. Finnish adults with type 1 diabetes (n= 2034). Main outcome measures. All-cause and cardiovascular mortality. Independent predictors of mortality were determined using the Cox and the Fine and Gray competing risks proportional hazards models. During a median of 11 years of follow-up, there were 173 deaths (8.5%, 1.0 per hundred person-years). Adiponectin was linearly associated with all-cause mortality [Cox model: hazard ratio (HR) 1.02, 95% confidence interval (CI) 1.01-1.03, P<0.001] and cardiovascular mortality (Fine and Gray model: HR 1.02, 95% CI 1.00-1.04, P=0.035) patients with the highest adiponectin concentrations had the shortest survival. The mortality risk associated with adiponectin was independent of glycaemic and lipid control, pre-existing cardiovascular disease, markers of inflammation and the presence and severity of kidney disease. Although adiponectin is generally considered to be a protective molecule, increased concentrations of adiponectin in type 1 diabetes are independently associated with all-cause and cardiovascular mortality. Moreover, the fact that this association was observed for the first time in patients with normal urinary albumin levels, who have few comorbidities, suggests that adiponectin is specifically linked with vascular damage in type 1 diabetes.
Publisher: American Diabetes Association
Date: 04-2010
DOI: 10.2337/DB10-ER04A
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-01-2018
DOI: 10.2215/CJN.10380917
Publisher: Springer Science and Business Media LLC
Date: 25-10-2007
Publisher: Bentham Science Publishers Ltd.
Date: 15-07-2016
DOI: 10.2174/1573403X12666160606123103
Abstract: Congestive heart failure (CHF) is a chronic and often devastating cardiovascular disorder with no cure. There has been much advancement in the last two decades that has seen improvements in morbidity and mortality. Clinicians have also noted variations in the responses to therapies. More detailed observations also point to clusters of diseases, phenotypic groupings, unusual severity and the rates at which CHF occurs. Medical genetics is playing an increasingly important role in answering some of these observations. This developing field in many respects provides more information than is currently clinically applicable. This includes making sense of the established single gene mutations or uncommon private mutations. In this thematic series which discusses the many factors that could be relevant for CHF care, once established treatments are available in the communities this section addresses a contextual role for medical genetics.
Publisher: American Physiological Society
Date: 03-2010
DOI: 10.1152/AJPRENAL.00591.2009
Abstract: Advanced glycation end products (AGEs) and the receptor for AGEs (RAGE) generate ROS, and therefore this study evaluated the effects of RAGE deletion, decreasing AGE accumulation, or lowering dietary AGE content on oxidative parameters in diabetic nephropathy (DN). Control and diabetic male wild-type and RAGE-deficient (RAGE −/− ) mice were fed high- or low-AGE diets, with two groups given the inhibitor of AGE accumulation, alagebrium chloride, and followed for 24 wk. Diabetic RAGE −/− mice were protected against albuminuria, hyperfiltration, glomerulosclerosis, decreased renal mitochondrial ATP production, and excess generation of both mitochondrial and cytosolic superoxide. Whereas glomerulosclerosis, tubulointerstitial expansion, and hyperfiltration were improved in diabetic mice treated with alagebrium, there was no effect on urinary albumin excretion. Both diabetic RAGE −/− and alagebrium-treated mice had an attenuation of renal RAGE expression and decreased renal and urinary AGE (carboxymethyllysine) levels. Low-AGE diets did not confer renoprotection, lower the AGE burden or renal RAGE expression, or improve cytosolic or mitochondrial superoxide generation. Renal uncoupling protein-2 gene expression and mitochondrial membrane potential were attenuated by all therapeutic interventions in diabetic mice. In the present study, erse approaches to block the AGE-RAGE axis had disparate effects on DN, which has potential clinical implications for the way this axis should be targeted in humans.
Publisher: Wiley
Date: 10-2001
DOI: 10.1034/J.1399-0012.2001.150509.X
Abstract: Although cytomegalovirus (CMV) infection is common in renal transplant recipients, urinary tract involvement has been rare. Only six cases of symptomatic ureteritis have been reported in renal transplant recipients and all within the last five years. We describe an additional four cases of CMV ureteritis. The presentation of CMV ureteritis is obstructive nephropathy often in the absence of systemic illness. Presentation may also mimic allograft rejection with minimal obstructive symptoms. We hypothesize that CMV ureteritis is an emerging complication of CMV disease, possibly due to changes in transplant practice.
Publisher: Springer Science and Business Media LLC
Date: 22-08-2018
DOI: 10.1007/S00125-018-4669-0
Abstract: Inhibition of the sodium-glucose cotransporter (SGLT) 2 in the proximal tubule of the kidney has a broad range of effects on renal function and plasma volume homeostasis, as well as on adiposity and energy metabolism across the entire body. SGLT2 inhibitors are chiefly used in type 2 diabetes for glucose control, achieving reductions in HbA
Publisher: S. Karger AG
Date: 2007
DOI: 10.1159/000101323
Abstract: The accumulation of interstitial matrix represents the final common pathway of most forms of kidney disease. Much of this matrix is synthesized by interstitial myofibroblasts, recruited from resident fibroblasts and circulating precursors. In addition, a significant proportion is derived from epithelial-mesenchymal transition (EMT) of tubuloepithelial cells. The importance of EMT has been demonstrated in experimental models, where blockade of EMT attenuates renal fibrosis. Although a number of factors may initiate EMT in the kidney, the most potent is transforming growth factor-β1 (TGF-β1). Moreover, many other prosclerotic factors have effects on EMT indirectly, via induction of TGF-β1. Signaling events in this pathway include activation of Smad/integrin-linked kinase (ILK) and connective tissue growth factor (CTGF). Basement membrane integrity is also a key regulator of EMT. In particular, overexpression of matrix metalloproteinase-2 has a key role in the initiation of EMT, membrane dissolution, and the interstitial transit of transformed mesenchymal cells. Endogenous inhibitors of EMT also play an important counterregulatory role both to prevent EMT and stimulate uncommitted cells to regain their tubular phenotype (mesenchymal-epithelial transition). Such inhibitors represent a potential therapeutic approach, offering a mechanism to slow or even redress established renal fibrosis.
Publisher: Wiley
Date: 04-2006
Publisher: Wiley
Date: 03-2009
Publisher: Portland Press Ltd.
Date: 12-12-2006
DOI: 10.1042/CS20050184
Abstract: Anaemia is common in patients with diabetes and associated with an increased risk of diabetic complications. Although the role of anaemia in heart failure is established, we hypothesize that anaemia also contributes to an increased risk of cardiac dysfunction in patients with Type II diabetes. In the present study, 228 consecutive adults with diabetes were investigated using transthoracic echocardiography. Echocardiographic parameters were correlated with the Hb (haemoglobin) level and adjusted for other risk factors for cardiac dysfunction using multivariate analysis. More than one in five patients (23%) had anaemia, which was an independent risk factor for cardiac dysfunction on echocardiography. Over one-third of all patients with evidence of abnormal cardiac function (diastolic and/or systolic dysfunction) on echocardiography had anaemia compared with & % of patients with normal echocardiographic findings. Most patients with anaemia had cardiac dysfunction (94%), with the major abnormality being diastolic dysfunction associated with an increased left ventricular mass and impaired relaxation indices. A continuous association between diastolic function and Hb was also observed in patients without anaemia. In patients with a history of cardiovascular disease, systolic dysfunction was twice as common in patients with anaemia. Anaemia was also correlated with plasma markers of cardiac risk, including BNP (brain natriuretic peptide), CRP (C-reactive protein) and AVP (arginine vasopressin). Notably, the predictive utility of these markers was eliminated after adjusting for Hb. Consequently, the inexpensive measurement of Hb may be a useful tool to identify diabetic patients at increased risk of cardiac dysfunction.
Publisher: Springer Science and Business Media LLC
Date: 20-06-2007
DOI: 10.1007/S00125-007-0718-9
Abstract: AGE contribute to the pathogenesis of diabetic complications, including dyslipidaemia and atherosclerosis. However, the precise mechanisms remain to be established. In the present study, we examined whether AGE modification of apolipoprotein A-I (apoA-I) affects its functionality, thus altering its cardioprotective profile. The ability of AGE-modified apoA-I to facilitate cholesterol and phospholipid efflux, stabilise ATP-binding cassette transporter A1 (ABCA1) and inhibit expression of adhesion molecules in human macrophages and monocytes was studied. The ability of AGE-modified apoA-I to promote cholesterol efflux from THP-1 macrophages, isolated human monocytes and from ABCA1-transfected HeLa cells was significantly reduced (>70%) compared with unmodified apoA-I. This effect was reversed by preventing AGE formation with aminoguanidine or reversing AGE modification using the cross-link breaker alagebrium chloride. AGE-modification of HDL also reduced its capacity to promote cholesterol efflux. AGE-apoA-I was also less effective than apoA-I in stabilising ABCA1 in THP-1 cells as well as in inhibiting expression of CD11b in human monocytes. AGE modification of apoA-I considerably impairs its cardioprotective, antiatherogenic properties, including the ability to promote cholesterol efflux, stabilise ABCA1 and inhibit the expression of adhesion molecules. These findings provide a rationale for targeting AGE in the management of diabetic dyslipidaemia.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2005
Publisher: American Diabetes Association
Date: 07-2004
DOI: 10.2337/DIABETES.53.7.1813
Abstract: Advanced glycation end product (AGE) formation may contribute to the progression of atherosclerosis, particularly in diabetes. The present study explored atherosclerosis in streptozotocin-induced diabetic apolipoprotein E–deficient (apoE−/−) mice that were randomized (n = 20) to receive for 20 weeks no treatment, the AGE cross-link breaker ALT-711, or the inhibitor of AGE formation aminoguanidine (AG). A sixfold increase in plaque area with diabetes was attenuated by 30% with ALT-711 and by 40% in AG-treated mice. Regional distribution of plaque demonstrated no reduction in plaque area or complexity within the aortic arch with treatment, in contrast to the thoracic and abdominal aortas, where significant attenuation was seen. Diabetes-associated accumulation of AGEs in aortas and plasma and decreases in skin collagen solubility were ameliorated by both treatments, in addition to reductions in the vascular receptor for AGE. Collagen-associated reductions in the AGEs carboxymethyllysine and carboxyethyllysine were identified with both treatments. Diabetes was also accompanied by aortic accumulation of total collagen, specifically collagens I, III, and IV, as well as increases in the profibrotic cytokines transforming growth factor-β and connective tissue growth factor and in cellular α-smooth muscle actin. Attenuation of these changes was seen in both treated diabetic groups. ALT-711 and AG demonstrated the ability to reduce vascular AGE accumulation in addition to attenuating atherosclerosis in these diabetic mice.
Publisher: MDPI AG
Date: 18-05-2022
Abstract: Circulating levels of soluble ACE2 are increased by diabetes. Although this increase is associated with the presence and severity of cardiovascular disease, the specific role of soluble ACE2 in atherogenesis is unclear. Previous studies suggested that, like circulating ACE, soluble ACE2 plays a limited role in vascular homeostasis. To challenge this hypothesis, we aimed to selectively increase circulating ACE2 and measure its effects on angiotensin II dependent atherogenesis. Firstly, in Ace2/ApoE DKO mice, restoration of circulating ACE2 with recombinant murine soluble (rmACE219-613 1 mg/kg/alternate day IP) reduced plaque accumulation in the aortic arch, suggesting that the phenotype may be driven as much by loss of soluble ACE2 as the reduction in local ACE2. Secondly, in diabetic ApoE KO mice, where activation of the renin angiotensin system drives accelerated atherosclerosis, rmACE219-613 also reduced plaque accumulation in the aorta after 6 weeks. Thirdly, to ensure consistent long-term delivery of soluble ACE2, an intramuscular injection was used to deliver a DNA minicircle encoding ACE219-613. This strategy efficiently increased circulating soluble ACE2 and reduced atherogenesis and albuminuria in diabetic ApoE KO mice followed for 10 weeks. We propose that soluble ACE2 has independent vasculoprotective effects. Future strategies that increase soluble ACE2 may reduce accelerated atherosclerosis in diabetes and other states in which the renin angiotensin system is upregulated.
Publisher: Cambridge University Press (CUP)
Date: 05-2010
DOI: 10.1017/S1462399410001481
Abstract: Common to all forms of chronic kidney disease is the progressive scarring of the tubulo-interstitial space, associated with the acquisition and accumulation of activated myofibroblasts. Many of these myofibroblasts are generated when tubular epithelial cells progressively lose their epithelial characteristics (cell–cell contact, microvilli, tight-junction proteins, apical–basal polarity) and acquire features of a mesenchymal lineage, including stress fibres, filopodia and augmented matrix synthesis. This process, known as epithelial to mesenchymal transition (EMT), plays an important role in progressive kidney disease. For EMT to occur in tubular cells, the transcriptional activation (and derepression) of genes required to sustain mesenchymal-type structures and functions (e.g. vimentin, α-smooth muscle actin) must occur alongside repression (or deactivation) of genes that act to maintain the epithelial phenotype (e.g. E-cadherin, bone morphogenic protein 7). Several factors have been suggested as potential initiators of EMT. With a few key exceptions, these triggers require the induction of transforming growth factor β (TGF-β) and downstream mediators, including SMADs, CTGF, ILK and SNAI1. Activation of TGF-β receptors is also able to stimulate a range of additional pathways (so-called non-SMAD activation), including RhoA, mitogen-activated protein kinase and phosphoinositide 3-kinase signalling cascades, that also contribute to EMT and renal fibrogenesis. This review examines in detail the molecular mediators of EMT in tubular cells and its potential role as a long-lasting mediator of metabolic stress.
Publisher: Elsevier BV
Date: 05-2012
DOI: 10.1016/J.ANNEMERGMED.2011.11.013
Abstract: The primary objective of this study is to determine the activities of pharmacists that lead to medication error interception in the emergency department (ED). This was a prospective, multicenter cohort study conducted in 4 geographically erse academic and community EDs in the United States. Each site had clinical pharmacy services. Pharmacists at each site recorded their medication error interceptions for 250 hours of cumulative time when present in the ED (1,000 hours total for all 4 sites). Items recorded included the activities of the pharmacist that led to medication error interception, type of orders, phase of medication use process, and type of error. Independent evaluators reviewed all medication errors. Descriptive analyses were performed for all variables. A total of 16,446 patients presented to the EDs during the study, resulting in 364 confirmed medication error interceptions by pharmacists. The pharmacists' activities that led to medication error interception were as follows: involvement in consultative activities (n=187 51.4%), review of medication orders (n=127 34.9%), and other (n=50 13.7%). The types of orders resulting in medication error interceptions were written or computerized orders (n=198 54.4%), verbal orders (n=119 32.7%), and other (n=47 12.9%). Most medication error interceptions occurred during the prescribing phase of the medication use process (n=300 82.4%) and the most common type of error was wrong dose (n=161 44.2%). Pharmacists' review of written or computerized medication orders accounts for only a third of medication error interceptions. Most medication error interceptions occur during consultative activities.
Publisher: Elsevier BV
Date: 12-1998
Publisher: Wiley
Date: 21-05-2005
DOI: 10.1111/J.1464-5491.2005.01516.X
Abstract: To estimate the prevalence of undiagnosed diabetes and impaired fasting glucose in older British men and women, using the 1999 World Health Organization (WHO) thresholds based on fasting glucose measurements. Participants in the British Regional Heart Study and the British Women's Heart and Health Study were selected from one socially representative general practice in 24 British towns. Included in this analysis were 3736 men and 3642 women aged 60-79 years (predominantly white), who provided a single fasting blood s le at a clinical examination between 1998 and 2001, and who had no previous diagnosis of diabetes. Two hundred and eleven men (5.7%) and 190 women (5.2%) had a fasting blood glucose level consistent with the WHO threshold for a diagnosis of diabetes (> or = 7.0 mmol/l), whilst a further 667 men (17.9%) and 642 women (17.6%) had impaired fasting glucose levels (6.1 < or = 7 mmol/l). When analyses were restricted to subjects who had fasted for at least 8 h, and whose blood s le was taken before 12.00 h, the predicted prevalence of undiagnosed diabetes (based on two separate measurements) was 6.7% in men and 6.0% in women. The predicted prevalence of impaired fasting glucose (based on two separate measurements) was approximately 20% in both sexes. More than one-fifth of older white British men and women have either undiagnosed diabetes or impaired fasting glucose according to new WHO criteria. Strategies for the primary and secondary prevention of Type 2 diabetes among older in iduals are urgently needed.
Publisher: Elsevier BV
Date: 03-2022
DOI: 10.1016/J.METABOL.2021.154961
Abstract: Type 2 diabetes is associated with an increased risk of cardiovascular disease, heart failure, chronic kidney disease, fatty liver disease, eye and foot disease. But equally, these conditions are associated with an increased risk of type 2 diabetes. Rather than being simply considered complications of diabetes, as exists within a 'pure' type 1 diabetes paradigm, both type 2 diabetes and its comorbidities are primarily caused by a failure to efficiently sequester excess energy leading to the accumulation of sick fat (adiposopathy). Type 2 diabetes is a symptom of a chronic disease complex, just as cardiovascular, renal, eye, foot and/or liver disease, are. In addition, each of these conditions feed forward so that dysfunction in one system accelerates dysfunction in another, partly through their shared pathogenesis and partly due dysfunction that follows in their wake. This review will explore the sticky, brittle conglomeration of CArdiac, Renal, Adipo-Metabolic, Eye and Liver disease (hereafter collectively known as CARAMEL disease) that is coincident in most patients with type 2 diabetes and contextualise the recent changes in diabetes guidelines that now specifically focus on identifying and aggressively managing these high-risk in iduals with it.
Publisher: Elsevier BV
Date: 07-2006
DOI: 10.1016/J.SEMNEPHROL.2006.05.003
Abstract: Anemia is a common finding in diabetes, particularly in patients with albuminuria or renal impairment. We recently showed that at least 1 in 5 outpatients with type 1 or type 2 diabetes in tertiary clinics have anemia, in whom it constitutes a significant additional burden. Anemia is associated strongly with an increased risk of diabetic complications including nephropathy, retinopathy, and heart failure. Although a number of factors contribute to an increased prevalence of anemia in diabetes, an uncoupling of hemoglobin concentration and renal erythropoietin synthesis associated with tubular dysfunction appears to be the dominant factor. In our patients with diabetes and anemia, more than three quarters had functional erythropoietin deficiency. This association was most pronounced in patients with renal impairment, in whom nearly half of all patients had anemia. However, 70% of anemic patients without renal impairment also had inappropriately low erythropoietin levels. Consequently, the likelihood of functional erythropoietin deficiency, as a cause of anemia in patients with diabetes, is not dependent on the severity of renal impairment. Although there is a clear rationale for correction of anemia in diabetes, it remains to be established whether this will lead to improved outcomes. Some small studies suggest improvement in cardiac outcomes and hospitalization. It is anticipated that large ongoing studies will help define the optimal approach to the management of anemia in diabetes.
Publisher: Bentham Science Publishers Ltd.
Date: 2005
Abstract: Diabetes as the dominant cause of ESRD is also the major cause of renal anaemia. However, most patients with diabetic kidney disease will succumb to co-morbid vascular disease or heart failure before developing severe renal impairment. In these patients, anaemia is also common finding, with a 2-3 times greater prevalence and earlier onset than in patients with renal impairment from other causes. We have recently shown that at least one in five outpatients with type 1 or type 2 diabetes in tertiary referral clinics have anaemia, in whom it constitutes a significant additional burden. Impaired renal erythropoietin release in response to declining haemoglobin levels appears to be the major contributor to anaemia in diabetes. This may be due to the predominance of damage to cells and vascular architecture of the renal tubulointerstitium associated with diabetic nephropathy that may be apparent, like albuminuria, before demonstrable changes in renal function. In addition, systemic inflammation, autonomic neuropathy and reduce red cell survival may also compound anaemia in diabetes. While anaemia may be considered a marker of diabetic kidney disease, reduced haemoglobin levels, even within the normal range, identify diabetic patients with an increased risk of hospitalisation and mortality. Anaemia may also be significant in determining the outcome of heart failure and hypoxia-induced organ damage in patients with diabetes. Upcoming studies will determine whether correction of anaemia in diabetes will lead to improved outcomes in these patients.
Publisher: AMPCo
Date: 02-2007
DOI: 10.5694/J.1326-5377.2007.TB00835.X
Abstract: To examine the frequency of dyslipidaemia and treatment with lipid-lowering drugs in patients with type 2 diabetes managed in Australian primary care. The NEFRON study (National Evaluation of the Frequency of Renal Impairment cO-existing with NIDDM [Non-Insulin Dependent Diabetes Mellitus]) was an incident-driven, cluster-stratified survey of 3893 patients with type 2 diabetes from across Australian primary care between April and September 2005. The most recent fasting lipid levels were compared with therapeutic targets for lipid control and current prescribing guidelines. 64% of patients with type 2 diabetes presenting in primary care received lipid-lowering medication. Despite the widespread use of statins (61%), 75% of patients had a total cholesterol level >or= 4.0 mmol/L, and 47% had a low-density lipoprotein (LDL) cholesterol level >or= 2.5 mmol/L. Few untreated patients met the Australian Pharmaceutical Benefits Scheme (PBS) criteria current at the time for subsidised primary prevention with lipid-lowering agents (4%). However, new PBS subsidy criteria will potentially include 93% of all diabetic patients seeing their general practitioner in primary care. Changes in the provision of subsidised therapy for high-risk diabetic patients are long overdue. However, more needs to be done to optimise management strategies, which still fail to achieve treatment targets in many treated patients.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2005
DOI: 10.1097/01.MJT.0000178769.52610.69
Abstract: Chronic hyperglycemia and oxidative stress in diabetes results in the formation and accumulation advanced glycation end products (AGEs). AGEs have a wide range of chemical, cellular, and tissue effects that contribute to the development of microvascular complications. In particular, AGEs appear to have a key role in the diabetic nephropathy. Their importance as downstream mediators of tissue injury in diabetic kidney disease is demonstrated by animal studies using inhibitors of advanced glycation to retard the development of nephropathy without directly influencing glycemic control. AGE modification of proteins may produce in changes charge, solubility, and conformation leading to molecular dysfunction as well as disrupting interactions with other proteins. AGEs also interact with specific receptors and binding proteins to influence the renal expression of growth factors and cytokines, implicated in the progression of diabetic renal disease. The effects of AGEs appears to be synergistic with other pathogenic pathways in diabetes including oxidative stress, hypertension, and activation of the renin-angiotensin system. Each of these pathways may be activated by AGEs, and each may promote the formation of AGEs in the vicious cycle associated with progressive renal damage. It is likely that therapies that inhibit the formation of AGEs or remove established AGE modifications will form an important component part of future therapy in patients with diabetes, acting in concert with conventional approaches to prevent diabetic renal injury.
Publisher: American Diabetes Association
Date: 26-05-2009
DOI: 10.2337/DC08-2186
Abstract: Most diabetic patients with impaired renal function have a urinary albumin excretion rate in the normal range. In these patients, the etiology of renal impairment is unclear, and it is also unclear whether this nonalbumunuric renal impairment is unique to diabetes. In this study, we examined the frequency and predictors of nonalbumunuric renal impairment (estimated glomerular filtration rate [eGFR] & ml/min per 1.73 m2) in a nationally representative cohort of 3,893 patients with type 2 diabetes and compared our findings with rates observed in the general population from the Australian Diabetes, Obesity and Lifestyle Study (AusDiab) survey (n = 11,247). Of the 23.1% of in iduals with type 2 diabetes who had eGFR & ml/min per 1.73 m2 (95% CI 21.8–24.5%), more than half (55%) had a urinary albumin excretion rate that was persistently in the normal range. This rate of renal impairment was predictably higher than that observed in the general population (adjusted odds ratio 1.3, 95% CI 1.1–1.5, P & 0.01) but was solely due to chronic kidney disease associated with albuminuria. In contrast, renal impairment in the absence of albuminuria was less common in those with diabetes than in the general population, independent of sex, ethnicity, and duration of diabetes (0.6, 0.5–0.7, P & 0.001). Nonalbuminuric renal impairment is not more common in those with diabetes. However, its impact may be more significant. New studies are required to address the pathogenesis, prevention, and treatment of nonalbuminuric renal disease.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-1999
Publisher: Public Library of Science (PLoS)
Date: 03-09-2013
Publisher: Wiley
Date: 04-2006
Publisher: Elsevier BV
Date: 06-2005
DOI: 10.1111/J.1523-1755.2005.00359.X
Abstract: The tubular excretion of creatinine significantly contributes to its clearance. Administration of an angtiotensin-converting enzyme (ACE) inhibitor is associated with increased organic ion clearance in experimental diabetes. This study examines the effect and implications of chronic ACE inhibition on renal organic ion excretion in patients with type 1 diabetes. S les were obtained from the Melbourne Diabetic Nephropathy Study Group (MDNSG) that randomized patients to receive perindopril (N= 11), nifedipine (N= 11), or placebo (N= 8). Albumin excretion rate, creatinine clearance, and isotopic glomerular filtration rate (GFR) were assessed at baseline and after 24 months. In addition, the clearance of the endogenous cations N-methylynicotinamide (NMN), creatinine, and the anion hippurate were determined by high-performance liquid chromatography (HPLC). Following treatment with the ACE inhibitor, perindopril, renal clearance of NMN was increased (+96%) (P < 0.05). There was no difference in patients treated with nifedipine (P= 0.25) and NMN clearance fell in the placebo-treated patients (-26%) (P < 0.05). Changes in NMN clearance were unaffected after adjusting for the effects of perindopril on GFR. However, they were attenuated after adjusting for hippurate clearance, a marker of renal blood flow. This effect of perindopril on NMN clearance was seen in both men and women, regardless of baseline clearance and was correlated with reduced albuminuria following perindopril treatment. Organic ion clearance is increased in patients with diabetes following chronic ACE inhibition. This is consistent with experimental models showing increased ion transporter expression and improved tubular blood flow, following blockade of the renin-angiotensin system (RAS). These findings may have implications for the interpretation of creatinine-based indices in patients with diabetes.
Publisher: American Diabetes Association
Date: 07-09-2010
DOI: 10.2337/DB10-0195
Abstract: To investigate the effect of the GPx1-mimetic ebselen on diabetes-associated atherosclerosis and renal injury in a model of increased oxidative stress. The study was performed using diabetic apolipoprotein E/GPx1 (ApoE−/−GPx1−/−)-double knockout (dKO) mice, a model combining hyperlipidemia and hyperglycemia with increased oxidative stress. Mice were randomized into two groups, one injected with streptozotocin, the other with vehicle, at 8 weeks of age. Groups were further randomized to receive either ebselen or no treatment for 20 weeks. Ebselen reduced diabetes-associated atherosclerosis in most aortic regions, with the exception of the aortic sinus, and protected dKO mice from renal structural and functional injury. The protective effects of ebselen were associated with a reduction in oxidative stress (hydroperoxides in plasma, 8-isoprostane in urine, nitrotyrosine in the kidney, and 4-hydroxynonenal in the aorta) as well as a reduction in VEGF, CTGF, VCAM-1, MCP-1, and Nox2 after 10 weeks of diabetes in the dKO aorta. Ebselen also significantly reduced the expression of proteins implicated in fibrosis and inflammation in the kidney as well as reducing related key intracellular signaling pathways. Ebselen has an antiatherosclerotic and renoprotective effect in a model of accelerated diabetic complications in the setting of enhanced oxidative stress. Our data suggest that ebselen effectively repletes the lack of GPx1, and indicate that ebselen may be an effective therapeutic for the treatment of diabetes-related atherosclerosis and nephropathy. Furthermore, this study highlights the feasibility of addressing two diabetic complications with one treatment regimen through the unifying approach of targeted antioxidant therapy.
Publisher: The Royal Society of Chemistry
Date: 24-09-2010
Publisher: SAGE Publications
Date: 20-09-2011
Abstract: Nrf-2 (NF-E2-related factor 2) is a regulator of anti-oxidant, anti-inflammatory and detoxification pathways. Coordinated augmentation of these key defence pathways via Nrf-2 signalling is being investigated for the treatment of chronic diseases, including diabetes and its complications. The first to reach commercial development is the triterpenoid, bardoxolone methyl. In recent clinical trial, bardoxolone rapidly improved kidney function on average by 5–10 ml/min within 4 weeks of therapy. Importantly, this improvement was sustained during one year of active treatment. This suggests that rather that overworking a failing system, bardoxolone appeared to safely augment renal function, at least to one year. If similar improvements in kidney function can be reproduced in the upcoming BEACON trial, it will represent a major advance on conventional therapy and new way to bring balance to the failing kidney.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2014
DOI: 10.1161/HYPERTENSIONAHA.114.03756
Abstract: The lineage of the Y chromosome accounts for up to 15 to 20 mm Hg in arterial pressure. Genes located on the Y chromosome from the spontaneously hypertensive rat (SHR) are associated with the renin–angiotensin system. Given the important role of the renin–angiotensin system in the renal regulation of fluid homeostasis and arterial pressure, we hypothesized that the origin of the Y chromosome influences arterial pressure via interaction between the intrarenal vasculature and the renin–angiotensin system. Sixteen-week-old normotensive rats (Wistar Kyoto [WKY]), spontaneously hypertensive stroke-prone rat (SHRSP), and 2 reciprocal Y consomic rat strains, 1 comprising the WKY autosomes and X chromosome with the Y chromosome from the hypertensive rat strain (WKY.SP Gla Y) and vice versa (SP.WKY Gla Y), were examined. SP.WKY Gla Y had lower systolic blood pressure than SHRSP (195±5 versus 227±8 mm Hg P .03), whereas WKY.SP Gla Y had higher systolic blood pressure compared with WKY (157±3 versus 148±3 mm Hg P .05), measured by radiotelemetry. Compared with WKY rats, SHRSP had higher plasma angiotensin(1-7) (Ang (1-7)):Ang II ratio (WKY: 0.13±0.01 versus SHRSP: 1.33±0.4 P .005), greater angiotensin II receptor type 2 and Mas receptor mRNA expression, and a blunted renal constrictor response to intrarenal Ang I and Ang(1-7) infusions. Introgression of the normotensive Y chromosome into the SHRSP background (SP.WKY Gla Y) restored responses in the SHRSP to WKY levels, evidenced by a reduction in plasma Ang(1-7):Ang II ratio (SP.WKY Gla Y: 0.24±0.02 P .01), angiotensin II receptor type 2, and Mas receptor mRNA expression and an increased vasoconstrictor response to intrarenal Ang I and Ang(1-7) infusion. This study demonstrates that the origin of the Y chromosome significantly impacts the renal vascular responsiveness and therefore may influence the long-term renal regulation of blood pressure.
Publisher: Elsevier BV
Date: 11-2004
DOI: 10.1111/J.1523-1755.2004.09225.X
Abstract: Blockade of the RAS with the ACE inhibitor ramipril prevents the accumulation of advanced glycation end products (AGEs) in experimental diabetes. Although AT1 receptor antagonists may inhibit AGE formation in vitro, their effect in normotensive animals with type 1 diabetes has not been established. Streptozotocin-induced diabetic and control animals were randomized (N=10/group) to receive the AT1 antagonist valsartan at a dose of 30 mg/kg/day by oral gavage for 24 weeks, or no intervention. Renal and plasma AGE accumulation was correlated with renal functional parameters. Valsartan reduced the albumin excretion rate consistent with its renoprotective effects. Renal and skin collagen accumulation of the non-fluorescent AGE carboxymethyllysine (CML) were increased in animals with diabetes, but normalized following treatment with valsartan. Renal fluorescence and skin collagen pentosidine levels were also increased by diabetes. However, valsartan only provided a modest attenuation of these parameters. In addition, diabetes was associated with increased plasma fluorescence, which was unaffected by AT1 antagonism. Renoprotective doses of valsartan are associated with a significant reduction in the accumulation of tissue and plasma CML. These effects were not the same for all AGEs, suggesting combination approaches will be required to optimize renoprotection in diabetes.
Publisher: Springer Science and Business Media LLC
Date: 06-2004
DOI: 10.1007/S00125-004-1411-X
Abstract: The impact of early vitamin E supplementation on vascular function in diabetes remains unresolved. Therefore, we examined the effects of vitamin E on functional and structural parameters and on chemical markers that are disturbed in diabetes in mesenteric and femoral arteries. Segments of both arteries, taken from control and 8-week-old streptozotocin diabetic Wistar rats that were treated or not with vitamin E, were mounted on wire and pressure myographs, after which endothelium-dependent and -independent vasodilation was assessed. Passive mechanical wall properties and the localisation and levels of protein kinase C (PKC)-beta(2) and AGE were evaluated in these vessels. Vitamin E supplementation was associated with improved endothelium-dependent and -independent vasodilatation in mesenteric arteries from diabetic rats. Impaired endothelium-dependent vasodilatation in diabetic mesenteric vessels was associated with PKC-beta(2) up-regulation and this was prevented by vitamin E supplementation. Increased AGE accumulation and plasma isoprostane levels in diabetic rats were not changed by vitamin E. In the femoral artery, vitamin E supplementation had no effect on endothelium-dependent or -independent vasodilatation, but did prevent the wall stiffening associated with diabetes. Early vitamin E supplementation has a beneficial effect on diabetes-induced endothelial dysfunction in resistance arteries. This benefit may arise from a direct effect on smooth muscle function, as a result of inhibition of the PKC-beta(2) isoform by vitamin E.
Publisher: SAGE Publications
Date: 2015
DOI: 10.4137/CMC.S18737
Abstract: Congestive heart failure (CHF) is a chronic condition usually without cure. Significant developments, particularly those addressing pathophysiology, mainly started at the bench. This approach has seen many clinical observations initially explored at the bench, subsequently being trialed at the bedside, and eventually translated into clinical practice. This evidence, however, has several limitations, importantly the generalizability or external validity. We now acknowledge that clinical management of CHF is more complicated than merely translating bench-to-bedside evidence in a linear fashion. This review aims to help explore this evolving area from an Australian perspective. We describe the continuation of research once core evidence is established and describe how clinician–scientist collaboration with a bedside-to-bench view can help enhance evidence translation and generalizability. We describe why an extension of the available evidence or generating new evidence is occasionally needed to address the increasingly erse cohort of patients. Finally, we explore some of the tools used by basic scientists and clinicians to develop evidence and describe the ones we feel may be most beneficial.
Publisher: SAGE Publications
Date: 2016
DOI: 10.4137/CMC.S38444
Abstract: Beta-blockers (BBs) are the mainstay prognostic medication for all stages of chronic heart failure (CHF). There are many classes of BBs, each of which has varying levels of evidence to support its efficacy in CHF. However, most CHF patients have one or more comorbid conditions such as diabetes, renal impairment, and/or atrial fibrillation. Patient enrollment to randomized controlled trials (RCTs) often excludes those with certain comorbidities, particularly if the symptoms are severe. Consequently, the extent to which evidence drawn from RCTs is generalizable to CHF patients has not been well described. Clinical guidelines also underrepresent this point by providing generic advice for all patients. The aim of this review is to examine the evidence to support the use of BBs in CHF patients with common comorbid conditions. We searched MEDLINE, PubMed, and the reference lists of reviews for RCTs, post hoc analyses, systematic reviews, and meta-analyses that report on use of BBs in CHF along with patient demographics and comorbidities. In total, 38 studies from 28 RCTs were identified, which provided data on six BBs against placebo or head to head with another BB agent in ischemic and nonischemic cardiomyopathies. Several studies explored BBs in older patients. Female patients and non-Caucasian race were underrepresented in trials. End points were cardiovascular hospitalization and mortality. Comorbid diabetes, renal impairment, or atrial fibrillation was detailed however, no reference to disease spectrum or management goals as a focus could be seen in any of the studies. In this sense, enrollment may have limited more severe grades of these comorbidities. RCTs provide authoritative information for a spectrum of CHF presentations that support guidelines. RCTs may provide inadequate information for more heterogeneous CHF patient cohorts. Greater Phase IV research may be needed to fill this gap and inform guidelines for a more global patient population.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 13-04-2012
DOI: 10.1161/CIRCRESAHA.112.266171
Abstract: Epigenetic changes are implicated in the persisting vascular effects of hyperglycemia. The precise mechanism whereby chromatin structure and subsequent gene expression are regulated by glucose in vascular endothelial cells remain to be fully defined. We have studied the molecular and functional mechanism whereby the Set7 methyltransferase associates with chromatin formation and histone methylation in vascular cells in response to current and previous exposure to glucose. To characterize the molecular and functional identity of the Set7 protein, we used vascular cells overexpressing or lacking Set7. Chromatin fractionation for mono-methylation of lysine 4 on histone H3 identified methyltransferase activity. Immunofluorescence experiments strongly suggest that Set7 protein accumulates in the nucleus in response to hyperglycemia. Moreover, activation of proinflammatory genes by high glucose is dependent on Set7 but distinguished by H3K4m1 gene patterns. We show that transient hyperglycemia regulates the expression of proinflammatory genes in vascular endothelial cells in vitro and the persistent increase in glucose-induced gene expression in the aorta of nondiabetic mice. This study uncovers that the response to hyperglycemia in vascular endothelial cells involves the H3K4 methyltransferase, Set7. This enzyme appears to regulate glucose-induced chromatin changes and gene expression not only by H3K4m1-dependent but also H3K4m1-independent pathways. Furthermore, Set7 appears to be responsible for sustained vascular gene expression in response to prior hyperglycemia and is a potential molecular mechanism for the phenomenon of hyperglycemic memory.
Publisher: American Diabetes Association
Date: 07-08-2014
DOI: 10.2337/DC14-0065
Abstract: Osteopontin (OPN) is a multifunctional protein suggested to be a player in the arterial disease of patients with type 2 diabetes. However, its role for complications in patients with type 1 diabetes (T1D) is unknown. We therefore investigated the associations between OPN and diabetic vascular complications and all-cause mortality in patients with T1D. Serum OPN was measured in 2,145 adults with T1D without end-stage renal disease (ESRD dialysis or transplantation) as part of the Finnish Diabetic Nephropathy (FinnDiane) Study. Data on renal status, cardiovascular disease (CVD), and all-cause mortality during follow-up were verified from medical files, hospital discharge registries, and the Finnish National Death Registry, respectively. The median follow-up time was 10.5 (interquartile range 8.9–11.8) years. Serum OPN was higher at baseline in patients who developed incident microalbuminuria (16.0 ± 0.9 vs. 14.1 ± 0.2 µg/L P = 0.04), progressed to ESRD (28.3 ± 1.7 vs. 15.4 ± 0.2 µg/L P & 0.001), suffered an incident CVD event (20.2 ± 1.2 vs. 15.5 ± 0.2 µg/L P & 0.001), or died (23.3 ± 1.4 vs. 15.8 ± 0.2 µg/L P & 0.001) during follow-up. In multivariate Cox regression analysis, OPN was independently associated with the development of incident microalbuminuria, an incident CVD event, and death, after adjustments for associated risk factors. Even after calculating reclassification indexes, OPN was predictive of CVD and all-cause mortality beyond the Framingham risk score covariates and hs-CRP. Serum OPN is a strong predictor of incipient diabetic nephropathy, a first-ever CVD event, and all-cause mortality in patients with T1D. Serum OPN may be of clinical significance for the risk prediction of CVD events in patients with T1D.
Publisher: Informa UK Limited
Date: 21-01-2013
DOI: 10.1517/14728214.2013.762356
Abstract: The need for new approaches to manage the increasing numbers of patients with diabetes and their burden of complications is urgent. Of these, chronic kidney disease imposes some of the highest costs, both in dollars and in terms of human suffering. In in iduals with diabetes, the presence and severity of kidney disease adversely affects their well-being, contributes to disease morbidity and increases their risk of a premature death. To collect information for the strategies previously or currently under investigation for managing kidney disease in patients with diabetes, a literature search was performed through the search engines PubMed and ClinicalTrials.gov. Despite advancing knowledge on the pathogenesis of diabetic kidney disease, and promising effects in experimental models, at present there are no new drugs that come close to providing the solutions we desire for our patients. Even when used in combination with standard care, renal complications are at best only modestly reduced, at the considerable expense of additional pill burden and exposure to serious off-target effects. Some of the most exciting advances over the last decade, including thiazolidinediones, direct renin inhibitors, endothelin antagonists and most recently bardoxolone methyl have all fallen at this last hurdle. Better targeted ('smarter') drugs appear to be the best hope for renoprotective therapy.
Publisher: Springer Science and Business Media LLC
Date: 29-12-2004
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2011
Publisher: The Endocrine Society
Date: 09-2004
DOI: 10.1210/JC.2004-0678
Publisher: Wiley
Date: 04-2006
Publisher: Springer Science and Business Media LLC
Date: 23-02-2016
DOI: 10.1007/S11892-016-0723-9
Abstract: Progressive kidney disease is a common companion to both type 1 and type 2 diabetes. However, the majority of people with diabetes do not develop diabetic kidney disease. This may in part be explained by good control of glucose, blood pressure, obesity and other risk factors for kidney disease. It may also be partly due to their genetic makeup or ethnicity. However, the vast majority of the variability in incident nephropathy remains unaccounted for by conventional risk factors or genetics. Epigenetics has recently emerged as an increasingly powerful paradigm to understand and potentially explain complex non-Mendelian conditions-including diabetic kidney disease. Persistent epigenetic changes can be acquired during development or as adaptations to environmental exposure, including metabolic fluctuations associated with diabetes. These epigenetic modifications-including DNA methylation, histone modifications, non-coding RNAs and other changes in chromatin structure and function-in idually and co-operatively act to register, store, retain and recall past experiences in a way to shape the transcription of specific genes and, therefore, cellular functions. This review will explore the emerging evidence for the role of epigenetic modifications in programming the legacy of hyperglycaemia for kidney disease in diabetes.
Publisher: Elsevier BV
Date: 06-2009
DOI: 10.1016/J.EXER.2009.01.009
Abstract: The aim of this study was to determine whether inner retinal dysfunction in diabetic rats is correlated with structural and/or biochemical changes in the retina and optic nerve. Using the electroretinogram (ERG -5.83 to 1.28 log cd.s.m(-2)) retinal function (photoreceptor, bipolar, amacrine and ganglion cell components) was measured in control (n=13 citrate buffer) and diabetic (n=13 streptozotocin, STZ, 50 mg kg(-1)) rats, 12 weeks following treatment. Retinae and optic nerves were analyzed for structural changes and retinae were assessed for alterations in growth factor/cytokine expression using quantitative real-time PCR. We found that phototransduction efficiency was reduced 12 weeks after STZ-induced diabetes (-30%), leading to reduced litude of ON-bipolar (-18%) and amacrine cell (-29%) dominated responses ganglion cell dysfunction (-84%) was more profound. In the optic nerve, nerve fascicle area and myelin sheath thickness were reduced (p<0.05), whereas the ratio of blood vessels and connective tissue to total nerve cross-sectional area was increased (p<0.05) in diabetic compared to control rats. In the retina, connective tissue growth factor (CTGF), transforming growth factor beta, type 2 receptor (TGFbeta-r2) mRNA and platelet-derived growth factor B (PDGF-B) mRNA were increased (p<0.035). Reduced ganglion cell function was correlated with increased CTGF and TGFbeta-r2, but not PDGF-B mRNA. In summary, the ganglion cell component exhibited the greatest level of dysfunction within the ERG components examined after 12 weeks of STZ-induced diabetes the level correlated with increased CTGF and TGFbeta-r2 mRNA, but not with gross morphological changes in the retina or optic nerve.
Publisher: The Royal Society of Chemistry
Date: 24-09-2010
Abstract: In September 2009, a meeting was held in Palm Cove, Australia, which brought together the world experts in the Maillard or 'browning' reaction. This reaction causes the browning of foods when they are heated and in chocolate, caramel and beer, this reaction is appetizing, contributing to aroma, taste and texture. But when these products accumulate in the body, this same process contributes to disease and ageing. The book is the proceedings of that meeting, held in response to a growing recognition of the role reactive carbonyl compounds play in food technology, nutrition and tissue ageing in biology and medicine. Reactive carbonyls now touch every aspect of food science, biology and medicine. Efforts to counteract the damage caused by these products are gaining acceptance as a basis for novel therapeutic approaches, and the fields of food technology, ageing and preventive medicine are experiencing an upsurge of interest in strategies to minimize the unwanted effects of the Maillard reaction. The meeting also fostered a balanced approach to understanding both the advantageous and deleterious properties of carbonyl compounds and their end products in food science, technology and medicine. The major audience of this book is the large body of scientists and worldwide industries with an interest in the Maillard reaction in foods and biology and medicine, with both basic and applied researchers and industry representatives from erse fields, who have interests in: * Chemistry of the Maillard Reaction * Biology and the Maillard Reaction * Enzymology, Receptors and Signal Transduction * Bioinformatics and Systems Biology * Physiology, Disease and Therapeutics * Food Science and Nutrition and the Maillard Reaction
Publisher: American Diabetes Association
Date: 04-2004
DOI: 10.2337/DIABETES.53.4.989
Abstract: The renin-angiotensin system (RAS) has an important role in the endocrine pancreas. Although angiotensin II has significant effects on cell proliferation and apoptosis, the contribution of the RAS to changes in islet structure and function associated with type 2 diabetes is yet to be defined. This study examined the specific effects of RAS blockade on islet structure and function in diabetes. Thirty-six male Zucker diabetic fatty (ZDF) rats, 10 weeks of age, were randomized to receive the angiotensin-converting enzyme inhibitor perindopril (8 mg/l in drinking water n = 12), irbesartan (15 mg/kg via gavage n = 12), or no treatment (n = 12) for 10 weeks. Results were compared with lean littermates (ZL) (n = 12) studied concurrently. ZDF rats had increased intra-islet expression of components of the RAS correlating with increased intraislet fibrosis, apoptosis, and oxidative stress. Disordered islet architecture, seen in ZDF rats, was attenuated after treatment with perindopril or irbesartan. Islet fibrogenesis was also diminished, as measured by picrosirius staining and expression of collagens I and IV. Gene expression of transforming growth factor-β1 was increased in the ZDF pancreas (ZL, 1.0 ± 0.1 ZDF, 2.0 ± 0.3 P & 0.05) and reduced after blockade of the RAS (ZDF + P, 1.3 ± 0.2 ZDF + I, 1.5 ± 0.1 vs. ZDF, both P & 0.05). Improvements in structural parameters were also associated with functional improvements in first-phase insulin secretion. These findings provide a possible mechanism for the reduced incidence of new-onset diabetes that has been observed in clinical trials of RAS blockade.
Publisher: Proceedings of the National Academy of Sciences
Date: 31-07-2023
Abstract: The ersity of COVID-19 disease in otherwise healthy people, from seemingly asymptomatic infection to severe life-threatening disease, is not clearly understood. We passaged a naturally occurring near-ancestral SARS-CoV-2 variant, capable of infecting wild-type mice, and identified viral genomic mutations coinciding with the acquisition of severe disease in young adult mice and lethality in aged animals. Transcriptomic analysis of lung tissues from mice with severe disease elucidated a host antiviral response dominated mainly by interferon and IL-6 pathway activation in young mice, while in aged animals, a fatal outcome was dominated by TNF and TGF-β signaling. Congruent with our pathway analysis, we showed that young TNF-deficient mice had mild disease compared to controls and aged TNF-deficient animals were more likely to survive infection. Emerging clinical correlates of disease are consistent with our preclinical studies, and our model may provide value in defining aberrant host responses that are causative of severe COVID-19.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2006
Publisher: American Physiological Society
Date: 09-2010
DOI: 10.1152/AJPRENAL.00538.2009
Abstract: Epithelial-to-mesenchymal transformation (EMT) of tubular cells into a myofibroblastic phenotype is an important mediator of renal scarring in chronic nephropathy. This study examines the role of the renin-angiotensin system (RAS) in this process. NRK-52E cells were exposed to angiotensin (ANG) II and ANG 1–7 in the presence or absence of inhibitors and agonists of RAS signaling. EMT was assessed at 3 days by expression of α-smooth muscle actin (α-SMA) and E-cadherin and the induction of a myofibroblastic phenotype. Expression of fibrogenic growth factors and matrix proteins was assessed by RT-PCR and immunofluorescence microscopy. To confirm findings in vivo, rats were also infused with ANG 1–7 (24 μg·kg −1 ·h −1 ) or saline via an osmotic minipump for 10 days, and renal fibrogenesis was then assessed. Treatment of NRK-52E cells with ANG II induced characteristic changes of EMT. Selective blockade of the AT 1 receptor or the AT 2 receptor failed to inhibit ANG II-induced EMT. However, blockade of the ANG 1–7 receptor, Mas-1, was able to prevent ANG II-dependent EMT. To confirm these findings, both ANG 1–7 and the selective Mas receptor agonist, AVE-0991, were able to induce NRK-52E cells in a dose-dependent manner. Exposing cells to recombinant ACE2 was also able to induce EMT. In addition, an infusion of ANG 1–7 induced the tubular expression of α-SMA and the expression of matrix proteins in the kidney. ANG II is a potent stimulus for EMT, but not through conventional pathways. This study points to the possible limitations of conventional RAS blockade, which not only fails to antagonize this pathway, but also may enhance it via augmenting the synthesis of ANG 1–7.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2003
DOI: 10.1097/01.ASN.0000077413.41276.17
Abstract: Nonenzymatic reactions between sugars and the free amino groups on proteins, lipids, and nucleic acids result in molecular dysfunction through the formation of advanced glycation end products (AGE). AGE have a wide range of chemical, cellular, and tissue effects through changes in charge, solubility, and conformation that characterize molecular senescence. AGE also interact with specific receptors and binding proteins to influence the expression of growth factors and cytokines, including TGF-beta1 and CTGF, thereby regulating the growth and proliferation of the various renal cell types. It seems that many of the pathogenic changes that occur in diabetic nephropathy may be induced by AGE. Drugs that either inhibit the formation of AGE or break AGE-induced cross-links have been shown to be renoprotective in experimental models of diabetic nephropathy. AGE are able to stimulate directly the production of extracellular matrix and inhibit its degradation. AGE modification of matrix proteins is also able to disrupt matrix-matrix and matrix-cell interactions, contributing to their profibrotic action. In addition, AGE significantly interact with the renin-angiotensin system. Recent studies have suggested that angiotensin-converting enzyme inhibitors are able to reduce the accumulation of AGE in diabetes, possibly via the inhibition of oxidative stress. This interaction may be a particularly important pathway for the development of AGE-induced damage, as it also can be attenuated by antioxidant therapy. In addition to being a consequence of oxidative stress, it is now clear that AGE can promote the generation of reactive oxygen species. It is likely that therapies that inhibit the formation of AGE will form an important part of future therapy in patients with diabetes, acting synergistically with conventional approaches to prevent diabetic renal injury.
Publisher: Elsevier BV
Date: 05-2006
DOI: 10.1016/J.BIOCEL.2005.08.007
Abstract: Activation of the renin-angiotensin system has a pivotal role in the pathogenesis of diabetic complications. However, recent evidence suggests that it may also contribute to the development of diabetes itself. In the endocrine pancreas, all the components of an active renin-angiotensin system are present, which modulate a range of activities including local blood flow, hormone release and prostaglandin synthesis. In both types 1 and 2 diabetes, there is an up-regulation of its expression and activity in the endocrine pancreas. Whether these changes have a direct pathogenetic role or reflect a response to local stress or tissue injury remains to be established. Angiotensin-mediated increases in oxidative stress, inflammation and free fatty acids levels potentially contribute to beta-cell dysfunction in diabetes. In addition, activation of the renin-angiotensin system appears to potentiate the action of other pathogenic pathways including glucotoxicity, lipotoxicity and advanced glycation. In experimental models of type 2 diabetes, blockade of the renin-angiotensin system with angiotensin converting enzyme inhibitors or angiotensin receptor antagonists results in the improvement of islet structure and function. Moreover, the incidence of de novo diabetes appears to be significantly reduced by blockade of the renin-angiotensin system in clinical studies. At least two large controlled trials are currently underway to study the role of renin-angiotensin system in the development of diabetes. It is hoped that these studies will demonstrate the true potential of the blockade of the renin-angiotensin system for the prevention of diabetes.
Publisher: Wiley
Date: 02-2007
Publisher: American Diabetes Association
Date: 23-07-2009
DOI: 10.2337/DC09-0477
Abstract: To examine the relationship between dietary fiber and the risk of type 2 diabetes in older men and the role of hepatic and inflammatory markers. The study was performed prospectively and included 3,428 nondiabetic men (age 60–79 years) followed up for 7 years, during which there were 162 incident cases of type 2 diabetes. Low total dietary fiber (lowest quartile ≤20 g/day) was associated with increased risk of diabetes after adjustment for total calorie intake and potential confounders (relative risk −1.47 [95% CI 1.03–2.11]). This increased risk was seen separately for both low cereal and low vegetable fiber intake. Dietary fiber was inversely associated with inflammatory markers (C-reactive protein, interleukin-6) and with tissue plasminogen activator and γ-glutamyl transferase. Adjustment for these markers attenuated the increased risk (1.28 [0.88–1.86]). Dietary fiber is associated with reduced diabetes risk, which may be partly explained by inflammatory markers and hepatic fat deposition.
Publisher: Elsevier BV
Date: 12-2014
Publisher: American Diabetes Association
Date: 08-2005
DOI: 10.2337/DIACARE.28.8.2019
Abstract: OBJECTIVE—The aim of this study was to estimate the prevalence of the metabolic syndrome in Finnish type 1 diabetic patients and to assess whether it is associated with diabetic nephropathy or poor glycemic control. RESEARCH DESIGN AND METHODS—In all, 2,415 type 1 diabetic patients (51% men, mean age 37 years, duration of diabetes 22 years) participating in the nationwide, multicenter Finnish Diabetic Nephropathy (FinnDiane) study were included. Metabolic syndrome was defined according to the National Cholesterol Education Program diagnostic criteria. Patients were classified as having normal albumin excretion rate (AER) (n = 1,261), microalbuminuria (n = 326), macroalbuminuria (n = 383), or end-stage renal disease (ESRD) (n = 164). Glycemic control was classified as good (HbA1c & .5%), intermediate (7.5–9.0%), or poor (& .0%). Creatinine clearance was estimated with the Cockcroft-Gault formula. RESULTS—The overall prevalence of metabolic syndrome was 38% in men and 40% in women. The prevalence was 28% in those with normal AER, 44% in microalbuminuric patients, 62% in macroalbuminuric patients, and 68% in patients with ESRD (P & 0.001). Patients with metabolic syndrome had a 3.75-fold odds ratio for diabetic nephropathy (95% CI 2.89–4.85), and all of the separate components of the syndrome were independently associated with diabetic nephropathy. The prevalence of metabolic syndrome was 31% in patients with good glycemic control, 36% in patients with intermediate glycemic control, and 51% in patients with poor glycemic control (P & 0.001). Similarly, metabolic syndrome increased with worsening creatinine clearance. CONCLUSIONS—The metabolic syndrome is a frequent finding in type 1 diabetes and increases with advanced diabetic nephropathy and worse glycemic control.
Publisher: Wiley
Date: 10-06-2021
DOI: 10.1111/DME.14608
Abstract: Aim of this study is to report severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection, responsible for coronavirus disease 2019 (COVID‐19), as a possible cause for type 1 diabetes by providing an illustrative clinical case of a man aged 45 years presenting with antibody‐negative diabetic ketoacidosis post‐recovery from COVID‐19 pneumonia and to explore the potential for SARS‐CoV‐2 to adhere to human islet cells. Explanted human islet cells from three independent solid organ donors were incubated with the SARS‐CoV‐2 spike protein receptor biding domain (RBD) fused to a green fluorescent protein (GFP) or a control‐GFP, with differential adherence established by flow cytometry. Flow cytometry revealed dose‐dependent specific binding of RBD‐GFP to islet cells when compared to control‐GFP. Although a causal basis remains to be established, our case and in vitro data highlight a potential mechanism by which SARS‐CoV‐2 infection may result in antibody‐negative type 1 diabetes.
Publisher: Springer Science and Business Media LLC
Date: 23-08-2011
Publisher: Springer Science and Business Media LLC
Date: 09-12-2008
DOI: 10.1007/S00125-008-1215-5
Abstract: Obesity and diabetes are associated with increased intracellular p38 mitogen-activated protein kinase (MAPK) signalling, which may promote tissue inflammation and injury. Activation of p38 MAPK can be induced by either of the immediate upstream kinases, MAP kinase kinase (MKK)3 or MKK6, and recent evidence suggests that MKK3 has non-redundant roles in the pathology attributed to p38 MAPK activation. Therefore, this study examined whether MKK3 signalling influences the development of obesity, type 2 diabetes and diabetic nephropathy. Wild-type and Mkk3 (also known as Map2k3) gene-deficient db/db mice were assessed for the development of obesity, type 2 diabetes and renal injury from 8 to 32 weeks of age. Mkk3 (+/+) db/db and Mkk3 (-/-) db/db mice developed comparable obesity and were similar in terms of incidence and severity of type 2 diabetes. At 32 weeks, diabetic Mkk3 (+/+) db/db mice had increased kidney levels of phospho-p38 and MKK3 protein. In comparison, kidney levels of phospho-p38 in diabetic Mkk3 ( -/- ) db/db mice remained normal, despite a fourfold compensatory increase in MKK6 protein levels. The reduced levels of p38 MAPK signalling in the diabetic kidneys of Mkk3 ( -/- ) db/db mice was associated with protection against the following: declining renal function, increasing albuminuria, renal hypertrophy, podocyte loss, mesangial cell activation and glomerular fibrosis. Diabetic Mkk3 ( -/- ) db/db mice were also significantly protected from tubular injury and interstitial fibrosis, which was associated with reduced Ccl2 mRNA expression and interstitial macrophage accumulation. MKK3-p38 MAPK signalling is not required for the development of obesity or type 2 diabetes, but plays a distinct pathogenic role in the progression of diabetic nephropathy in db/db mice.
Publisher: Elsevier BV
Date: 04-2008
DOI: 10.1016/J.DIABRES.2007.10.024
Abstract: While CKD is a common finding in patients with type 2 diabetes, the clinical response to its identification is often problematic. This study aims to determine the frequency of albuminuria in patients with type 2 diabetes in the primary care setting and examine the factors which influence its management. Expressions of interest were invited from all registered GPs across Australia, from whom 500 investigators were randomly selected. Investigators were requested to document the clinical characteristics of 10-15 consecutively presenting patients with type 2 diabetes. Results from the most recent urinalysis were classified according to guidelines, then systematically compared to classifications provided by GPs themselves and their management strategies. One in three patients had an elevated urinary albumin excretion (UAE, 34.6%, 95% CI, 33.3-35.9%) on their most recent urinalysis. The presence of microalbuminuria or proteinuria, as identified by the GP, was not associated with a perceived increase in cardiovascular risk. In addition, the use of aspirin and the prescribing of agents to block the RAS were not significantly linked to UAE. Similarly, the perceived adequacy of blood pressure control was not significantly different whether or not microalbuminuria or proteinuria was identified to be present. An elevated UAE is a common finding in general practice. However, it fails to significantly influence their clinical care. Additional education to ensure appropriate case recognition and management of kidney disease is needed, focusing on the significance of albuminuria to the care of patients with type 2 diabetes.
Publisher: American Diabetes Association
Date: 17-02-2011
DOI: 10.2337/DC10-1723
Abstract: Many guidelines recommend that patients with type 2 diabetes should aim to reduce their intake of salt. However, the precise relationship between dietary salt intake and mortality in patients with type 2 diabetes has not been previously explored. Six hundred and thirty-eight patients attending a single diabetes clinic were followed in a prospective cohort study. Baseline sodium excretion was estimated from 24-h urinary collections (24hUNa). The predictors of all-cause and cardiovascular mortality were determined by Cox regression and competing risk modeling, respectively. The mean baseline 24hUNa was 184 ± 73 mmol/24 h, which remained consistent throughout the follow-up (intrain idual coefficient of variation [CV] 23 ± 11%). Over a median of 9.9 years, there were 175 deaths, 75 (43%) of which were secondary to cardiovascular events. All-cause mortality was inversely associated with 24hUNa, after adjusting for other baseline risk factors (P & 0.001). For every 100 mmol rise in 24hUNa, all-cause mortality was 28% lower (95% CI 6–45%, P = 0.02). After adjusting for the competing risk of noncardiovascular death and other predictors, 24hUNa was also significantly associated with cardiovascular mortality (sub-hazard ratio 0.65 [95% CI 0.44–0.95] P = 0.03). In patients with type 2 diabetes, lower 24-h urinary sodium excretion was paradoxically associated with increased all-cause and cardiovascular mortality. Interventional studies are necessary to determine if dietary salt has a causative role in determining adverse outcomes in patients with type 2 diabetes and the appropriateness of guidelines advocating salt restriction in this setting.
Publisher: Springer Science and Business Media LLC
Date: 27-04-2010
DOI: 10.1007/S00125-010-1757-1
Abstract: Diabetic nephropathy is an inflammatory disease with prominent leucocyte infiltration of the kidneys. While the importance of macrophages in diabetic renal injury has been clearly demonstrated, the role of lymphocytes is still unknown. We therefore examined the development of diabetic renal injury in lymphocyte-deficient mice. Streptozotocin was used to induce diabetes in Rag1(-/-) mice, which lack mature T and B lymphocytes, and in wild-type (Rag1(+/+) ) controls. The development of renal injury was examined over 20 weeks of diabetes. Both groups developed equivalent diabetes, however only Rag1(+/+) mice had kidney infiltration with CD4, CD8, CD22 and forkhead box P3-positive cells, as well as glomerular immunoglobulin deposition. At 20 weeks, Rag1(+/+) mice exhibited renal hypertrophy, increased mesangial and interstitial matrix, kidney macrophage accumulation, tubular injury, progressive albuminuria and a decline in renal function. In comparison, diabetic Rag1(-/-) mice showed similar histological damage, matrix expansion, macrophage accrual and loss of renal function, but were protected from increasing albuminuria. This protection was associated with protection against loss of podocytes and glomerular podocin production, and with reduced glomerular macrophage activation. These results show that lymphocytes contribute to the development of diabetic albuminuria, which may partly arise from increasing glomerular macrophage activation and podocyte damage. In contrast, lymphocytes do not appear to promote tubular injury, increased matrix deposition or decline in renal function in a mouse model of type 1 diabetes. Our findings suggest that innate immunity rather than adaptive immune responses are the major inflammatory contributor to the progression of diabetic renal injury.
Publisher: American Diabetes Association
Date: 21-03-2011
DOI: 10.2337/DC10-1722
Abstract: Many guidelines recommend reduced consumption of salt in patients with type 1 diabetes, but it is unclear whether dietary sodium intake is associated with mortality and end-stage renal disease (ESRD). In a nationwide multicenter study (the FinnDiane Study) between 1998 and 2002, 2,807 enrolled adults with type 1 diabetes without ESRD were prospectively followed. Baseline urinary sodium excretion was estimated on a 24-h urine collection. The predictors of all-cause mortality and ESRD were determined by Cox regression and competing risk modeling, respectively. The median follow-up for survival analyses was 10 years, during which 217 deaths were recorded (7.7%). Urinary sodium excretion was nonlinearly associated with all-cause mortality, such that in iduals with the highest daily urinary sodium excretion, as well as the lowest excretion, had reduced survival. This association was independent age, sex, duration of diabetes, the presence and severity of chronic kidney disease (CKD) (estimated glomerular filtration rate [eGFR] and log albumin excretion rate), the presence of established cardiovascular disease, and systolic blood pressure. During follow-up, 126 patients developed ESRD (4.5%). Urinary sodium excretion was inversely associated with the cumulative incidence of ESRD, such that in iduals with the lowest sodium excretion had the highest cumulative incidence of ESRD. In patients with type 1 diabetes, sodium was independently associated with all-cause mortality and ESRD. Although we have not demonstrated causality, these findings support the calls for caution before applying salt restriction universally. Clinical trials must be performed in diabetic patients to formally test the utility/risk of sodium restriction in this setting.
Publisher: American Diabetes Association
Date: 13-10-2014
DOI: 10.2337/DB13-0932
Abstract: The deleterious effects of high glucose levels and enhanced metabolic flux on the vasculature are thought to be mediated by the generation of toxic metabolites, including reactive dicarbonyls like methylglyoxal (MG). In this article, we demonstrate that increasing plasma MG to levels observed in diabetic mice either using an exogenous source (1% in drinking water) or generated following inhibition, its primary clearance enzyme, glyoxalase-1 (with 50 mg/kg IP bromobenzyl-glutathione cyclopentyl diester every second day), was able to increase vascular adhesion and augment atherogenesis in euglycemic apolipoprotein E knockout mice to a similar magnitude as that observed in hyperglycemic mice with diabetes. The effects of MG appear partly mediated by activation of the receptor for advanced glycation end products (RAGE), as deletion of RAGE was able to reduce inflammation and atherogenesis associated with MG exposure. However, RAGE deletion did not completely prevent inflammation or vascular damage, possibly because the induction of mitochondrial oxidative stress by dicarbonyls also contributes to inflammation and atherogenesis. Such data would suggest that a synergistic combination of RAGE antagonism and antioxidants may offer the greatest utility for the prevention and management of diabetic vascular complications.
Publisher: American Diabetes Association
Date: 11-2002
DOI: 10.2337/DIABETES.51.11.3274
Abstract: The effect of ACE inhibition on the formation of advanced glycation end products (AGEs) and oxidative stress was explored. Streptozocin-induced diabetic animals were randomized to no treatment, the ACE inhibitor ramipril (3 mg/l), or the AGE formation inhibitor aminoguanidine (1 g/l) and followed for 12 weeks. Control groups were followed concurrently. Renal AGE accumulation, as determined by immunohistochemistry and both serum and renal fluorescence, were increased in diabetic animals. This was attenuated by both ramipril and aminoguanidine to a similar degree. Nitrotyrosine, a marker of protein oxidation, also followed a similar pattern. The receptor for AGEs, gene expression of the membrane-bound NADPH oxidase subunit gp91phox, and nuclear transcription factor-κB were all increased by diabetes but remained unaffected by either treatment regimen. Two other AGE receptors, AGE R2 and AGE R3, remained unchanged for the duration of the study. The present study has identified a relationship between the renin-angiotensin system and the accumulation of AGEs in experimental diabetic nephropathy that may be linked through oxidative stress
Publisher: Cambridge University Press (CUP)
Date: 03-02-2005
DOI: 10.1017/S0031182004006936
Abstract: Trypanosomatids are early ergent parasites which include several species of medical interest. Trypanosoma rangeli is not pathogenic for humans but shows a high immunological cross-reactivity with Trypanosoma cruzi , the causative agent of Chagas' disease that affects more than 17 million people throughout the world. Recent studies have suggested that T. cruzi KMP-11 antigen could be a good candidate for the induction of immunoprotective cytotoxic responses against T. cruzi natural infection. In the present paper the genes coding for the T. rangeli kinetoplastid membrane protein-11 have been characterized. The results show that the locus encoding this protein is formed by 4 gene units measuring 550 nucleotides in length, organized in tandem, and located in different chromosomes in KP1(+) and KP1(−) strains. The gene units are transcribed as a single mRNA of 530 nucleotides in length. Alignment of the T. rangeli KMP-11 deduced amino acid sequence with the homologous KMP-11 protein from T. cruzi revealed an identity of 97%. Interestingly, the T and B cell epitopes of the T. cruzi KMP-11 protein are conserved in the T. rangeli KMP-11 amino acid sequence.
Publisher: Bentham Science Publishers Ltd.
Date: 06-2005
Abstract: Prolonged hyperglycemia, dyslipidemia and oxidative stress in diabetes result in the production and accumulation of AGEs. It is now clear that AGEs contribute to the development and progression of cardiovascular disease in diabetes, as well as other complications. AGEs are thought to act through receptor-independent and dependent mechanisms to promote vascular damage, fibrosis and inflammation associated with accelerated atherogenesis. As a result, novel therapeutic agents to reduce the accumulation of AGEs in diabetes have gained interest as potential cardioprotective approaches. A variety of agents have been developed which are examined in detail in this review. These include aminoguanidine, ALT-946, pyridoxamine, benfotiamine, OPB-9195, alagebrium chloride, N-phenacylthiazolium bromide and LR-90. In addition, it has been demonstrated that a number of established therapies have the ability to reduce the accumulation of AGEs in diabetes including ACE inhibitors, angiotensin receptor antagonists, metformin, peroxisome proliferators receptor agonists, metal chelators and some antioxidants. The fact that many of these inhibitors of AGEs are effective in experimental models, despite their disparate mechanisms of action, supports the keystone role of AGEs in diabetic vascular damage. Nonetheless, the clinical utility of AGE inhibition remains to be firmly established. Optimal metabolic and blood pressure control, that is achieved early and sustained indefinitely, remains the best recourse for inhibition of AGEs until more specific interventions become a clinical reality.
Publisher: Bentham Science Publishers Ltd.
Date: 08-2009
Publisher: Springer Science and Business Media LLC
Date: 28-02-2020
Publisher: Wiley
Date: 04-2006
Publisher: Bioscientifica
Date: 08-2005
DOI: 10.1677/JME.1.01720
Abstract: Type 2 diabetes is characterized by islet dysfunction resulting in hyperglycemia, which can then lead to further deterioration in islet function. A possible mechanism for hyperglycemia-induced islet dysfunction is the accumulation of advanced glycation end products (AGE). The DBA/2 mouse develops pancreatic islet dysfunction when exposed to a high glucose environment and/or obesity-induced insulin resistance. To determine the biochemical cause of dysfunction, DBA/2 and C57BL/6 control islets were incubated in 11.1 mM or 40 mM glucose in the absence or presence of the AGE inhibitor aminoguanidine (AG) for 10 days. Basal (2.8 mM glucose) insulin release was increased in both DBA/2 and C57BL/6 islets incubated with 40 mM vs 11.1 mM glucose for 10 days. Chronic exposure to hyperglycemia decreased glucose (20 mM)-stimulated insulin secretion in DBA/2 but not in C57BL/6 islets. AG significantly increased fold-induced insulin release in high glucose cultured DBA/2 mouse islets, but did not affect C57BL/6 islet function. DBA/2 islet glucokinase was significantly reduced following 40 mM glucose culture, compared with 11.1 mM glucose cultured DBA/2 islets and 40 mM glucose cultured C57BL/6 islets. Incubation of islets with AG resulted in a normalization of DBA/2 islet glucokinase levels. In conclusion, chronic high glucose-induced increases in AGE can result in islet dysfunction and this is associated with reduced glucokinase levels in a mouse model with susceptibility to islet failure.
Publisher: Elsevier BV
Date: 06-2015
DOI: 10.1016/J.HLC.2014.12.007
Abstract: Congestive Heart Failure (CHF) is an ambulatory care sensitive condition, associated with significant morbidity and mortality, rarely with cure. Outpatient based pharmacological management represents the main and most important aspect of care, and is usually lifelong. This narrative styled opinion review looks at the pharmacological agents recommended in the guidelines in context of the Northern Territory (NT) of Australia. We explore the concept of validity, a term used to describe the basis of standardising a particular trial or study and the population to which it is applicable. We aim to highlight the problems of the current guidelines based approach. We also present alternatives that could utilise the core principles from major trials, while incorporating regional considerations, which could benefit clients living in the NT and remote Australia.
Publisher: Portland Press Ltd.
Date: 04-02-2013
DOI: 10.1042/CS20120352
Abstract: It is recommended that in iduals with diabetes restrict their dietary sodium intake. However, although salt intake is correlated with BP (blood pressure), it also partly determines the activation state of the RAAS (renin–angiotensin–aldosterone system), a key mediator of diabetes-associated atherosclerosis. apoE KO (apolipoprotein E knockout) mice were allocated for the induction of diabetes with streptozotocin or citrate buffer (controls) and further randomized to isocaloric diets containing 0.05%, 0.3% or 3.1% sodium with or without the ACEi [ACE (angiotensin-converting enzyme) inhibitor] perindopril. After 6 weeks of study, plaque accumulation was quantified and markers of atherogenesis were assessed using RT–PCR (reverse transcription–PCR) and ELISA. The association of sodium intake and adverse cardiovascular and mortality outcomes were explored in 2648 adults with Type 1 diabetes without prior CVD (cardiovascular disease) from the FinnDiane study. A 0.05% sodium diet was associated with increased plaque accumulation in diabetic apoE KO mice, associated with activation of the RAAS. By contrast, a diet containing 3.1% sodium suppressed atherogenesis associated with suppression of the RAAS, with an efficacy comparable with ACE inhibition. In adults with Type 1 diabetes, low sodium intake was also associated with an increased risk of all-cause mortality and new-onset cardiovascular events. However, high sodium intake was also associated with adverse outcomes, leading to a J-shaped relationship overall. Although BP lowering is an important goal for the management of diabetes, off-target actions to activate the RAAS may contribute to an observed lack of protection from cardiovascular complications in patients with Type 1 diabetes with low sodium intake.
Publisher: MDPI AG
Date: 21-12-2022
DOI: 10.3390/IJMS24010152
Abstract: Accumulation of advanced glycation endproducts (AGEs) is linked to decline in renal function, particularly in patients with diabetes. Major forms of AGEs in serum are protein-bound AGEs and AGE free adducts. In this study, we assessed levels of AGEs in subjects with and without diabetes, with normal renal function and stages 2 to 4 chronic kidney disease (CKD), to identify which AGE has the greatest progressive change with decline in renal function and change in diabetes. We performed a cross-sectional study of patients with stages 2–4 CKD, with and without diabetes, and healthy controls (n = 135). Nine protein-bound and free adduct AGEs were quantified in serum. Most protein-bound AGEs increased moderately through stages 2–4 CKD whereas AGE free adducts increased markedly. Methylglyoxal-derived hydroimidazolone MG-H1 free adduct was the AGE most responsive to CKD status, increasing 8-fold and 30-fold in stage 4 CKD in patients without and with diabetes, respectively. MG-H1 Glomerular filtration flux was increased 5-fold in diabetes, likely reflecting increased methylglyoxal glycation status. We conclude that serum MG-H1 free adduct concentration was strongly related to stage of CKD and increased in diabetes status. Serum MG-H1 free adduct is a candidate AGE risk marker of non-diabetic and diabetic CKD.
Publisher: Oxford University Press (OUP)
Date: 10-2001
Publisher: Wiley
Date: 06-2005
DOI: 10.1111/J.1440-1711.2005.01341.X
Abstract: Although educational programs have had some impact, immunization against HIV will be necessary to control the AIDS pandemic. To be effective, vaccination will need to be accessible and affordable, directed against multiple antigens, and delivered in multiple doses. Plant-based vaccines that are heat-stable and easy to produce and administer are suited to this type of strategy. Pilot studies by a number of groups have demonstrated that plant viral expression systems can produce HIV antigens in quantities that are appropriate for use in vaccines. In addition, these plant-made HIV antigens have been shown to be immunogenic. However, given the need for potent cross-clade humoral and T-cell immunity for protection against HIV, and the uncertainty surrounding the efficacy of protein subunit vaccines, it is most likely that plant-made HIV vaccines will find their niche as booster immunizations in prime-boost vaccination schedules.
Publisher: SAGE Publications
Date: 2018
Abstract: Heart failure is a leading cause for hospitalisation and for readmission, especially in patients over the age of 65. Diabetes is an increasingly common companion to heart failure. The presence of diabetes and its associated comorbidity increases the risk of adverse outcomes and premature mortality in patients with heart failure. In particular, patients with diabetes are more likely to be readmitted to hospital soon after discharge. This may partly reflect the greater severity of heart disease in these patients. In addition, agents that reduce the chances of readmission such as β-blockers, renin-angiotensin-aldosterone system blockers, and mineralocorticoid receptor antagonists are underutilised because of the perceived increased risks of adverse drug reactions and other limitations. In some cases, readmission to hospital is precipitated by acute decompensation of heart failure (re-exacerbation) leading to pulmonary congestion and/or refractory oedema. However, it appears that for most of the patients admitted and then discharged with a primary diagnosis of heart failure, most readmissions are not due to heart failure, but rather due to comorbidity including arrhythmia, infection, adverse drug reactions, and renal impairment/reduced hydration. All of these are more common in patients who also have diabetes, and all may be partly preventable. The many different reasons for readmission underline the critical value of multidisciplinary comprehensive care in patients admitted with heart failure, especially those with diabetes. A number of new strategies are also being developed to address this area of need, including the use of SGLT2 inhibitors, novel nonsteroidal mineralocorticoid antagonists, and neprilysin inhibitors.
Publisher: Springer Science and Business Media LLC
Date: 30-07-2015
DOI: 10.1038/NRDP.2015.18
Publisher: S. Karger AG
Date: 2012
DOI: 10.1159/000342487
Abstract: Heart failure mortality is significantly increased in patients with baseline renal impairment and those with underlying heart failure who subsequently develop renal dysfunction. This accelerated progression occurs independent of the cause or grade of renal dysfunction and baseline risk factors. Recent large prospective databases have highlighted the depth of the current problem, while longitudinal population studies support an increasing disease burden. We have extensively reviewed the epidemiological and therapeutic data among these patients. The evidence points to a progression of heart failure early in renal impairment, even in the albuminuric stage. The data also support poor prescription of prognostic therapies. As renal function is the most important prognostic factor in heart failure, it is important to establish the current understanding of the disease burden and the therapeutic implications.
Publisher: Hindawi Limited
Date: 14-06-2013
DOI: 10.1111/PEDI.12028
Abstract: Although a diagnosis of coeliac disease (CD) may be confronting to children with type 1 diabetes and their families, we hypothesize that children with CD have lower urinary albumin excretion, a marker of renal dysfunction. Twenty-four children with type 1 diabetes and biopsy-proven CD, on a gluten-free diet for at least 1 yr, were recruited from a single paediatric diabetes clinic alongside 55 children with type 1 diabetes but without CD matched for age, gender, duration of diabetes, and glycaemic control. Despite comparable diabetes exposure, glycaemic control and nutritional status, children with type 1 diabetes and CD had a lower urinary albumin creatinine ratio than in diabetic subjects without CD (0.9 ± 0.3 mg/mmol vs. 1.6 ± 0.3 mg/mmol p = 0.01). Participants with CD also showed slower progression in albuminuria over 5-yr of follow-up while a small but significant increase was observed in the children with diabetes alone (1.6 ± 0.3 mg/mmol follow-up 2.4 ± 0.5 mg/mmol p = 0.02). As urinary albumin excretion is continuously associated with the risk of kidney disease, it is possible to speculate that CD or its management confers a degree of renoprotection. Larger studies are required to test this hypothesis.
Publisher: Elsevier BV
Date: 03-1999
Publisher: AIP Publishing
Date: 26-04-2022
DOI: 10.1063/5.0088325
Abstract: Thermodiffusion is the migration of a species due to a temperature gradient and is the driving phenomenon in many applications ranging from early cancer detection to uranium enrichment. Molecular dynamics (MD) simulations can be a useful tool for exploring the rather complex thermodiffusive behavior of species, such as proteins and ions. However, current MD models of thermodiffusion in aqueous ionic solutions struggle to quantitatively predict the Soret coefficient, which indicates the magnitude and direction of species migration under a temperature gradient. In this work, we aim to improve the accuracy of MD thermodiffusion models by assessing how well different water models can recreate thermodiffusion in a benchmark aqueous NaCl solution. We tested four of the best available rigid non-polarizable water models (TIP3P-FB, TIP4P-FB, OPC3, and OPC) and the commonly used TIP3P and SPC/E water models for their ability to predict the inversion temperature and Soret coefficient in 0.5, 2, and 4M aqueous NaCl solutions. Each water model predicted a noticeably different ion distribution yielding different inversion temperatures and magnitudes of the Soret coefficient. By comparing the modeled Soret coefficients to published experimental values, we determine TIP3P-FB to be the water model that best recreates thermodiffusion in aqueous NaCl solutions. Our findings can aid future works in selecting the most accurate rigid non-polarizable water model, including water and ion parameters for investigating thermodiffusion through MD simulations.
Publisher: American Diabetes Association
Date: 15-02-2018
DOI: 10.2337/DB17-0538
Abstract: Signaling via the receptor of advanced glycation end products (RAGE)—though complex and not fully elucidated in the setting of diabetes—is considered a key injurious pathway in the development of diabetic nephropathy (DN). We report here that RAGE deletion resulted in increased expression of fibrotic markers (collagen I and IV, fibronectin) and the inflammatory marker MCP-1 in primary mouse mesangial cells (MCs) and in kidney cortex. RNA sequencing analysis in MCs from RAGE−/− and wild-type mice confirmed these observations. Nevertheless, despite these gene expression changes, decreased responsiveness to transforming growth factor-β was identified in RAGE−/− mice. Furthermore, RAGE deletion conferred a more proliferative phenotype in MCs and reduced susceptibility to staurosporine-induced apoptosis. RAGE restoration experiments in RAGE−/− MCs largely reversed these gene expression changes, resulting in reduced expression of fibrotic and inflammatory markers. This study highlights that protection against DN in RAGE knockout mice is likely to be due in part to the decreased responsiveness to growth factor stimulation and an antiapoptotic phenotype in MCs. Furthermore, it extends our understanding of the role of RAGE in the progression of DN, as RAGE seems to play a key role in modulating the sensitivity of the kidney to injurious stimuli such as prosclerotic cytokines.
Publisher: American Diabetes Association
Date: 12-2006
DOI: 10.2337/DC06-1288
Publisher: Wiley
Date: 02-2007
Publisher: AMPCo
Date: 10-2006
Publisher: S. Karger AG
Date: 2011
DOI: 10.1159/000324945
Abstract: Prolonged hyperglycemia, dyslipidemia and oxidative stress in diabetes result in the increased production and accumulation of advanced glycation end products (AGEs) in the kidney. Covalent AGE modifications significantly influence the structure and function of key protein targets. In addition, activation of AGE receptors, alone or in combination with other ligands, is able to promote renal damage, fibrosis and inflammation associated with diabetic nephropathy. The actions of AGEs synergize and potentiate the activity of other pathogenic mediators in the diabetic kidney, including oxidative stress, protein kinase C and renin-angiotensin system activation, which subsequently promote the development and progression of kidney disease in a vicious and progressive cycle. Their importance as downstream mediators of hyperglycemia in diabetes has been ly demonstrated in studies using mechanistically different inhibitors of advanced glycation to retard the development of kidney disease without directly influencing plasma glucose levels. Furthermore, direct exposure to AGEs is able to generate lesions similar to those seen in diabetic nephropathy. The human body has a number of natural defenses against AGE accumulation, which are reduced in diabetic in iduals, and in particular those with nephropathy, while the receptor for AGEs and its ligands are significantly increased. Given such data, a number of different pharmacological agents have been developed to reduce AGEs and with it prevent diabetic kidney disease. Although many have proved effective in experimental models of diabetes, their clinical utility remains unproven.
Publisher: American Diabetes Association
Date: 10-2007
DOI: 10.2337/DC07-0030
Publisher: Elsevier BV
Date: 2013
DOI: 10.1016/J.ATHEROSCLEROSIS.2012.08.018
Abstract: Angiotensin converting enzyme 2 (ACE2) is a homolog of angiotensin converting enzyme (ACE) which generates angiotensin II from angiotensin I. ACE, its product angiotensin II and the downstream angiotensin type I receptor are important components of the renin-angiotensin system (RAS). Angiotensin II, the most important component of the RAS, promotes the development of atherosclerosis. The identification of ACE2 in 2000 opened a new chapter of research on the regulation of the RAS. ACE2 degrades pro-atherosclerotic angiotensin II and generates anti-atherosclerotic angiotensin 1-7. In this review, we explored the importance of ACE2 in protecting experimental animals from developing atherosclerosis and its involvement in human atherosclerosis. We also examined the published evidence assessing the importance of ACE2 in different cell types relevant to atherosclerosis and putative underlying cellular and molecular mechanisms linking ACE2 with protection from atherosclerosis. ACE2 shifts the balance from angiotensin II to angiotensin 1-7 inhibiting the progression of atherosclerosis in animal models.
Publisher: Portland Press Ltd.
Date: 15-01-2008
DOI: 10.1042/CS20070261
Abstract: The aim of the present study was to determine the prevalence and predictors of an abnormal echocardiogram in patients with Type 2 diabetes. Cardiac function and structure were rigorously assessed by comprehensive transthoracic echocardiographic techniques in 229 patients with Type 2 diabetes. Cardiovascular risk factors and diabetic complications were assessed, and predictors of an abnormal echocardiogram were identified using multivariate logistic regression analysis. An abnormal echocardiogram was present in 166 patients (72%). LVH (left ventricular hypertrophy) occurred in 116 patients (51%), and cardiac dysfunction was found in 146 patients (64%), of whom 109 had diastolic dysfunction alone and 37 had systolic±diastolic dysfunction. Independent predictors of an abnormal echocardiogram were obesity, age, the number of antihypertensive drugs used (all P& .001) and creatinine clearance (P& .05). The risk of an abnormal echocardiogram increased by 9% for each year over 50 years of age {OR (odds ratio), 1.09 [95% CI (confidence interval), 1.04–1.15]}, 3-fold if obesity was present [BMI (body mass index) & OR, 4.2 (95% CI, 1.9–9.0)] and by 80% for each antihypertensive agent used [OR, 1.8 (95% CI, 1.3–2.4) per agent]. In conclusion, an abnormal cardiac echocardiogram is common in patients with Type 2 diabetes. Importantly, although cardiac abnormalities can be predicted by traditional risk factors, such as age, obesity and renal function, the absence of micro- or macro-vascular complications does not predict a normal echocardiogram. We suggest that an echocardiogram identifies those with Type 2 diabetes at increased cardiovascular risk due to occult LVH and diastolic dysfunction, and this information may lead to more aggressive management of known risk factors in the clinic.
Publisher: Hindawi Limited
Date: 2008
DOI: 10.1155/2008/245410
Abstract: Peroxisome proliferators activated receptors (PPARs) are ligand-activated nuclear transcription factors that play important roles in lipid and glucose homeostasis. To the extent that PPAR agonists improve diabetic dyslipidaemia and insulin resistance, these agents have been considered to reduce cardiovascular risk. However, data from murine models suggests that PPAR agonists also have independent anti-atherosclerotic actions, including the suppression of vascular inflammation, oxidative stress, and activation of the renin angiotensin system. Many of these potentially anti-atherosclerotic effects are thought to be mediated by transrepression of nuclear factor-kB, STAT, and activator protein-1 dependent pathways. In recent clinical trials, PPAR agonists have been shown to be effective in the primary prevention of cardiovascular events, while their cardiovascular benefit in patients with established cardiovascular disease remains equivocal. However, the use of PPAR agonists, and more recently dual PPAR/ coagonists, has been associated with an excess in cardiovascular events, possibly reflecting unrecognised fluid retention with potent agonists of the PPAR receptor. Newer pan agonists, which retain their anti-atherosclerotic activity without weight gain, may provide one solution to this problem. However, the complex biologic effects of the PPARs may mean that only vascular targeted agents or pure transrepressors will realise the goal of preventing atherosclerotic vascular disease.
Publisher: American Diabetes Association
Date: 17-09-2010
DOI: 10.2337/DB10-0552
Abstract: Advanced glycation end products (AGEs) and the renin-angiotensin system (RAS) are both implicated in the development of diabetic retinopathy. How these pathways interact to promote retinal vasculopathy is not fully understood. Glyoxalase-I (GLO-I) is an enzyme critical for the detoxification of AGEs and retinal vascular cell survival. We hypothesized that, in retina, angiotensin II (Ang II) downregulates GLO-I, which leads to an increase in methylglyoxal-AGE formation. The angiotensin type 1 receptor blocker, candesartan, rectifies this imbalance and protects against retinal vasculopathy. Cultured bovine retinal endothelial cells (BREC) and bovine retinal pericytes (BRP) were incubated with Ang II (100 nmol/l) or Ang II+candesartan (1 μmol/l). Transgenic Ren-2 rats that overexpress the RAS were randomized to be nondiabetic, diabetic, or diabetic+candesartan (5 mg/kg/day) and studied over 20 weeks. Comparisons were made with diabetic Sprague-Dawley rats. In BREC and BRP, Ang II induced apoptosis and reduced GLO-I activity and mRNA, with a concomitant increase in nitric oxide (NO•), the latter being a known negative regulator of GLO-I in BRP. In BREC and BRP, candesartan restored GLO-I and reduced NO•. Similar events occurred in vivo, with the elevated RAS of the diabetic Ren-2 rat, but not the diabetic Sprague-Dawley rat, reducing retinal GLO-I. In diabetic Ren-2 rats, candesartan reduced retinal acellular capillaries, inflammation, and inducible nitric oxide synthase and NO•, and restored GLO-I. We have identified a novel mechanism by which candesartan improves diabetic retinopathy through the restoration of GLO-I.
Publisher: Bentham Science Publishers Ltd.
Date: 10-2004
Abstract: Advanced glycation end products (AGEs) in diabetic nephropathy have been extensively researched over the last decade and are now firmly established as major players in this disease. The enigma remains the search for the ideal AGE inhibition therapy, which is a great challenge in the context of the structural ersity inherent to AGE chemistry. Certainly, there is a requirement to standardize measurements of circulating and tissue levels of AGEs and to characterize the pathogenic potential of specific AGE moieties. In order to develop more effective, targeted approaches to combat diabetic nephropathy, the mechanisms of action of selective AGE inhibitors and the inter-relationships of advanced glycation with other pathogenic pathways must be addressed.
Publisher: Portland Press Ltd.
Date: 03-07-2012
DOI: 10.1042/CS20110668
Abstract: Local and systemic AngII (angiotensin II) levels are regulated by ACE2 (angiotensin-converting enzyme 2), which is reduced in diabetic tissues. In the present study, we examine the effect of ACE2 deficiency on the early cardiac and vascular changes associated with experimental diabetes. Streptozotocin diabetes was induced in male C57BL6 mice and Ace2-KO (knockout) mice, and markers of RAS (renin–angiotensin system) activity, cardiac function and injury were assessed after 10 weeks. In a second protocol, diabetes was induced in male ApoE (apolipoprotein E)-KO mice and ApoE/Ace2-double-KO mice, and plaque accumulation and markers of atherogenesis assessed after 20 weeks. The induction of diabetes in wild-type mice led to reduced ACE2 expression and activity in the heart, elevated circulating AngII levels and reduced cardiac Ang-(1–7) [angiotensin-(1–7)] levels. This was associated structurally with thinning of the LV (left ventricular) wall and mild ventricular dilatation, and histologically with increased cardiomyocyte apoptosis on TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling) staining and compensatory hypertrophy denoted by an increased cardiomyocyte cross-sectional area. By contrast Ace2-KO mice failed to increase circulating AngII concentration, experienced a paradoxical fall in cardiac AngII levels and no change in Ang-(1–7) following the onset of diabetes. At the same time the major phenotypic differences between Ace2-deficient and Ace2-replete mice with respect to BP (blood pressure) and cardiac hypertrophy were eliminated following the induction of diabetes. Consistent with findings in the heart, the accelerated atherosclerosis that was observed in diabetic ApoE-KO mice was not seen in diabetic ApoE/Ace2-KO mice, which experienced no further increase in plaque accumulation or expression in key adhesion molecules beyond that seen in ApoE/Ace2-KO mice. These results point to the potential role of ACE2 deficiency in regulating the tissue and circulating levels of AngII and their sequelae in the context of diabetes, as well as the preservation or augmentation of ACE2 expression or activity as a potential therapeutic target for the prevention of CVD (cardiovascular disease) in diabetes.
Publisher: Wiley
Date: 03-03-2009
DOI: 10.1111/J.1365-2265.2008.03357.X
Abstract: Anaemia is frequently found in patients with diabetes, in whom it is associated with increased morbidity and mortality. Low testosterone levels are also common in men with type 2 diabetes. We hypothesized that low testosterone levels are also associated with anaemia in men with type 2 diabetes, over the effects of chronic kidney disease. Cross-sectional cohort study, performed in 2005 in a tertiary diabetes clinic. Patients 464 men with type 2 diabetes. Anaemia (haemoglobin (Hb) < 13.7 g/dl in men aged < 60, or < 13.2 g/dl in men aged 60 and older). About 24% of study participants had anaemia, which was associated with the presence and severity of chronic kidney disease, systemic inflammation, increased age, and reduced iron availability. In addition, testosterone levels were independently associated with reduced Hb levels, determining between 6 and 8% of the total variability in raw Hb levels in this population after adjusting for these other factors. In iduals with total testosterone level < 10 nmol/l (43% of the cohort) were more likely to have anaemia (adjusted odds ratio 1.7 95% CI 1.1-2.8). Similarly, anaemia was twice as common in in iduals with a calculated free testosterone of < 0.23 nmol/l (adjusted odds ratio 2.0, 95% CI 1.2-3.1). These findings suggest that testosterone deficiency may contribute to the increased frequency of anaemia in men with type 2 diabetes. However, the appropriate clinical response to testosterone deficiency in anaemic patients remains to be established by prospective clinical trials.
Publisher: S. Karger AG
Date: 2011
DOI: 10.1159/000324943
Abstract: Progressive albuminuria is the sine qua non of diabetic nephropathy. It is not only a marker of renal damage but also significantly contributes to its development and progression. However, the precise mechanisms by which escalating amounts of albumin leave the blood stream, cross the endothelial glycocalyx, the glomerular basement membrane and the slit pores between the foot processes of the podocytes, transit through Bowman's space, bypass the resorptive mechanisms of the nephron and ultimately pass into the urineremain hotly debated. Certainly, diabetes is associated with significant dysfunction at each of these levels, and will be discussed in detail in this review. Moreover, dilation of the afferent and constriction of the efferent arterioles triggered by defective autoregulation and subsequently by loss of peritubular capillaries also act to increase the glomerular transcapillary hydrostatic pressure and facilitate a far greater transit of albumin into the urine. Importantly, none of these mechanisms exists in isolation. Indeed, the most likely reason for progression of albuminuria is the fact that dysfunction initiated by compromise of one component will inevitably modify other parts, and ultimately affect the whole nephron function. From this 'holonephric' view of albuminuria, the best treatment will be a combination that can promote regression and restore the integrity of the entire pathway, as while fixing one part may slow the process, because of the integrated nature of renal function, it will not completely prevent nephropathy.
Publisher: Wiley
Date: 04-2006
Publisher: American Society for Clinical Investigation
Date: 15-02-2023
DOI: 10.1172/JCI160959
Publisher: Elsevier BV
Date: 04-2005
DOI: 10.1053/J.ACKD.2005.01.008
Abstract: Far from being bystanders in diabetic nephropathy, changes in the proximal tubule are important for the development of progressive diabetic kidney disease. The proximal tubule is uniquely susceptible to a variety of metabolic and hemodynamic factors associated with diabetes. Renal function and prognosis correlate better with structural lesions in the tubuli and cortical interstitium than with classical glomerular changes of diabetic nephropathy. The proximal tubules show a variety of poorly characterized changes, which have led to the notion that tubular damage represents a "final common pathway" for proteinuric renal injury. However, tubular hypertrophy, reduced organic ion transport, and other tubular changes reviewed in this paper, are already apparent before the onset of proteinuria in diabetes. Indeed, increased tubuloglomerular feedback and defective uptake and lysosomal processing may independently contribute to hyperfiltration and urinary protein loss, respectively. This finding does not mean that glomerular or vascular dysfunction do not contribute to progressive nephropathy. However, although sub iding the nephron for the purposes of analysis and scientific discovery may be useful, the interactions between tubule, glomerulus, and interstitium are likely key to the understanding of complex disorders such as diabetic nephropathy. From this "holonephric" point of view, an understanding of the changes in the diabetic tubule forms an important component to the understanding of kidney disease in diabetes.
Publisher: American Diabetes Association
Date: 02-2006
DOI: 10.2337/DIACARE.29.02.06.DC05-0809
Abstract: OBJECTIVE—Dyslipidemia contributes to the progression of microvascular disease in diabetes. However, different lipid variables may be important at different stages of nephropathy. This study examines the pattern of dyslipidemia associated with the progression of nephropathy in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS—A total of 152 patients with type 1 diabetes were recruited in order to represent various phases of nephropathy. Patients were followed for 8–9 years, during which time they received standard care. Renal progression was defined a priori as a doubling in albumin excretion (in patients with normo- or microalbuminuria) or a decline in creatinine clearance (in those with macroalbuminuria). A panel of lipid variables was determined and correlated with indexes of progression. RESULTS—In patients with normoalbuminuria (n = 66), progression was associated with male sex (P & 0.05), borderline albuminuria (P = 0.02), and LDL-free cholesterol (P = 0.02). In patients with microalbuminuria (n = 51), progression was independently associated with triglyceride content of VLDL and intermediate-density lipoprotein (both P & 0.05). In patients with macroalbuminuria (n = 36), a significant decline in the renal function (& ml · min−1 · year−1) was independently associated with poor glycemic control, hypertension, and LDL size (P & 0.05). When all patients with progressive nephropathy were analyzed together, only LDL cholesterol was predictive on multivariate analysis (P & 0.05), which masked the importance of triglyceride enrichment in microalbuminuria. CONCLUSIONS—Lipid variables are associated with progression of diabetic kidney disease, but the relationship is not the same at all stages. This finding has implications for the design of renoprotective strategies and the interpretation of clinical trials in type 1 diabetes.
Publisher: Elsevier BV
Date: 04-2017
Publisher: Springer Berlin Heidelberg
Date: 2014
Publisher: Elsevier BV
Date: 12-2016
DOI: 10.1016/J.KINT.2016.09.010
Abstract: The prevalence of diabetes around the world has reached epidemic proportions and is projected to increase to 642 million people by 2040. Diabetes is already the leading cause of end-stage kidney disease (ESKD) in most developed countries, and the growth in the number of people with ESKD around the world parallels the increase in diabetes. The presence of kidney disease is associated with a markedly elevated risk of cardiovascular disease and death in people with diabetes. Several new therapies and novel investigational agents targeting chronic kidney disease patients with diabetes are now under development. This conference was convened to assess our current state of knowledge regarding optimal glycemic control, current antidiabetic agents and their safety, and new therapies being developed to improve kidney function and cardiovascular outcomes for this vulnerable population.
Publisher: Elsevier BV
Date: 03-2005
DOI: 10.1016/J.VACCINE.2004.11.018
Abstract: Plant-based vaccination strategies have the potential to overcome the limitations of the current measles vaccine. The measles virus hemagglutinin (MV-H) protein has been expressed in tobacco. Oral immunisation of mice with plant-derived MV-H protein resulted in MV-specific antibodies and secretory IgA, indicative of humoral and mucosal immune responses. In addition, boosting with oral plant-derived MV-H protein following a MV-H DNA prime, resulted in a greater response than could be induced with either vaccine alone. Collectively, this research represents a significant step towards an effective oral measles vaccine that would be temperature-stable, easy to administer and amenable to inexpensive manufacture.
Publisher: American Diabetes Association
Date: 11-07-2013
DOI: 10.2337/DC13-ER08A
Publisher: University of Tokushima Faculty of Medicine
Date: 2008
DOI: 10.2152/JMI.55.29
Abstract: Circulating low molecular weight (<10 kDa) fluorophores (LMW-F) measured by non-specific fluorescence spectroscopy may detect small advanced glycation end-products (AGEs) not recognized by other assays. This longitudinal study assessed correlates of LMW-F and predictive power of LMW-F levels for vascular health in Type 1 diabetes (T1DM) patients. Fasting patients with T1DM (n=37) were studied twice at intervals of 12-60 months (mean+/-SD, 33+/-15 months). LMW-F levels were also measured once in 112 healthy control subjects. Relative to controls, LMW-F levels were higher in diabetic subjects at initial and final time points (mean+/-SD), 5.4+/-1.9 AU/ml and 4.5+/-1.8 AU/ml respectively vs. 3.8+/-2.1 AU/ml p=0.0001 and p=0.06). Baseline LMW-F levels predicted subsequent hs-CRP and oxLDL/LDL values. LMW-F levels decreased significantly over time in diabetes (5.4+/-1.9 vs. 4.5+/-1.8 AU/ml p=0.02). Rises in LMW-F levels in in idual diabetic subjects correlated significantly with worsening renal function (BUN), glycemia (HbA1c) and with vascular dysfunction (systemic vascular resistance). LMW-F levels predict levels of inflammation and oxidation in T1DM. Changes in LMW-F levels in T1DM reflect variations in glycemia and renal function. Biochemical characterization of LMW-F would facilitate understanding of the potential utility of LMW-F as a therapeutic target.
Publisher: Springer Science and Business Media LLC
Date: 03-06-2020
DOI: 10.1186/S13063-020-04404-0
Abstract: The investigational medicinal product GKT137831 is a selective inhibitor of NOX 1 and 4 isoforms of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase family of enzymes, which has the potential to ameliorate diabetic kidney disease. An investigator-initiated, double-blind, randomised, placebo-controlled, multicentre phase 2 clinical trial started recruitment in December 2017, with the aim of evaluating the efficacy and safety of GKT13783, in adults with type 1 diabetes mellitus and persistently elevated urinary albumin excretion over a period of 48 weeks. The trial is currently recruiting in Australia and New Zealand, with recruitment expected to end on 30 June 2020. The primary outcome measure of the trial is the urinary albumin excretion level measured at 48 weeks of treatment. This statistical analysis plan presents an update to the published trial protocol and provides a comprehensive description of the statistical methods that will be used for the analysis of the data from this trial. In doing so, we follow the “Guidelines for the content of statistical analysis plans in clinical trials” to support transparency and reproducibility of the trial findings. With the use of this prior statistical analysis plan, we aim to minimise bias in the reporting of the findings of this trial, which evaluates the investigational medicinal product GKT137831. The results of the trial are expected to be published in 2022. ANZCTR registry: ACTRN12617001187336 . Registered on 14 July 2017. Universal Trial Number: U1111-1187-2609 Protocol number: T1DGKT137831 Genkyotex trial number: GSN000241.
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 22-06-2004
Publisher: Elsevier BV
Date: 04-2003
Publisher: Oxford University Press (OUP)
Date: 05-2010
Publisher: Portland Press Ltd.
Date: 17-06-2014
DOI: 10.1042/CS20140045
Abstract: RAGE (receptor for advanced glycation end-products) is expressed on multiple cell types implicated in the progression of atherosclerosis and plays a role in DAA (diabetes-associated atherosclerosis). The aim of the present study was to determine the relative role of either BM (bone marrow)- or non-BM-derived RAGE in the pathogenesis of STZ (streptozotocin)-induced DAA. Male ApoE (apolipoprotein E)-null (ApoE−/−:RAGE+/+) and ApoE:RAGE-null (ApoE−/−:RAGE−/−) mice at 7 weeks of age were rendered diabetic with STZ. At 8 weeks of age, ApoE−/− and ApoE−/−:RAGE−/− control and diabetic mice received BM from either RAGE-null or RAGE-bearing mice, generating various chimaeras. After 10 and 20 weeks of diabetes, mice were killed and gene expression and atherosclerotic lesion formation were evaluated respectively. Deletion of RAGE in either the BM cells or non-BM cells both resulted in a significant attenuation in DAA, which was associated with reduced VCAM-1 (vascular cell adhesion molecule-1) expression and translated into reduced adhesion in vitro. In conclusion, the results of the present study highlight the importance of both BM- and non-BM-derived RAGE in attenuating the development of DAA.
Publisher: American Diabetes Association
Date: 21-05-2011
DOI: 10.2337/DB10-1110
Abstract: Diabetic nephropathy is associated with dedifferentiation of podocytes, losing the specialized features required for efficient glomerular function and acquiring a number of profibrotic, proinflammatory, and proliferative features. These result from tight junction and cytoskeletal rearrangement, augmented proliferation, and apoptosis. Experiments were performed in conditionally immortalized human podocytes developed by transfection with the temperature-sensitive SV40-T gene. Cells were then cultured in the presence of transforming growth factor (TGF)-β1 or angiotensin II in the presence or absence of a selective inhibitor of the TGF-β type I receptor kinase, SB-431542. Gene and protein expression were then examined by real-time RT-PCR and immunofluorescence, and correlated with changes observed in vivo in experimental diabetes. Treatment of cells with TGF-β1 resulted in dynamic changes in their morphology, starting with retraction and shortening of foot processes and finishing with the formation of broad and complex tight junctions between adjacent podocytes. This dedifferentiation was also associated with dose- and time-dependent reduction in the expression of glomerular epithelial markers (nephrin, p-cadherin, zonnula occludens-1) and increased expression of mesenchymal markers (α−smooth muscle actin, vimentin, nestin), matrix components (fibronectin, collagen I, and collagen IV α3), cellular proliferation, and apoptosis. The induction of diabetes in mice was also associated with similar changes in morphology, protein expression, and proliferation in glomerular podocytes. In response to TGF-β and other TGF-dependent stimuli, mature podocytes undergo dedifferentiation that leads to effacement of foot processes, morphologic flattening, and increased formation of intercellular tight junctions. This simplification of their phenotype to a more embryonic form is also associated with reentry of mature podocytes into the cell cycle, which results in enhanced proliferation and apoptosis. These “pathoadaptive” changes are seen early in the diabetic glomerulus and ultimately contribute to albuminuria, glomerulosclerosis, and podocytopenia.
Publisher: American Diabetes Association
Date: 12-12-2012
DOI: 10.2337/DB11-0555
Publisher: Elsevier BV
Date: 2004
Publisher: S. Karger AG
Date: 02-11-2010
DOI: 10.1159/000320359
Abstract: Activation of the intra-renal renin-angiotensin system (RAS) and the subsequent generation of angiotensin II (Ang II) are important mediators of haemodynamic changes in both health and disease. However, the effects of locally produced Ang II are not limited to haemodynamic actions. Ang II is also an important stimulus for tubular hypertrophy with the induction of growth factors, including transforming growth factor (TGF)-β sub /sub and connective tissue growth factor. In this article, we explore the direct pro-fibrotic effects of Ang II and its role in inducing tubular epithelial to mesenchymal transition (EMT, also known as type 2 EMT), a known mediator of renal fibrogenesis. There is accumulating evidence that Ang II is able to induce EMT by both TGF-dependent and TGF-independent actions, both in vitro and in vivo. Moreover, blockade of the RAS has synergistic renoprotective effects across a number of causally different forms of renal disease. There is hope that targeted combinations to offset angiotensin-converting enzyme escape in the setting of RAS blockade will eventually achieve the long-term efficacy that has been expected for so long.
Publisher: Hindawi Limited
Date: 2012
DOI: 10.1155/2012/456529
Abstract: Pharmaceutical agonists of peroxisome proliferator-activated receptors (PPARs) are widely used in the management of type 2 diabetes, chiefly as lipid-lowering agents and oral hypoglycaemic agents. Although most of the focus has been placed on their cardiovascular effects, both positive and negative, these agents also have significant renoprotective actions in the diabetic kidney. Over and above action on metabolic control and effects on blood pressure, PPAR agonists also appear to have independent effects on a number of critical pathways that are implicated in the development and progression of diabetic kidney disease, including oxidative stress, inflammation, hypertrophy, and podocyte function. This review will examine these direct and indirect actions of PPAR agonists in the diabetic kidney and explore recent findings of clinical trials of PPAR agonists in patients with diabetes.
Publisher: American Diabetes Association
Date: 17-06-2011
DOI: 10.2337/DC11-0834
Publisher: Bentham Science Publishers Ltd.
Date: 15-07-2016
DOI: 10.2174/1573403X12666160606121458
Abstract: Congestive heart failure (CHF) therapeutics is generated through a well-described evidence generating process. Phases 1 - 3 of this process are required prior to approval and widespread clinical use. Phase 3 in almost all cases is a methodologically sound randomized controlled trial (RCT). After this phase it is generally accepted that the treatment has a significant, independent and prognostically beneficial effect on the pathophysiological process. A major criticism of RCTs is the population to whom the result is applicable. When this population is significantly different from the trial cohort the external validity comes into question. Should the continuation of the evidence generating process continue these problems might be identified. Post marketing surveillance through phase 4 and comparative effectiveness studies through phase 5 trials are often underperformed in comparison to the RCT. These processes can help identify remote adverse events and define new hypotheses for community level benefits. This review is aimed at exploring the post-marketing scene for CHF therapeutics from an Australian health system perspective. We explore the phases of clinical trials, the level of evidence currently available and options for ensuring greater accountability for community level CHF clinical outcomes.
Publisher: Elsevier BV
Date: 2014
DOI: 10.1038/KI.2013.372
Abstract: Renal fibrosis results from excessive accumulation of extracellular matrix mainly driven by transforming growth factor-β1 (TGF-β1). Certain microRNAs have been implicated in this disease, and here we examine the role of let-7b. Rat proximal tubular epithelial cells (NRK52E) were treated with TGF-β1 for 3 days to assess the expression of markers of fibrosis and let-7b. These factors were also assessed in two mouse models representing early and more advanced diabetic nephropathy and in the non-diabetic adenine-induced renal fibrosis model. TGF-β1 downregulated the expression of let-7b and induced fibrogenesis in NRK52E cells. Ectopic expression of let-7b repressed TGF-β1 receptor 1 (TGFBR1) expression directly by targeting the two let-7b binding sites in the 3'-untranslated region of that gene, reduced expression of extracellular matrix proteins, decreased SMAD3 activity, and attenuated the profibrotic effects of TGF-β1. Knockdown of let-7b elevated TGFBR1 expression and mimicked some of the profibrotic effects of TGF-β1. Consistent with these observations, let-7b expression was also reduced in models of both diabetic and non-diabetic renal fibrosis with the upregulation of TGFBR1. Thus, let-7b microRNA represents a potential new target for the treatment of renal fibrosis in diabetic and non-diabetic nephropathy.
Publisher: Springer Science and Business Media LLC
Date: 25-07-2019
DOI: 10.1007/S11886-019-1174-0
Abstract: Coronary artery disease (CAD) is the leading contributor to cardiovascular disease it is the most prevalent non-communicable disease globally and has high morbidity, mortality and health care cost. Risk stratification is defined as prevention or containment of disease prior to it occurring or progressing, and non-invasive surrogates include history, examination, biomarkers and non-invasive imaging. This review aims to highlight advancement in current diagnostic strategies and explores gaps for CAD secondary to atherosclerosis and non-obstructive vascular diseases. Cardiac risk scores have largely proven inadequate in risk stratifying heterogeneous patient populations. Greater emphasis should also be provided to posttest risk stratification. Non-invasive imaging with MRI is the most accurate but least cost efficacious presently due to availability and expertise. Echocardiography and nuclear imaging have good accuracy, but radiation limits the latter. Novel echocardiographic technologies may increase its appeal. Cardiac CT angiography is increasingly promising. Non-invasive and minimally invasive imaging has significantly influenced the cost-efficacy trajectory of coronary artery disease diagnosis and management. Recent studies suggest that future guidelines will incorporate more subclassifications from the findings of these novel technologies and for more erse patient demographics.
Publisher: Elsevier BV
Date: 08-2011
DOI: 10.1038/KI.2011.79
Abstract: Intervention in the renin-angiotensin-aldosterone-system (RAAS) is associated with slowing the progressive loss of renal function. During initiation of therapy, however, there may be an acute fall in glomerular filtration rate (GFR). We tested whether this initial fall in GFR reflects a renal hemodynamic effect and whether this might result in a slower decline in long-term renal function. We performed a post hoc analysis of the Reduction of Endpoints in Non-Insulin-Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan (RENAAL) trial. Patients assigned to losartan had a significantly greater acute fall in estimated (eGFR) during the first 3 months compared to patients assigned to placebo, but a significantly slower long-term mean decline of eGFR thereafter. A large interin idual difference, however, was noticed in the acute eGFR change. When patients were ided into tertiles of initial fall in eGFR, the long-term eGFR slope calculated from baseline was significantly higher in patients with an initial fall compared to those with an initial rise. When eGFR decline was calculated from 3 months to the final visit, excluding the initial effect, patients with a large initial fall in eGFR had a significant lower long-term eGFR slope compared to those with a moderate fall or rise. This relationship was independent of other risk markers or change in risk markers for progression of renal disease such as blood pressure and albuminuria. Thus, the greater the acute fall in eGFR, during losartan treatment, the slower the rate of long-term eGFR decline. Hence, interpretation of trial results relying on slope-based GFR outcomes should separate the initial drug-induced GFR change from the subsequent long-term effect on GFR.
Publisher: Wiley
Date: 02-2007
Publisher: American Physiological Society
Date: 04-2014
DOI: 10.1152/AJPRENAL.00264.2013
Abstract: The degradation of ANG II by angiotensin-converting enzyme 2 (ACE2), leading to the formation of ANG(1–7), is an important step in the regulation of the renin-angiotensin-aldosterone system (RAAS), and one that is significantly altered in the diabetic kidney. This study examined the role of ACE2 in the hyperfiltration associated with diabetes. Streptozotocin diabetes was induced in male C57BL6 mice and ACE2 knockout (KO) mice. C57BL6 mice were further randomized to receive the selective ACE2 inhibitor MLN-4760. After 2 wk of study, animals were subjected to micropuncture experiments. The renal reserve was further assessed in C57BL6 mice and ACE2 KO mice after exposure to a high-protein diet. The induction of diabetes in wild-type mice was associated with increased renal ACE2 activity, hyperfiltration, and renal hypertrophy. On micropuncture, diabetes was associated with increased tubular free flow and stop-flow pressure, enhanced tubuloglomerular feedback reactivity, and an increased maximal response indicative of increased glomerular hydrostatic capillary pressure. Each of these increases were prevented in diabetic ACE2 KO mice and diabetic mice treated with a selective ACE2 inhibitor for 2 wk. However, unlike chronically treated animals, ACE2 inhibition with MLN-4760 had no acute effect on stop-flow pressure or tubuloglomerular feedback reactivity. ACE2 KO mice also failed to increase their creatinine clearance in response to a high-protein diet. The results of our study suggest that ACE2 plays a key role in the recruitment of the renal reserve and hyperfiltration associated with diabetes.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2012
DOI: 10.1161/HYPERTENSIONAHA.112.191767
Abstract: Dietary salt intake is a major determinant of the activation state of renin-angiotensin-aldosterone system. Given the important role of the renin-angiotensin-aldosterone system in plaque accumulation, we investigated its role in the development of atherogenesis associated with sodium intake in apolipoprotein E knockout mice. Six-weeks of a low-salt diet (containing 0.03% sodium) resulted in a 4-fold increase in plaque accumulation in apolipoprotein E knockout mice when compared with mice receiving normal chow (containing 0.30% sodium). This was associated with activation of the renin-angiotensin-aldosterone system, increased vascular expression of adhesion molecules and inflammatory cytokines, and increased adhesion of labeled leukocytes across the whole aorta on a dynamic flow assay. These changes were blocked with the angiotensin-converting enzyme inhibitor perindopril (2 mg/kg per day). A high-salt diet (containing 3% sodium) attenuated vascular inflammation and atherogenesis, associated with suppression of the renin-angiotensin-aldosterone system, although systolic blood pressure levels were modestly increased (5±1 mmHg). Constitutive activation of the renin-angiotensin-aldosterone system in angiotensin-converting enzyme 2 apolipoprotein E knockout mice was also associated with increased atherosclerosis and vascular adhesion, and this was attenuated by a high-salt diet associated with suppression of the renin-angiotensin-aldosterone system. By contrast, a low-salt diet failed to further activate the renin-angiotensin-aldosterone system or to increase atherosclerosis in angiotensin-converting enzyme 2 apolipoprotein E knockout mice. Together, these data validate a relationship between salt-mediated renin-angiotensin-aldosterone system activation and atherogenesis, which may partly explain the inconclusive or paradoxical findings of recent observational studies, despite clear effects on blood pressure.
Publisher: Wiley
Date: 17-12-2017
DOI: 10.1111/NEP.12956
Abstract: To describe the detailed associations of albuminuria among a contemporary cohort of Aboriginal and Torres Strait Islander people to inform strategies for chronic kidney disease prevention and management. A cross-sectional analysis of Indigenous participants of the eGFR Study. Clinical, biochemical and anthropometric measures were collected (including body-circumferences, blood pressure (BP) triglycerides, HbA1c, liver function tests, creatinine urine- microscopic-haem, albumin: creatinine ratio (ACR), prescriptions- angiotensin converting enzyme inhibitor or angiotensin receptor II antagonist (ACEI/ARB). Albuminuria and diabetes were defined by an ACR>3.0 mg/mmol, and HbA1c≥48 mmol/mol or prior history respectively. Waist: hip ratio (WHR), and estimated glomerular filtration rate (eGFR) were calculated. ACR was non-normally distributed a logarithmic transformation was applied (in base 2), with each unit increase in log2-albuminuria representing a doubling of ACR. 591 participants were assessed (71% Aboriginal, 61.6% female, mean age 45.1 years, BMI 30.2 kg/m Albuminuria is associated with diabetes, central obesity and haematuria. High ACEI/ARB prescribing for adults with diabetes and albuminuria was observed. Further understanding of the links between fat deposition, haematuria and albuminuria is required.
Publisher: Massachusetts Medical Society
Date: 15-12-2016
DOI: 10.1056/NEJMC1612304
Publisher: Wiley
Date: 04-2006
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2005
Publisher: Humana Press
Publisher: Oxford University Press (OUP)
Date: 29-10-2011
DOI: 10.1093/NDT/GFR600
Abstract: Angiotensin II (AngII) contributes to salt-driven kidney damage. In this study, we aimed at investigating whether and how the renal damage associated with a high-salt diet could result from changes in the ratio between angiotensin-converting enzyme (ACE) and angiotensin-converting enzyme 2 (ACE2). Forty-eight rats randomly allocated to three different dietary contents of salt were studied for 4 weeks after undergoing a left uninephrectomy. We focussed on kidney functional, structural and molecular changes. At the same time, we studied kidney molecular changes in 20 weeks old Ace2-knockout mice (Ace2KO), with and without ACE inhibition. A high salt content diet significantly increased the glomerular ACE/ACE2 ratio. This was associated with increased oxidative stress. To assess whether these events were related, we measured renal oxidative stress in Ace2KO, and found that the absence of ACE2 promoted oxidative stress, which could be prevented by ACE inhibition. One of the mechanisms by which a high-salt diet leads to renal damage seems to be the modulation of the ACE/ACE2 ratio which in turn is critical for the cause of oxidative stress, through AngII.
Publisher: American Diabetes Association
Date: 29-01-2018
DOI: 10.2337/DC17-1618
Abstract: The current study investigated whether the risk of mortality in patients with type 1 diabetes without any signs of albuminuria is different than in the general population and matched control subjects without diabetes. We studied a nationwide, population-based Finnish register of 10,737 patients diagnosed with type 1 diabetes during 1980–2005 and followed for 10 years and 2,544 adults with long-standing diabetes drawn from the Finnish Diabetic Nephropathy Study (FinnDiane). Mortality was compared with the general Finnish population and 6,655 control subjects without diabetes. The standardized mortality ratio (SMR) was increased during the first 10 years after the diagnosis (2.58 [95% CI 2.07–3.18], P & 0.001). Mortality in adults with long-standing diabetes, but without albuminuria, was no different from that of the general population (1.02 [0.84–1.22], P = 0.83). However, it was higher compared with that of control subjects without diabetes (1.33 [1.06–1.66], P = 0.01). Excess mortality was largely due to acute diabetes complications and ischemic heart disease, which remained more than fourfold higher (mortality rate ratio 4.34 [2.49–7.57]) in adults with type 1 diabetes than in control subjects without diabetes, despite the absence of albuminuria. By contrast, deaths due to alcohol and drugs were reduced in adults with type 1 diabetes (P = 0.007), especially in men. Excess mortality in type 1 diabetes is the result of its complications. Acute complications drive an increased SMR in the first years. In in iduals who remain free of albuminuria, mortality due to ischemic heart disease is still four times higher, and acute complications also occur.
Publisher: Portland Press Ltd.
Date: 12-03-2012
DOI: 10.1042/CS20110403
Abstract: Deficiency of ACE2 (angiotensin-converting enzyme 2), which degrades Ang (angiotensin) II, promotes the development of glomerular lesions. However, the mechanisms explaining why the reduction in ACE2 is associated with the development of glomerular lesions have still to be fully clarified. We hypothesized that ACE2 may regulate the renoprotective actions of ANP (atrial natriuretic peptide). The aim of the present study was to investigate the effect of ACE2 deficiency on the renal production of ANP. We evaluated molecular and structural abnormalities, as well as the expression of ANP in the kidneys of ACE2-deficient mice and C57BL/6 mice. We also exposed renal tubular cells to AngII and Ang-(1–7) in the presence and absence of inhibitors and agonists of RAS (renin–angiotensin system) signalling. ACE2 deficiency resulted in increased oxidative stress, as well as pro-inflammatory and profibrotic changes. This was associated with a down-regulation of the gene and protein expression on the renal production of ANP. Consistent with a role for the ACE2 pathway in modulating ANP, exposing cells to either Ang-(1–7) or ACE2 or the Mas receptor agonist up-regulated ANP gene expression. This work demonstrates that ACE2 regulates renal ANP via the generation of Ang-(1–7). This is a new mechanism whereby ACE2 counterbalances the renal effects of AngII and which explains why targeting ACE2 may be a promising strategy against kidney diseases, including diabetic nephropathy.
Publisher: American Physiological Society
Date: 2012
DOI: 10.1152/AJPREGU.00256.2011
Abstract: The complex role of the renin-angiotensin-system (RAS) in arterial pressure regulation has been well documented. Recently, we demonstrated that chronic low-dose angiotensin II (ANG II) infusion decreases arterial pressure in female rats via an AT 2 R-mediated mechanism. Estrogen can differentially regulate components of the RAS and is known to influence arterial pressure regulation. We hypothesized that AT 2 R-mediated depressor effects evident in females were estrogen dependent and thus would be abolished by ovariectomy and restored by estrogen replacement. Female Sprague-Dawley rats underwent ovariectomy or sham surgery and were treated with 17β-estradiol or placebo. Mean arterial pressure (MAP) was measured via telemetry in response to a 2-wk infusion of ANG II (50 ng·kg −1 ·min −1 sc) or saline. MAP significantly decreased in females treated with ANG II (−10 ± 2 mmHg), a response that was abolished by ovariectomy (+4 ± 2 mmHg) and restored with estrogen replacement (−6 ± 2 mmHg). Cardiac and renal gene expression of components of the RAS was differentially regulated by estrogen, such that overall, estrogen shifted the balance of the RAS toward the vasodilatory axis. In conclusion, estrogen-dependent mechanisms offset the vasopressor actions of ANG II by enhancing RAS vasodilator pathways in females. This highlights the potential for these vasodilator pathways as therapeutic targets, particularly in women.
Publisher: Elsevier BV
Date: 03-2007
Publisher: Wiley
Date: 02-2007
Publisher: Springer Science and Business Media LLC
Date: 03-05-2006
DOI: 10.1007/S00125-006-0275-7
Abstract: We compared the predictive performance of a GFR based on serum cystatin C levels with commonly used creatinine-based methods in subjects with diabetes. In a cross-sectional study of 251 consecutive clinic patients, the mean reference (plasma clearance of (99m)Tc-diethylene-triamine-penta-acetic acid) GFR (iGFR) was 88+/-2 ml min(-1) 1.73 m(-2). A regression equation describing the relationship between iGFR and 1/cystatin C levels was derived from a test population (n=125) to allow for the estimation of GFR by cystatin C (eGFR-cystatin C). The predictive performance of eGFR-cystatin C, the Modification of Diet in Renal Disease 4 variable formula (MDRD-4) and Cockcroft-Gault (C-G) formulas were then compared in a validation population (n=126). There was no difference in renal function (ml min(-1) 1.73 m(-2)) as measured by iGFR (89.2+/-3.0), eGFR-cystatin C (86.8+/-2.5), MDRD-4 (87.0+/-2.8) or C-G (92.3+/-3.5). All three estimates of renal function had similar precision and accuracy. Estimates of GFR based solely on serum cystatin C levels had the same predictive potential when compared with the MDRD-4 and C-G formulas.
Publisher: American Diabetes Association
Date: 09-2008
DOI: 10.2337/DB07-1808
Abstract: OBJECTIVE—Activation of the receptor for advanced glycation end products (RAGE) in diabetic vasculature is considered to be a key mediator of atherogenesis. This study examines the effects of deletion of RAGE on the development of atherosclerosis in the diabetic apoE−/− model of accelerated atherosclerosis. RESEARCH DESIGN AND METHODS—ApoE−/− and RAGE−/−/apoE−/− double knockout mice were rendered diabetic with streptozotocin and followed for 20 weeks, at which time plaque accumulation was assessed by en face analysis. RESULTS—Although diabetic apoE−/− mice showed increased plaque accumulation (14.9 ± 1.7%), diabetic RAGE−/−/apoE−/− mice had significantly reduced atherosclerotic plaque area (4.9 ± 0.4%) to levels not significantly different from control apoE−/− mice (4.3 ± 0.4%). These beneficial effects on the vasculature were associated with attenuation of leukocyte recruitment decreased expression of proinflammatory mediators, including the nuclear factor-κB subunit p65, VCAM-1, and MCP-1 and reduced oxidative stress, as reflected by staining for nitrotyrosine and reduced expression of various NADPH oxidase subunits, gp91phox, p47phox, and rac-1. Both RAGE and RAGE ligands, including S100A8/A9, high mobility group box 1 (HMGB1), and the advanced glycation end product (AGE) carboxymethyllysine were increased in plaques from diabetic apoE−/− mice. Furthermore, the accumulation of AGEs and other ligands to RAGE was reduced in diabetic RAGE−/−/apoE−/− mice. CONCLUSIONS—This study provides evidence for RAGE playing a central role in the development of accelerated atherosclerosis associated with diabetes. These findings emphasize the potential utility of strategies targeting RAGE activation in the prevention and treatment of diabetic macrovascular complications.
Publisher: American Diabetes Association
Date: 04-2003
DOI: 10.2337/DIACARE.26.4.1164
Abstract: OBJECTIVE—Anemia is common in diabetes, potentially contributing to the pathogenesis of diabetes complications. This study aims to establish the prevalence and independent predictors of anemia in a cross-sectional survey of 820 patients with diabetes in long-term follow-up in a single clinic. RESEARCH DESIGN AND METHODS—A full blood count was obtained in addition to routine blood and urine test results for all patients over a 2-year period to encompass all patterns of review. Predictors of the most recent Hb concentration and anemia were identified using multiple and logistic regression analysis. RESULTS—A total of 190 patients (23%) had unrecognized anemia (Hb & g/dl for women and & g/dl for men). This prevalence is two to three times higher than for patients with comparable renal impairment and iron stores in the general population. Independent predictors for Hb were transferrin saturation, glomerular filtration rate (GFR), sex, albumin excretion rate, and HbA1c level (all P & 0.0001). Microalbuminuric patients were & times (odds ratio [OR] 2.3) and macroalbuminuric patients & times (OR 10.1) as likely to have anemia than normoalbuminuric patients with preserved renal function (GFR & ml/min). CONCLUSIONS—Anemia is a common accompaniment to diabetes, particularly in those with albuminuria or reduced renal function. Additional factors present in diabetes may contribute to the development of increased risk for anemia in patients with diabetes.
Publisher: American Medical Association (AMA)
Date: 28-02-2005
DOI: 10.1001/ARCHINTE.165.4.466
Abstract: Diabetes mellitus is associated with an increased prevalence of anemia, particularly in patients with nephropathy. We undertook this survey to determine the relationship between anemia and the renal production of erythropoietin in patients with diabetes mellitus. The clinical data of 722 patients were obtained, including markers of diabetic complications. Erythropoietin levels were measured in the same s les. Patients with a full blood cell count, iron indexes, and renal function within the normal range (n = 151) were used to define the reference range for this population. Anemic patients who had erythropoietin levels within this range were defined as having an "inappropriate erythropoietin response to anemia." Of the 722 patients, 168 (23.3%) had anemia, of whom 130 (77.4%) had erythropoietin levels inappropriately within the normal range. Although 55.4% of anemic patients had moderate renal impairment, erythropoietin levels were also inappropriately low in 69.2% of anemic patients with normal renal function. However, most of these patients (17 of 26) had diabetic kidney disease, as denoted by albuminuria. The failure to produce erythropoietin in response to a declining hemoglobin level is a common contributor to anemia in patients with diabetes mellitus. This seems to be a manifestation of diabetic kidney disease, in the presence or absence of renal impairment.
Publisher: Informa UK Limited
Date: 2010
DOI: 10.3109/07853891003777109
Abstract: Diabetic nephropathy (DN) is a severe long-term complication of diabetes characterized by continuous albuminuria, a relentless decline in renal function, and an increased arterial blood pressure. Our aim was to find out if single nucleotide polymorphisms (SNPs) within the SLC22A1, SLC22A2, and SLC22A3 genes encoding organic cation transporters (OCTs) associate with DN or hypertension. We selected 90 SNPs ( approximately 1 SNP/4 kb) in and surrounding SLC22A1, SLC22A2, and SLC22A3 using the HapMap data. The SNPs were tested for association with DN and hypertension in 1,086 unrelated Finnish patients with type 1 diabetes mellitus (T1DM). Eight of the SNPs were genotyped in 1,252 additional Finnish patients to verify the findings. We detected nominal evidence of association (P < 0.05) between the SLC22A2 (SNPs rs653753, rs596881, and rs316019) and SLC22A3 (SNPs rs376563, rs2048327, rs2457576, and rs1567438) genes and DN and hypertension in Finnish men with T1DM. We were not, however, able to replicate the associations, and none of them reached the significance limit adjusted for multiple testing (P < 0.00009). There was no clear association between the SLC22A1, SLC22A2, and SLC22A3 genes and DN or hypertension. Although several SLC22A2 and SLC22A3 SNPs indicated association, lack of association was evident after the replication study.
Publisher: Oxford University Press (OUP)
Date: 06-03-2006
DOI: 10.1093/NDT/GFL053
Abstract: Advanced glycation end products (AGEs) have biological properties that may contribute to the premature cardiovascular mortality of haemodialysis patients. This study examines the hypothesis that low molecular weight forms of fluorescent AGEs (LMW fluorescence) predict mortality in haemodialysis patients. The LMW fluorescence was measured in 85 patients treated with chronic haemodialysis and prospectively followed for 4 years. The primary outcome of all-cause mortality was assessed using Cox proportional hazards regression model. At the end of the follow-up period 37 (44%) patients died. The median LMW fluorescence level was 24.2 arbitrary units (range: 10.6-148.1 AU) and the receiver operator characteristic (ROC) curve cut-off for mortality was 37.0 AU. The LMW fluorescence predicted death both as a binary variable at the ROC cut-off, and as a continuous log-transformed variable when adjusted for age, albumin and C-reactive protein (CRP). Adjusted for age, albumin and CRP, the hazard ratio for mortality was 3.05 (1.41-6.60, P = 0.005) for LMW fluorescence as a binary variable and 2.71 per log unit (1.37-5.38, P = 0.004) as a continuous log-transformed variable. The low molecular weight forms of AGEs predict mortality in patients receiving chronic haemodialysis, and may be important in the mechanisms leading to atherosclerosis and inflammation in such patients.
Publisher: Elsevier BV
Date: 09-2004
Publisher: Springer Science and Business Media LLC
Date: 04-04-2006
DOI: 10.1007/S00125-006-0215-6
Abstract: Anaemia is a common finding in patients with diabetes, particularly in those with overt nephropathy or renal impairment. In tertiary clinics, at least one outpatient in five with diabetes has anaemia, for whom it constitutes a significant additional burden. Anaemia is associated with an increased risk of diabetic complications including nephropathy, retinopathy and macrovascular disease. Anaemia may also be significant in determining the outcome of heart failure and hypoxia-induced organ damage in diabetes. While several factors contribute to the increased prevalence of anaemia in diabetes, the failure of the kidney to increase erythropoietin in response to falling haemoglobin appears to be the dominant factor. Although there is a clear rationale for correcting anaemia in people with diabetes, it remains to be established whether this will lead to improved outcomes. Moreover, the balance of risks, costs, and benefits remains to be established in patients with diabetes. The Trial to Reduce Cardiovascular Events with Aranesp (darbepoetin alpha) Therapy (TREAT) is a randomised controlled trial designed to determine the impact of anaemia correction on mortality and non-fatal cardiovascular events in patients with type 2 diabetes and stage 3-4 nephropathy. It is anticipated that TREAT will help to define the optimal approach to the management of anaemia in diabetes.
Publisher: Bioscientifica
Date: 09-05-2023
DOI: 10.1530/EC-23-0005
Abstract: Sodium‐glucose co-transporter 2 (SGLT2) inhibitors have recently emerged as an effective means to protect kidney function in people with type 2 diabetes and chronic kidney disease (CKD). In this review, we explore the role of SGLT2 inhibition in these in iduals. SGLT2 inhibitors specifically act to inhibit sodium and glucose reabsorption in the early proximal tubule of the renal nephron. Although originally developed as glucose-lowering agents through their ability to induce glycosuria, it became apparent in cardiovascular outcome trials that the trajectory of kidney function decline was significantly slowed and the incidence of serious falls in kidney function was reduced in participants receiving an SGLT2 inhibitor. These observations have recently led to specific outcome trials in participants with CKD, including DAPA-CKD, CREDENCE and EMPA-KIDNEY, and real-world studies, like CVD-REAL-3, that have confirmed the observation of kidney benefits in this setting. In response, recent KDIGO Guidelines have recommended the use of SGLT2 inhibitors as first-line therapy in patients with CKD, alongside statins, renin–angiotensin–aldosterone system inhibitors and multifactorial risk factor management as indicated. However, SGLT2 inhibitors remain significantly underutilized in the setting of CKD. Indeed, an inertia paradox exists, with patients with more severe disease less likely to receive an SGLT2 inhibitor. Concerns regarding safety appear unfounded, as acute kidney injury, hyperkalaemia, major acute cardiovascular events and cardiac death in patients with CKD appear to be lower following SGLT2 inhibition. The first-in-class indication of dapagliflozin for CKD may begin a new approach to managing kidney disease in type 2 diabetes.
Publisher: Elsevier BV
Date: 05-2006
Abstract: Diabetic nephropathy shows a higher incidence in male subjects, which may in part be owing to genetic factors. The angiotensin II type 2 receptor (AT2), present in the renal glomerulus, may oppose the deleterious effects of the type I receptor (AT1) through vasodilatation and growth inhibition. We determined whether the functional intronic G1675A or A1818T polymorphism of the X-chromosomal AT2 gene is associated with blood pressure levels or with kidney function. We genotyped 996 (538 female/458 male subjects) Finnish patients with type I diabetes from the FinnDiane-study in a cross-sectional study. DNA s les were lified using standard polymerase chain reaction protocol and the genotypes were determined by the minisequencing method. Male patients with the AA haplotype had a lower glomerular filtration rate (83 +/- 32 vs 94 +/- 34 ml min(-1) 1.73 m(-2), P = 0.008) and a higher pulse pressure (PP) (62 +/- 18 vs 57 +/- 15 mm Hg, P = 0.002 P < 0.05 after adjustment for age) than did those with the GT haplotype. No differences between the genotypes or haplotypes and these variables were evident in females. In males, the G1675A was also an independent variable in a linear regression analysis with PP (r(2) = 0.16, coefficient=3.64, s.e.m.=1.38, P < 0.01) as the dependent variable. These data suggest a gender-specific association between the AT2 gene and kidney function and premature aging of the arterial tree in patients with type I diabetes.
Publisher: American Diabetes Association
Date: 17-07-2012
DOI: 10.2337/DB11-1546
Abstract: Advanced glycation end products (AGEs) are important mediators of diabetic nephropathy that act through the receptor for AGEs (RAGE), as well as other mechanisms, to promote renal inflammation and glomerulosclerosis. The relative contribution of RAGE-dependent and RAGE-independent signaling pathways has not been previously studied in vivo. In this study, diabetic RAGE apoE double-knockout (KO) mice with streptozotocin-induced diabetes were treated with the AGE inhibitor, alagebrium (1 mg/kg/day), or the ACE inhibitor, quinapril (30 mg/kg/day), for 20 weeks, and renal parameters were assessed. RAGE deletion attenuated mesangial expansion, glomerular matrix accumulation, and renal oxidative stress associated with 20 weeks of diabetes. By contrast, inflammation and AGE accumulation associated with diabetes was not prevented. However, treatment with alagebrium in diabetic RAGE apoE KO mice reduced renal AGE levels and further reduced glomerular matrix accumulation. In addition, even in the absence of RAGE expression, alagebrium attenuated cortical inflammation, as denoted by the reduced expression of monocyte chemoattractant protein-1, intracellular adhesion molecule-1, and the macrophage marker cluster of differentiation molecule 11b. These novel findings confirm the presence of important RAGE-independent as well as RAGE-dependent signaling pathways that may be activated in the kidney by AGEs. This has important implications for the design of optimal therapeutic strategies for the prevention of diabetic nephropathy.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2002
Publisher: American Physiological Society
Date: 15-07-2012
DOI: 10.1152/AJPRENAL.00028.2012
Abstract: While low nephron number is associated with increased risk of developing cardiovascular and renal disease, the functional consequences of a high nephron number are unknown. We tested the hypothesis that a high nephron number provides protection against hypertensive and renal insults. Mean arterial pressure (MAP) and renal function were characterized in male wild-type (WT) and transforming growth factor-β2 heterozygous ( Tgfb2 +/− ) mice under basal conditions and following a chronic high-salt diet. Kidneys were collected for unbiased stereological analysis. Baseline MAP and renal function were indistinguishable between genotypes. The chronic high-salt diet (5% NaCl for 4 wk followed by 8% NaCl for 4 wk) led to similar step-wise increases in urine volume, Na + excretion, and albuminuria in the genotypes. The 5% NaCl diet induced modest and similar increases in MAP (3.5 ± 1.6 and 3.4 ± 0.8 mmHg in WT and Tgfb2 +/− , respectively). After the step up to the 8% NaCl diet, MAP increased further in WT (+15.9 ± 5.1 mmHg), but not Tgfb2 +/− (−0.1 ± 1.0 mmHg), mice. Nephron number was 30% greater in Tgfb2 +/− than WT mice and was not affected by the chronic high-salt diet. Mean glomerular volume was lower in Tgfb2 +/− than WT mice, and the chronic high-salt diet induced significant glomerular hypertrophy. In a separate cohort of mice, an acute, 7-day, 8% NaCl diet induced similar rises in MAP in the genotypes. This is the first study to examine the physiological characteristics of a model of high nephron number, and the findings are consistent with this phenotype providing protection against chronic, but not acute, hypertensive insults.
Publisher: Elsevier BV
Date: 11-2007
DOI: 10.1016/J.ATHEROSCLEROSIS.2006.11.021
Abstract: Recent reports have suggested that dual peroxisome proliferator-activated receptor (PPAR) alpha/gamma agonists are associated with adverse cardiovascular events. This study aimed to investigate the actions of the non-thiazolidinedione PPARalpha/gamma agonist, compound 3q, on plaque development in the apolipoprotein E knockout (apoE KO) mouse, a recognised model of accelerated plaque development. Six-week-old male apoE KO mice were randomised to receive the dual PPARalpha/gamma agonist, compound 3q (3 mg/kg/day), the PPARgamma agonist, rosiglitazone (20 mg/kg/day), the PPARalpha agonist, gemfibrozil (100 mg/kg/day) by gavage or no treatment for 20 weeks (n=12/group). Gemfibrozil and rosiglitazone significantly reduced lesion area. However, compound 3q was associated with a three-fold increase in total plaque area (versus control p<0.001). This was associated with an upregulation of markers of plaque instability including vascular cell adhesion molecule-1 (3.5-fold, p<0.001), P-selectin (3.4-fold, p<0.001) monocyte chemoattractant protein-1 (3.4-fold p<0.001) as well as the scavenger receptor, CD36 (2-fold, p<0.01). These disparate effects were observed with the dual PPAR agonist despite lowering LDL cholesterol and improving insulin sensitivity to a similar extent to PPARalpha and gamma agonists used in idually. The finding of increased atherogenesis following a dual PPARalpha/gamma agonist is consistent with recent clinical findings. These data provide an important framework for further exploring the potential utility and safety of combinatorial approaches.
Publisher: Springer Science and Business Media LLC
Date: 24-05-2011
DOI: 10.1007/S00125-011-2186-5
Abstract: Activation of the receptor for AGE (RAGE) is implicated in the development and progression of vascular complications of diabetes. In this study, we explore factors and mortality outcomes associated with soluble RAGE (sRAGE) in a multicentre nationwide cohort of Finnish adults with type 1 diabetes. Baseline sRAGE concentrations were estimated in 3,100 adults with type 1 diabetes. Clinical and biological variables independently associated with sRAGE were identified using multivariate regression analysis. Independent predictors of mortality were determined using Cox and Fine-Gray proportional-hazards models. The main independent determinants of sRAGE concentrations were estimated glomerular filtration rate, albuminuria, body mass index, age, duration of diabetes, HbA(1c) and insulin dose (all p < 0.05). During a median of 9.1 years of follow-up there were 202 deaths (7.4 per 1,000 patient years). sRAGE was independently associated with all-cause (Cox model: HR 1.03) and cardiovascular mortality (Fine-Gray competing risks model: HR 1.06) such that patients with the highest sRAGE concentrations had the greatest risk of mortality, after adjusting for age, sex, macrovascular disease, HDL-cholesterol, HbA(1c), triacylglycerol, high-sensitivity C-reactive protein (hsCRP) and the presence and severity of chronic kidney disease. Although polymorphisms in the gene coding for RAGE were significantly associated with sRAGE concentrations, none were associated with mortality outcomes. Increased concentrations of sRAGE are associated with increased all-cause and cardiovascular mortality in type 1 diabetes, potentially reflecting the activation and production of RAGE in the context of accelerated vascular disease. These novel findings highlight the importance of the RAGE activation in the prevention and management of diabetic complications.
Publisher: Springer Science and Business Media LLC
Date: 12-2003
DOI: 10.1007/S00018-003-3342-Y
Abstract: The recombinant protein RTL1Tc, encoded by the non-LTR (long terminal repeat) retrotransposon L1Tc from Trypanosoma cruzi, has been shown to have reverse transcriptase (RT) activity using poly(rA)/oligo(dT) and poly(rC)/oligo(dG) homopolymers as template rimers. The optimal RT activity was detected at a concentration of 5 mM Mg2+, pH 8 and between 28 and 37% degrees C. Site-directed mutagenesis in the RT catalytic site proved that substitution of aspartic acid 313 for isoleucine (RT D313IL1Tc) practically abolishes the RT activity of the RTL1Tc protein. RT-polymerase chain reaction assays revealed that the RTL1Tc protein has the ability to use both homologous and heterologous RNA templates. Also, it is shown that the RTL1Tc protein is capable of synthesizing complementary DNA molecules by consecutive switching of the oligo molecule, which the protein uses as a template. This template switching may be involved in the retroelement integration process.
Publisher: Oxford University Press (OUP)
Date: 21-04-2004
DOI: 10.1093/NDT/GFH248
Publisher: Wiley
Date: 06-2005
Abstract: Incomplete digestion of advanced glycation end product (AGE)-modified protein results in the formation of low-molecular weight degradation products incorporating AGE modifications (LMW-AGEs). In addition to being biomarkers of AGE modification, LMW-AGEs may have a high toxic potential, being free to interact with AGE receptors at distant sites via the circulation. Several free AGEs have been identified, including pentosidine, N(epsilon)-(carboxymethyl)lysine (CML), and free-imidazole AGEs. In addition, fluorescence (370 nm [excitation]/440 nm [emission]) in the LMW phase of serum correlates with tissue fluorescence, an established marker for AGE modification. In experimental diabetes, LMW fluorescence increases with duration of disease and is normalized with the AGE inhibitor aminoguanidine. LMW fluorescence is also higher in patients with diabetes, in whom it is associated with glomerular filtration rate and hemoglobin. Patients with hyperfiltration have lower LMW fluorescence than those with normal renal function, which may protect them from AGE accumulation in the short term. These findings provide clinical support for the association between AGEs and progressive renal injury in diabetes.
Publisher: Wiley
Date: 06-2005
Abstract: Characteristic tissue fluorescence is associated with advanced glycation end product (AGE) accumulation in experimental diabetes models, but its utility in patients with type 1 diabetes remains to be established. We studied 148 patients with type 1 diabetes and 77 healthy age-matched control subjects. Low-molecular weight (LMW) fluorophore levels were estimated in plasma s les obtained after an overnight fast. Intra- and interassay coefficients of variation were 4.7% and 6.4%, respectively. LMW fluorophore levels were significantly higher in patients with diabetes than in control subjects (6.3 +/- 0.6 AU/mL vs. 4.1 +/- 0.3 P = 0.007). However, all of this difference came from patients with microvascular complications (n = 67, 7.5 +/- 1.3). There was no significant difference in LMW fluorescence between complication-free patients (4.4 +/- 0.2) and control subjects (P > 0.05). On multivariate analysis, LMW fluorophores correlated with measures of renal function (P < 0.05) but not with diabetes per se. In addition, there was no correlation between LMW fluorophores and the markers of oxidative stress or systemic inflammation. Longitudinal and interventional studies are required to determine whether the association between LMW fluorophores and nephropathy is cause or effect.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-09-2020
DOI: 10.1161/CIRCRESAHA.120.316653
Abstract: Treatment efficacy for diabetes mellitus is largely determined by assessment of HbA1c (glycated hemoglobin A1c) levels, which poorly reflects direct glucose variation. People with prediabetes and diabetes mellitus spend % of their time outside the optimal glucose range. These glucose variations, termed transient intermittent hyperglycemia (TIH), appear to be an independent risk factor for cardiovascular disease, but the pathological basis for this association is unclear. To determine whether TIH per se promotes myelopoiesis to produce more monocytes and consequently adversely affects atherosclerosis. To create a mouse model of TIH, we administered 4 bolus doses of glucose at 2-hour intervals intraperitoneally once to WT (wild type) or once weekly to atherosclerotic prone mice. TIH accelerated atherogenesis without an increase in plasma cholesterol, seen in traditional models of diabetes mellitus. TIH promoted myelopoiesis in the bone marrow, resulting in increased circulating monocytes, particularly the inflammatory Ly6-C hi subset, and neutrophils. Hematopoietic-restricted deletion of S100a9 , S100a8 , or its cognate receptor Rage prevented monocytosis. Mechanistically, glucose uptake via GLUT (glucose transporter)-1 and enhanced glycolysis in neutrophils promoted the production of S100A8/A9. Myeloid-restricted deletion of Slc2a1 (GLUT-1) or pharmacological inhibition of S100A8/A9 reduced TIH-induced myelopoiesis and atherosclerosis. Together, these data provide a mechanism as to how TIH, prevalent in people with impaired glucose metabolism, contributes to cardiovascular disease. These findings provide a rationale for continual glucose control in these patients and may also suggest that strategies aimed at targeting the S100A8/A9-RAGE (receptor for advanced glycation end products) axis could represent a viable approach to protect the vulnerable blood vessels in diabetes mellitus. A graphic abstract is available for this article.
Publisher: Elsevier BV
Date: 05-2014
DOI: 10.1053/J.ACKD.2014.03.004
Abstract: Diabetes continues to cast a long shadow over the lives of many people. It is now clear that even transient hyper- or hypoglycemia or increased glycemic variability around healthy mean glucose levels can have long-lasting and long-term effects on the development and progression of diabetic complications, including cardiovascular disease, kidney disease, retinopathy, and neuropathy. Even after glycemic control has been achieved and maintained for many years, it appears hard to undo the changes that are instilled, including epigenetic programming, compositional changes, post-translational modifications, or simply lead time toward an inevitable fate. This phenomenon has become known as "metabolic memory" or the "legacy effect," but it may be better characterized as "metabolic karma," in which the intent and actions of an in idual (with respect to metabolic control) influence the future health of that in idual. This "bad karma" has been used to explain many clinical observations surrounding diabetes and its management, including the lack of benefits in many short- and intermediate-term trials, and the potential utility of early intensive glycemic control. Further understanding the molecular basis of a metabolic legacy in diabetes will certainly provide new targets for intervention.
Publisher: Springer Science and Business Media LLC
Date: 2006
DOI: 10.2165/00003495-200666170-00005
Abstract: The current pandemic of diabetes mellitus will inevitably be followed by an epidemic of chronic kidney disease. It is anticipated that 25-40% of patients with type 1 diabetes and 5-40% of patients with type 2 diabetes will ultimately develop diabetic kidney disease. The control of blood pressure represents a key component for the prevention and management of diabetic nephropathy. There is a strong epidemiological connection between hypertension in diabetes and adverse outcomes in diabetes. Hypertension is closely linked to insulin resistance as part of the 'metabolic syndrome'. Diabetic nephropathy may lead to hypertension through direct actions on renal sodium handling, vascular compliance and vasomotor function. Recent clinical trials also support the utility of blood pressure reduction in the prevention of diabetic kidney disease. In patients with normoalbuminuria, transition to microalbuminuria can be prevented by blood pressure reduction. This action appears to be significant regardless of whether patients have elevated blood pressure or not. The efficacy of ACE inhibition appears to be greater than that achieved by other agents with a similar degree of blood pressure reduction although large observational studies suggest the risk of microalbuminuria may be reduced by blood pressure reduction, regardless of modality. In patients with established microalbuminuria, ACE inhibitors and angiotensin receptor antagonists (angiotensin receptor blockers [ARBs]) consistently reduce the risk of progression from microalbuminuria to macroalbuminuria, over and above their antihypertensive actions. The clinical utility of combining these strategies remains to be established. In patients with overt nephropathy, blood pressure reduction is associated with reduced urinary albumin excretion and, subsequently, a reduced risk of renal impairment or end stage renal disease. In addition to actions on systemic blood pressure, it is now clear that ACE inhibitors and ARBs also reduce proteinuria in patients with diabetes. This anti-proteinuric activity is distinct from other antihypertensive agents and diuretics. Although there is a clear physiological rationale for blockade of the renin angiotensin system, which is strongly supported by clinical studies, to achieve the optimal lowering of blood pressure, particularly in the setting of established diabetic renal disease, a number of different antihypertensive agents will always be needed. In the end, the choice of agents should be in idualised to achieve the maximal tolerated reduction in blood pressure and albuminuria. Ultimately, no matter how it is achieved, so long as it is achieved, renal risk can be reduced by agents that lower blood pressure and albuminuria.
Publisher: Elsevier BV
Date: 03-2015
DOI: 10.1016/J.METABOL.2014.11.004
Abstract: This study aimed at investigating the effects of genetic angiotensin-converting enzyme (ACE) 2 deficiency on glucose homeostasis in the pancreas and skeletal muscle and their reversibility following ACE inhibition. ACE2-knockout and C57bl6J mice were placed on a standard diet (SD) or a high-fat diet (HFD) for 12 weeks. An additional group of ACE2-knockout mice was fed a SD and treated with the ACE inhibitor, perindopril (2 mg kg(-1)day(-1)). Glucose and insulin tolerance tests, indirect calorimetry measurements and EchoMRI were performed. Non-esterfied 'free' fatty acid oxidation rate in skeletal muscle was calculated by measuring the palmitate oxidation rate. β-cell mass was determined by immunostaining. Insulin, collectrin, glucose transporter protein, and peroxisome proliferator-activated receptor-γ expression were analysed by RT-PCR. Markers of mithocondrial biogenesis/content were also evaluated. ACE2-knockout mice showed a β-cell defect associated with low insulin and collectrin levels and reduced compensatory hypertrophy in response to a HFD, which were not reversed by perindopril. On the other hand, ACE2 deficiency shifted energy metabolism towards glucose utilization, as it increased the respiratory exchange ratio, reduced palmitate oxidation and PCG-1α expression in the skeletal muscle, where it up-regulated glucose transport proteins. Treatment of ACE2-knockout mice with perindopril reversed the skeletal muscle changes, suggesting that these were dependent on Angiotensin II (Ang II). ACE2-knockout mice display a β-cell defect, which does not seem to be dependent on Ang II but may reflect the collectrin-like action of ACE2. This defect seemed to be compensated by the fact that ACE2-knockout mice shifted their energy consumption towards glucose utilisation via Ang II.
Publisher: Wiley
Date: 02-2007
Publisher: Bentham Science Publishers Ltd.
Date: 09-2021
DOI: 10.2174/1573403X16666201113093548
Abstract: At least half of all heart failure (CHF) patients will have a comorbidity that could be undertreated, requires additional speciality input and/or polypharmacy. These patients are then at risk of iatrogenic and disease-related complications and readmissions if not closely supervised. Common comorbidities of relevance are cardiorenal and cardiometabolic syndromes (DM, obesity, OSA), chronic airways disease, elderly age, and accompanying pharmacotherapies. The structure of community practice often leaves primary, speciality, and allied health care in silos. For ex le, cardiology speciality training in Australia creates excellent sub-specialists to deliver diagnostic and therapeutic advances. A casualty of this process has been the gradual alienation of general cardiology toward general internal medical specialists and primary care practitioners. The consequences are largely noticed in community practice. The issue is compounded by suboptimal communication of information. This review explores these issues from a cardiology sub-speciality lens firstly cross speciality areas that are important for cardiologists to maintain their skill, and finally, to obtain a brief overview of disease management and identify game-changing common denominators such as endothelial dysfunction and self-management.
Publisher: Elsevier BV
Date: 09-2013
DOI: 10.1016/J.DIABET.2013.05.002
Abstract: Feedback activation of neurohormonal pathways in the setting of kidney or heart failure contributes to the development and progression of dysfunction in the other. Diabetes and its management independently activate these same pathogenic pathways, feeding into this vicious cycle and contributing to a poor prognosis. One of the most important of these neurohormonal pathways is the sympathetic nervous system (SNS). The activity of the SNS in increased in patients with chronic kidney disease, even in the absence of renal impairment or heart failure. There is a strong relationship between SNS overactivity and prognosis, and evidence that blockade of SNS reduces morbidity and mortality in patients with diabetes. However, modulation of SNS is underutilised as a strategy to protect both the diabetic kidney and the heart. This is partly because of the historically poor tolerability, adverse haemodynamic and metabolic effects, lack of selectivity of β-blockers and the lack of specificity of other interventions that might modify SNS activation. The advent of "vasodilating β-blockers" with better tolerability as well as more favourable effects on renal function and metabolic profiles opens the door for their more widespread utility in patients with diabetes. Radiofrequency renal sympathectomy and baroreflex activation technologies also offer exciting new ways to tackle the challenge of sympathetic overactivity.
Publisher: Wiley
Date: 04-2006
Publisher: Springer Science and Business Media LLC
Date: 10-05-2012
DOI: 10.1007/S00125-012-2570-9
Abstract: We investigated the contribution of AGEs to the impairment of reverse cholesterol transport (RCT) variables in diabetic in iduals and in two animal models of diabetic obesity and of renal impairment. The capacity of plasma and HDL from 26 in iduals with moderately controlled type 2 diabetes to support cholesterol efflux was compared with 26 age- and sex-matched in iduals without diabetes. We also compared the rates of RCT in vivo in two animal models: db/db mice and mice with chronic renal failure. Diabetic in iduals had characteristic dyslipidaemia and higher levels of plasma AGEs. The capacity of whole plasma, ApoB-depleted plasma and isolated HDL to support cholesterol efflux was greater for diabetic patients compared with controls despite their lower HDL-cholesterol levels. The capacity of plasma to support cholesterol efflux correlated with plasma levels of cholesteryl ester transfer protein and levels of ApoB, but not with levels of AGE. RCT was severely impaired in db/db mice despite elevated HDL-cholesterol levels and no change in AGE concentration, whereas RCT in uraemic mice was unaffected despite elevated AGE levels. AGEs are unlikely to contribute significantly to the impairment of RCT in type 2 diabetes.
Publisher: American Diabetes Association
Date: 12-06-2013
DOI: 10.2337/DC12-2170
Abstract: Osteoprotegerin (OPG) is involved in the process of vascular calcification. We investigated whether OPG is associated with the development and progression of diabetes complications in adults with type 1 diabetes (T1D). Serum OPG was measured in 1,939 adults with T1D participating in the Finnish Diabetic Nephropathy (FinnDiane) Study. Patients with end-stage renal disease (dialysis or transplantation) at baseline were excluded from analysis. Data on cardiovascular (CV) events and mortality during follow-up were verified from hospital discharge registries (ICD codes) and the Finnish National Death Registry, respectively. The follow-up time was 10.4 ± 2.0 (mean ± SD) years. Only patients with macroalbuminuria and/or renal impairment had elevated OPG concentrations, when compared with participants without overt kidney disease. Patients with retinopathy or CV disease also had higher OPG concentrations, but this was attributable to their higher frequency of chronic kidney disease. OPG predicted an incident CV event (hazard ratio 1.21 [95% CI 1.01–1.45] P = 0.035) and peripheral vascular disease/ utation events (1.46 [1.13–1.88] P = 0.004) during follow-up. We showed that serum OPG is an independent predictor of CV complications. OPG may be directly involved in extraosseous calcification, resulting in stiffening of the arteries and subsequent vascular insufficiency in patients with T1D.
Publisher: Springer Science and Business Media LLC
Date: 17-09-2013
Publisher: Elsevier BV
Date: 04-2014
DOI: 10.1093/BJA/AEU403
Abstract: Delay in diagnosis of anaemia during preoperative assessment poses logistic problems, leading to multiple clinic visits, inadequate preoperative management, and unnecessary delay of surgery. Therefore, we tested an instant spectrophotometric haemoglobin (SpHb) measurement technique to facilitate this assessment. We evaluated portable instant SpHb vs standard laboratory screening of anaemia between March 2012 and December 2013. Paired Hb measurements were performed on 726 patients using SpHb (Pronto-7, Masimo Corporation, Irvine, CA, USA) and Hb measured on the same day using an automated analyser. The results were obtained from a group of 638 patients from the pre-anaesthetic clinic with expected normal Hb values, and 88 patients from the oncology clinic with known low Hb. Median (range) SpHb was 129.5 (67-171) compared with 136 g litre(-1) (63-178) Hb measured using the automated system. Identifying Hb below a threshold of 130 g litre(-1) for males had a high sensitivity (93%), while identifying a threshold of 120 g litre(-1) for females had lower sensitivity (75%). The specificity for males (77%) and females (81%) was similar. Mean measurement bias and agreement: tolerability interval ratio was -8.1 g litre(-1) and 2.78 for men and -3.1 g litre(-1) and 2.44 for women. SpHb was sensitive as a preliminary screening tool for detecting true low Hb values in males, but less sensitive in females. Instant SpHb measurement may enable prompt routine preoperative anaemia management, but its precision was lower than expected. This study is approved by the Tasmanian Human Ethics Committee, Australia and was registered prospectively in the Australian and New Zealand Clinical Trials Registry (www.ANZCTR.org.au/ ACTRN12611001256965) and the World Health Organization Clinical Trials Registry (apps.who.int/trialsearch/trial.aspx?trialid=ACTRN12611001256965).
Publisher: Elsevier BV
Date: 10-2006
DOI: 10.1053/J.AJKD.2006.06.011
Abstract: Anemia is a common finding in patients with diabetes, for whom it constitutes an additional burden. The aim of this study is to clarify the natural history of anemia in patients with type 2 diabetes and describe factors that predict a decrease in hemoglobin (Hb) levels. A 5-year prospective cohort study was designed as a follow-up of 503 in iduals with type 2 diabetes in a single diabetes clinic. In addition to standard management, a full blood count was obtained at each routine visit. No intervention was undertaken to modify Hb levels. At baseline, 12% of patients had anemia, and an additional 13% developed anemia during follow-up. Overall Hb levels decreased by -0.07 +/- 0.01 g/dL/y, suggesting that anemia is the end point of a process that begins more than 10 years previously with the initiation of vascular damage. The greatest decreases in Hb levels were seen in patients with macroalbuminuria, renal impairment, or established macrovascular disease at baseline (all P 1.5 mL/s) or normoalbuminuria had stable Hb levels during the 5-year follow-up. In patients with anemia in our cohort who were managed conservatively, Hb levels decreased by 0.09 +/- 0.03 g/dL/y. This decrease was associated with HbA1c levels, but not renal function. This study defines the natural history of Hb levels in patients with type 2 diabetes. Early identification of anemia may be achieved by means of annual or biannual screening in high-risk groups with nephropathy, advanced age, or macrovascular disease. These data are important for developing a rational response to the prevention and management of anemia.
Publisher: Elsevier BV
Date: 06-2004
Publisher: Springer Science and Business Media LLC
Date: 15-01-2021
DOI: 10.1038/S41598-021-81180-0
Abstract: We investigated the association between diet and risk of hospitalisation for diabetic ketoacidosis (DKA) or hypoglycaemia in type 1 diabetes. Food records were used to assess dietary intake. Data on DKA and hypoglycaemia hospitalisations, within two years of dietary assessments, were obtained from registries. Analyses were conducted with and without macronutrient substitution. Data were available from 1391 participants, 28 (2.0%) and 55 (4.0%) of whom were hospitalised due to DKA or hypoglycaemia, respectively. In the adjusted model, self-reported alcohol intake was associated with increased (per 10 g: B = 1.463, 95% CI = 1.114–1.922, p = 0.006 per E%: B = 1.113, 95% CI = 1.027–1.206, p = 0.009), and fibre intake with reduced (per g/MJ: B = 0.934, 95% CI = 0.878–0.995, p = 0.034) risk of DKA hospitalisation. Substituting carbohydrates for fats was associated with increased risk for hypoglycaemia hospitalisation (B = 1.361, 95% CI = 1.031–1.795, p = 0.029), while substituting alcohol for carbohydrates (B = 1.644, 95% CI = 1.006–2.685, p = 0.047) or proteins (B = 2.278, 95% CI = 1.038–4.999, p = 0.040) increased the risk for DKA hospitalisation. In conclusion, refraining from alcohol intake is a preventable risk factor for DKA, while higher fibre intake seems rather protective. Increasing carbohydrate intake while decreasing that of fats, is associated with higher hypoglycaemia risk. Whether this is a cause or effect of hypoglycaemia remains to be established.
Publisher: Elsevier BV
Date: 03-2020
DOI: 10.1016/J.CCT.2019.105892
Abstract: Kidney disease caused by type 1 diabetes can progress to end stage renal disease and can increase mortality risk. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox) plays a major role in producing oxidative stress in the kidney in diabetes, and its activity is attenuated by GKT137831, an oral Nox inhibitor with predominant inhibitory action on Nox-1 and Nox - 4. Previous studies have demonstrated renoprotective effects with GKT137831 in various experimental models of type 1 diabetes-related kidney disease. This study will evaluate the effect of GKT137831 in treating clinical diabetic kidney disease. This is a multi-center, randomized, placebo-controlled trial, parallel arm study evaluating the effect on albuminuria of treatment with GKT137831 400 mg BID for 48 weeks. The study will randomize 142 participants who have persistent albuminuria and estimated glomerular filtration rate (eGFR) at baseline of at least 40 ml/min/1.73m Difference between arms in urine albumin to creatinine ratio. Secondary outcome measures include eGFR. This study is important because it may identify a new way of slowing renal disease progression in people with type 1 diabetes and albuminuria already receiving standard of care treatment.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2012
Publisher: Springer Science and Business Media LLC
Date: 2007
DOI: 10.1038/NCPNEPH0378
Abstract: Anemia is a common finding in patients with diabetes due to the high burden of chronic kidney disease in this population. Anemia is more prevalent and is found earlier in patients with diabetes than in those with kidney disease from other causes. The increased risk of anemia in diabetes probably reflects changes in the renal tubulointerstitium associated with diabetic kidney disease, which disrupt the delicate interaction between interstitial fibroblasts, capillaries and tubular cells required for normal hemopoietic function. In particular, the uncoupling of the hemoglobin concentration from renal erythropoietin synthesis seems to be the key factor underlying the development of anemia. Systemic inflammation, functional hematinic deficiencies, erythropoietin resistance and reduced red cell survival also drive anemia in the setting of impaired renal compensation. Although anemia can be considered a marker of kidney damage, reduced hemoglobin levels independently identify diabetic patients with an increased risk of microvascular complications, cardiovascular disease and mortality. Nevertheless, a direct role in the development or progression of diabetic complications remains to be clearly established and the clinical utility of correcting anemia in diabetic patients has yet to be demonstrated in randomized controlled trials. Correction of anemia certainly improves performance and quality of life in diabetic patients. In the absence of additional data, treatment should be considered palliative, and any functional benefits must be matched against costs to the patient and the health system.
Publisher: Bentham Science Publishers Ltd.
Date: 15-07-2016
DOI: 10.2174/1573403X12666160606120254
Abstract: Increasing numbers of older patients with type 2 diabetes, and their improved survival from cardiovascular events is seeing a massive increase in patients with both diabetes and heart failure. Already, at least a third of all patients with heart failure have diabetes. This close association is partly because all the major risk factors for heart failure also cluster in patients with type 2 diabetes, including obesity, hypertension, advanced age, sleep apnoea, dyslipidaemia, anaemia, chronic kidney disease, and coronary heart disease. However, diabetes may also cause cardiac dysfunction in the absence of overt macrovascular disease, as well as complicate the response to therapy. Current management is focused on targeting modifiable risk factors for heart failure including hyperglycaemia, dyslipidaemia, hypertension, obesity and anemia. But although these are important risk markers, none of these interventions substantially prevents heart failure or improves its outcomes. Much more needs to be done to focus on this issue, including the inclusion of hospital admission for heart failure as a pre-specified component of the primary composite cardiovascular outcomes and new trials in heart failure management specifically in the context of diabetes.
Publisher: American Physiological Society
Date: 08-2008
DOI: 10.1152/AJPENDO.00024.2008
Abstract: A diet high in fat induces cardiac hypertrophy, inflammation, and oxidative stress. Although such actions have largely been ascribed to fat deposition, the accumulation of advanced glycation end products (AGEs) and subsequent activation of the receptor for AGEs (RAGE) may also represent important mediators of cardiac injury following exposure to a Western diet. In this study, male C57BL6J and RAGE knockout mice were placed on either a standard diet (7% fat) or a Western “fast-food” diet (21% fat). Animals receiving a high-fat diet were further randomized to receive the AGE inhibitor alagebrium chloride (1 mg·kg −1 ·day −1 ) and followed for 16 wk. A Western diet was associated with cardiac hypertrophy, inflammation, mitochondrial-dependent superoxide production, and cardiac AGE accumulation in wild-type mice. Although RAGE-KO mice fed a Western diet also became obese and accumulated intramyocardial lipid, cardiomyocyte hypertrophy, inflammation, and oxidative stress were attenuated compared with wild-type mice. Similarly, mice of both strains receiving alagebrium chloride had reduced levels of inflammation and oxidative stress, in association with a reduction in cardiac AGEs and RAGE. This study suggests that AGEs represent important mediators of cardiac injury associated with a Western fast-food diet. These data point to the potential utility of AGE-reducing strategies in the prevention and management of cardiac disease.
Publisher: Springer Berlin Heidelberg
Date: 2014
Publisher: American Diabetes Association
Date: 2011
DOI: 10.2337/DB11-ER01
Publisher: Wiley
Date: 04-2006
Publisher: Oxford University Press (OUP)
Date: 07-1998
Abstract: Nowadays, there is a huge gap between autonomous vehicles and mankind in terms of the decision response against some dangerous scenarios, which would has stressed the potential users out and even made them nervous. To efficiently identify the possible sensitivity scenarios, a new neural network configuration, named sensitive non-associative learning network (SNAL), is proposed. In such structure, the modulated interneurons, excited by abnormal scene stimulation for scene processing, are well processed and utilized to improve the training structure which refers to the sensitization mechanism in non-associative learning in neurobiology and the neural structure of Aplysia. When encountering the sensitivity scenes that the automatic driving agent is not good at or has not seen, the modulated interneuron facilitates the full connection layer neurons for the decision-making process, so as to change the final automatic driving strategy. In the process of constructing the model, a method to measure the similarity of the convolution feature map is proposed, which provides a new investigation tool for the properties of convolution networks after the feature extraction. Based on the Morris-Lecar equation in neurobiology, the dynamic model of modulating interneurons in the network is constructed. The automatic control optimization of the model is carried out by imitating the biological properties. The optimization method provides a reference for introducing neurobiological mechanism into deep learning and automatic control. To validate the effectiveness of the proposed method, the simulation test are executed and the existing methods are compared accordingly. The results show that the proposed SNAL algorithm can effectively recognize the sensitivity mechanism. Furthermore, compared with the existing algorithms, such as CNN, LSTM, ViT, the proposed algorithm can make better defensive strategies for potentially dangerous scenes rarely seen or not seen in the training stage. This sensitivity mechanism is more in line with the human driving intuition when dealing with abnormal driving scenes, and makes the decision more interpretable, significantly improving the traffic ability of autonomous vehicles under the sensitive scenes. In addition, this configuration can be easily combined with the existing mainstream neural network models and has good expansibility.
Publisher: Wiley
Date: 04-2006
Publisher: Taylor & Francis
Publisher: AMPCo
Date: 08-2006
DOI: 10.5694/J.1326-5377.2006.TB00499.X
Abstract: To estimate the frequency of chronic kidney disease (CKD) in a clinic-based s le of patients with type 2 diabetes in the setting of Australian primary care. Expressions of interest were invited from all registered general practitioners in Australia: 500 GP investigators were randomly selected from each stratum (state and urban versus rural location), proportional to the census population, and asked to recruit and provide data for 10-15 consecutively presenting adults with type 2 diabetes between April and September 2005. Estimated glomerular filtration rate (eGFR) less than 60 mL/min/1.73 m(2) and evidence of kidney damage on urinalysis (eg, microalbuminuria). 348 GP investigators submitted data for 3893 in iduals with type 2 diabetes (52% men median age, 66 years). Almost one in every four patients consulting their GPs had an eGFR < 60 mL/min/1.73 m(2) (23.1% 95% CI, 21.8%-24.5%). More than one in three had an elevated urinary albumin-creatinine ratio (ACR) (34.6% 95% CI, 33.3%-35.9%). There was an overlap of 10.4% of patients with both an eGFR < 60 mL/min/1.73 m(2) and an elevated urinary ACR, meaning that almost one in two patients with type 2 diabetes consulting their GPs (47.1% 95% CI, 45.8%-48.4%) had CKD. CKD was significantly more common in women, in older people, and in in iduals with established macrovascular disease. CKD is a common complication of type 2 diabetes, found in about half of all patients with type 2 diabetes consulting their GPs. Efforts to increase the recognition of CKD will lead to improved care, and possibly survival, of patients with type 2 diabetes.
Publisher: Springer Science and Business Media LLC
Date: 14-02-2009
DOI: 10.1007/S00125-009-1277-Z
Abstract: Coeliac disease is common in type 1 diabetes. It is managed with a gluten-free diet, characterised by foods low in AGEs. We hypothesised that this diet would lead to lower plasma AGEs and be associated with reduced albuminuria. From a single paediatric clinic, we recruited 21 children with type 1 diabetes and biopsy-proven coeliac disease, and 38 in iduals with diabetes alone. The groups were matched for age, sex, duration of disease and metabolic control. Participants completed a detailed clinical and dietary history. Blood s les were taken for HbA(1c), coeliac serology, thyroid function, serum IgA levels and plasma AGEs, and urine s les were obtained for estimation of the albumin/creatinine ratio (ACR). All the in iduals with coeliac disease were asymptomatic, with negative transglutaminase antibodies. There were no significant differences between the groups in terms of age (14 years), sex (29% male), duration of diabetes (7 years), mean HbA(1c) (8.3%), lipid levels or treatment regimens. However, children with diabetes and coeliac disease had twofold lower levels of urinary ACR than with those diabetes alone (p = 0.04). This was associated with lower levels of circulating AGEs (p = 0.03). These associations were independent of metabolic control, diabetes management and other potentially confounding variables, such as household exposure to cigarette smoke. Adherence to a gluten-free diet may provide additional benefits for in iduals with coeliac disease, and potentially those with type 1 diabetes.
Publisher: Wiley
Date: 27-02-2008
Publisher: American Diabetes Association
Date: 07-2006
DOI: 10.2337/DC05-1788
Abstract: OBJECTIVE—To investigate the role of intrarenal vascular disease in the pathogenesis of nonalbuminuric renal insufficiency in type 2 diabetes. RESEARCH DESIGN AND METHODS—We studied 325 unselected clinic patients who had sufficient clinical and biochemical information to calculate an estimated glomerular filtration rate (eGFR) using the Modified Diet in Renal Disease six-variable formula, at least two estimations of urinary albumin excretion rates (AER), and a renal duplex scan to estimate the resistance index of the interlobar renal arteries. The resistance index, measured as part of a complications surveillance program, was compared in patients with an eGFR & or ≥60 ml/min per 1.73 m2 who were further stratified into normo- (AER & ), micro- (20–200), or macroalbuminuria (& 200 μg/min) categories. RESULTS—Patients with an eGFR & ml/min per 1.73 m2 had a higher resistance index of the renal interlobar arteries compared with patients with an eGFR ≥60 ml/min per 1.73 m2. However, the resistance index was elevated to a similar extent in patients with an eGFR & ml/min per 1.73 m2 regardless of albuminuric status (normo- 0.74 ± 0.01, micro- 0.73 ± 0.01, and macroalbuminuria resistance index 0.75 ± 0.11). Multiple regression analysis revealed that increased age (P & 0.0001), elevated BMI (P = 0.0001), decreased eGFR (P & 0.01), and decreased diastolic blood pressure (P & 0.01), but not an increased AER, were independently associated with an elevated resistance index in patients with impaired renal function. CONCLUSIONS—Subjects with type 2 diabetes and reduced glomerular filtration rate had similar degrees of intrarenal vascular disease, as measured by the intrarenal arterial resistance index, regardless of their AER status. The pathological mechanisms that determine the relationship between impaired renal function and AER status in subjects with type 2 diabetes remain to be elucidated.
Publisher: Elsevier BV
Date: 1998
DOI: 10.1016/S0936-6555(98)80087-3
Abstract: Sister Joseph's nodule is traditionally regarded as a sign of poor prognosis in untreatable malignancy. We describe a patient with a metastatic umbilical nodule in non-Hodgkin's lymphoma who had a good outcome. The possible mechanisms of tumour spread to the umbilicus and reasons for its rarity in lymphoma are discussed. The need for histological confirmation to exclude treatable disease is emphasized.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 18-04-2003
DOI: 10.1161/01.RES.0000065620.39919.20
Abstract: The formation of advanced glycation end products (AGEs) on extracellular matrix components leads to accelerated increases in collagen cross linking that contributes to myocardial stiffness in diabetes. This study determined the effect of the crosslink breaker, ALT-711 on diabetes-induced cardiac disease. Streptozotocin diabetes was induced in Sprague-Dawley rats for 32 weeks. Treatment with ALT-711 (10 mg/kg) was initiated at week 16. Diabetic hearts were characterized by increased left ventricular (LV) mass and brain natriuretic peptide (BNP) expression, decreased LV collagen solubility, and increased collagen III gene and protein expression. Diabetic hearts had significant increases in AGEs and increased expression of the AGE receptors, RAGE and AGE-R3, in association with increases in gene and protein expression of connective tissue growth factor (CTGF). ALT-711 treatment restored LV collagen solubility and cardiac BNP in association with reduced cardiac AGE levels and abrogated the increase in RAGE, AGE-R3, CTGF, and collagen III expression. The present study suggests that AGEs play a central role in many of the alterations observed in the diabetic heart and that cleavage of preformed AGE crosslinks with ALT-711 leads to attenuation of diabetes-associated cardiac abnormalities in rats. This provides a potential new therapeutic approach for cardiovascular disease in human diabetes.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2010
DOI: 10.1161/CIRCRESAHA.110.219279
Abstract: Angiotensin-converting enzyme (ACE)2 opposes the actions of angiotensin (Ang) II by degrading it to Ang 1-7. Given the important role of Ang II/Ang 1-7 in atherogenesis, we investigated the impact of ACE2 deficiency on the development of atherosclerosis. C57Bl6 , Ace2 knockout (KO), apolipoprotein E ( ApoE ) KO and ApoE/Ace2 double KO mice were followed until 30 weeks of age. Plaque accumulation was increased in ApoE/Ace2 double KO mice when compared to ApoE KO mice. This was associated with increased expression of adhesion molecules and inflammatory cytokines, including interleukin-6, monocyte chemoattractant protein-1, and vascular cell adhesion molecule-1, and an early increase in white cell adhesion across the whole aortae on dynamic flow assay. In the absence of a proatherosclerotic ( ApoE KO ) genotype, ACE2 deficiency was also associated with increased expression of these markers, suggesting that these differences were not an epiphenomenon. ACE inhibition prevented increases of these markers and atherogenesis in ApoE/ACE2 double KO mice. Bone marrow macrophages isolated from Ace2 KO mice showed increased proinflammatory responsiveness to lipopolysaccharide and Ang II when compared to macrophages isolated from C57Bl6 mice. Endothelial cells isolated from Ace2 KO mice also showed increased basal activation and elevated inflammatory responsiveness to TNF-α. Similarly, selective inhibition of ACE2 with MLN-4760 also resulted in a proinflammatory phenotype with a physiological response similar to that observed with exogenous Ang II (10 −7 mol/L). Genetic Ace2 deficiency is associated with upregulation of putative mediators of atherogenesis and enhances responsiveness to proinflammatory stimuli. In atherosclerosis-prone ApoE KO mice, these changes potentially contribute to increased plaque accumulation. These findings emphasize the potential utility of ACE2 repletion as a strategy to reduce atherosclerosis.
Publisher: Wiley
Date: 02-2007
Publisher: Wiley
Date: 03-2009
DOI: 10.1111/J.1445-5994.2008.01696.X
Abstract: Hypertension is a major risk factor for adverse outcomes in type 2 diabetes and an important target for intervention. Despite this, the management of blood pressure (BP) remains suboptimal, particularly in patients at increased risk for cardiovascular and chronic kidney disease. The aim of this study was to estimate the frequency of hypertension and its management in consecutive clinic-based s les of patients with type 2 diabetes in Australian primary care. BP levels and antihypertensive management strategies were compared in patients with type 2 diabetes recruited as part of the Developing Education on Microalbuminuria for Awareness of reNal and cardiovascular risk in Diabetes (DEMAND) study in 2003 (n = 1831) and the National Evaluation of the Frequency of Renal impairment cO-existing with Non-insulin-dependent diabetes (NEFRON) study in 2005 (n = 3893). Systolic BP levels and the use of antihypertensive therapies were examined in patients with and without chronic kidney disease. The patient characteristics in both studies were similar in that more than 80% of patients in both studies were hypertensive. Systolic BP targets of < or =130 mmHg were achieved in approximately half of all treated patients in both studies. However, the use of antihypertensive therapy either alone or in combination increased from 70.4% in DEMAND to 79.5% in NEFRON 2 years later (P < 0.001). Despite this, antihypertensive therapy continued to be underutilized in high-risk groups, including in those with established chronic kidney disease. The DEMAND and NEFRON studies both show that BP control is achievable in Australian general practice, with more than half of all patients seeing their general practitioners achieving a target systolic BP < or =130 mmHg. However, more needs to be done to further reduce BP levels, particularly in patients at high risk of adverse outcomes.
Publisher: Springer Science and Business Media LLC
Date: 23-02-2006
DOI: 10.1007/S00125-006-0175-X
Abstract: The aim of this study was to investigate the effects of a secondary renal insult, due to chronic infusion of AGEs on renal function, and on early pathological markers in rats with a developmental nephron deficit. Female Wistar-Kyoto rats were fed a low-protein diet (LPD 8.7% casein) or a normal-protein diet (NPD 20% casein) during pregnancy and lactation. Nephron number was estimated in 4-week-old female offspring. Male offspring were allowed to grow to 20 weeks of age, when AGEs derived from BSA (AGE-BSA) or BSA was infused subcutaneously (20 mg kg(-1) day(-1)) for 4 weeks. At 24 weeks, blood pressure, renal function and circulating and renal AGEs were assessed. Real-time PCR was used to investigate early molecular markers of renal pathology. As expected, maternal protein restriction led to reduced nephron endowment in LPD offspring. This alone did not affect blood pressure or lead to hyperfiltration in adulthood. However, when coupled with the secondary renal insult, the expression of the genes encoding transforming growth factor-beta(1) and procollagen III was significantly upregulated in the kidneys. In addition, there was renal accumulation of AGEs in LPD offspring, and this was exacerbated by AGE infusion. Our results demonstrate that the adult kidney with a reduced nephron endowment is more vulnerable to secondary renal insult from AGE-BSA. Since AGE formation is markedly elevated with hyperglycaemia, our findings suggest that a developmental or acquired deficit may render the kidney susceptible to diabetic renal disease.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2012
Publisher: Informa Healthcare
Date: 30-06-2012
DOI: 10.1517/17425255.2012.697152
Abstract: The coordinated activation of Nrf-2-dependent signaling pathway is currently being investigated in a range of chronic diseases. Bardoxolone methyl is a potent, orally bioavailable Nrf-2 agonist. In a recent 52-week study, treatment with bardoxolone methyl improved renal function in patients with chronic kidney disease (CKD) and type 2 diabetes. This improvement was sustained for the duration of the treatment. Such agonists potentially offer new options for the complex management of renal impairment. A literature search was performed to analyze the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of bardoxolone methyl in both healthy volunteers and patients. Updated information about bardoxolone methyl, either after single administration or after chronic administration is also included. A special focus has been put on the putative mechanisms of action and potential toxicity profiles as well as an ongoing trials in patients with CKD and type 2 diabetes. The development of an agent that leads to sustained improvement in renal function comes as a welcome relief to the millions of in iduals with diabetes and CKD. However, much remains to be established regarding its actions in a complex and pleiotropic signalling cascade. Other triterpenoids with different PK/PD profiles are currently under development.
Publisher: Oxford University Press (OUP)
Date: 05-1999
Publisher: Springer Science and Business Media LLC
Date: 15-07-2010
Publisher: Baishideng Publishing Group Inc.
Date: 26-08-2020
Publisher: Bentham Science Publishers Ltd.
Date: 06-05-2019
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2017
DOI: 10.1161/ATVBAHA.117.310129
Abstract: Recent evidence suggests an important role for angiotensin-converting enzyme 2 (ACE2) in limiting abdominal aortic aneurysm (AAA). This study examined the effect of ACE2 deficiency on AAA development and the efficacy of resveratrol to upregulate ACE2 in experimental AAA. Ace2 deletion in apolipoprotein-deficient mice ( ApoE −/− Ace2 −/y ) resulted in increased aortic diameter and spontaneous aneurysm of the suprarenal aorta associated with increased expression of inflammation and proteolytic enzyme markers. In humans, serum ACE2 activity was negatively associated with AAA diagnosis. ACE2 expression was lower in infrarenal biopsies of patients with AAA than organ donors. AAA was more severe in ApoE −/− Ace2 −/y mice compared with controls in 2 experimental models. Resveratrol (0.05/100-g chow) inhibited growth of pre-established AAAs in ApoE −/− mice fed high-fat chow and infused with angiotensin II continuously for 56 days. Reduced suprarenal aorta dilatation in mice receiving resveratrol was associated with elevated serum ACE2 and increased suprarenal aorta tissue levels of ACE2 and sirtuin 1 activity. In addition, the relative phosphorylation of Akt and ERK (extracellular signal-regulated kinase) 1/2 within suprarenal aorta tissue and gene expression for nuclear factor of kappa light polypeptide gene enhancer in B cells 1, angiotensin type-1 receptor, and metallopeptidase 2 and 9 were significantly reduced. Upregulation of ACE2 in human aortic smooth muscle cells by resveratrol in vitro was sirtuin 1-dependent. This study provides experimental evidence of an important role for ACE2 in limiting AAA development and growth. Resveratrol upregulated ACE2 and inhibited AAA growth in a mouse model.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2003
Publisher: Springer Science and Business Media LLC
Date: 27-11-2007
DOI: 10.1038/NCPNEPH0679
Publisher: American Diabetes Association
Date: 28-04-2009
DOI: 10.2337/DB08-1543
Abstract: This study aimed to identify clinical features associated with premature mortality in a large contemporary cohort of adults with type 1 diabetes. The Finnish Diabetic Nephropathy (FinnDiane) study is a national multicenter prospective follow-up study of 4,201 adults with type 1 diabetes from 21 university and central hospitals, 33 district hospitals, and 26 primary health care centers across Finland. During a median 7 years of follow-up, there were 291 deaths (7%), 3.6-fold (95% CI 3.2–4.0) more than that observed in the age- and sex-matched general population. Excess mortality was only observed in in iduals with chronic kidney disease. In iduals with normoalbuminuria showed no excess mortality beyond the general population (standardized mortality ratio [SMR] 0.8, 95% CI 0.5–1.1), independent of the duration of diabetes. The presence of microalbuminuria, macroalbuminuria, and end-stage kidney disease was associated with 2.8, 9.2, and 18.3 times higher SMR, respectively. The increase in mortality across each stage of albuminuria was equivalent to the risk conferred by preexisting macrovascular disease. In addition, the glomerular filtration rate was independently associated with mortality, such that in iduals with impaired kidney function, as well as those demonstrating hyperfiltration, had an increased risk of death. An independent graded association was observed between the presence and severity of kidney disease and mortality in a large contemporary cohort of in iduals with type 1 diabetes. These findings highlight the clinical and public health importance of chronic kidney disease and its prevention in the management of type 1 diabetes.
Publisher: Wiley
Date: 04-2010
Publisher: Springer Science and Business Media LLC
Date: 04-10-2000
Abstract: Patients with diabetes have an increased risk for allograft rejection, possibly related to peri-operative hyperglycaemia. Hyperglycaemia is also common following transplantation in patients without diabetes. We hypothesise that exposure of allograft tissue to hyperglycaemia could influence the risk for rejection in any patient with high sugars. To investigate the relationship of peri-operative glucose control to acute rejection in renal transplant patients without diabetes, all patients receiving their first cadaveric graft in a single center were surveyed and patients without diabetes receiving cyclosporin-based immunosuppression were reviewed (n = 230). Records of the plasma blood glucose concentration following surgery and transplant variables pertaining to allograft rejection were obtained. All variables suggestive of association were entered into multivariate logistic regression analysis, their significance analysed and modeled. Hyperglycaemia (>8.0 mmol/L) occurs in over 73% of non-diabetic patients following surgery. Glycaemic control immediately following renal transplantation independently predicted acute rejection (Odds ratio=1.08). 42% of patients with a glucose < 8.0 mmol/L following surgery developed rejection compared to 71% of patients who had a serum glucose above this level. Hyperglycaemia was not associated with any delay of graft function. Hyperglycaemia is associated with an increased risk for allograft rejection. This is consistent with similar findings in patients with diabetes. We hypothesise a causal link concordant with epidemiological and in vitro evidence and propose further clinical research.
Publisher: Bentham Science Publishers Ltd.
Date: 15-07-2016
DOI: 10.2174/1573403X12666160606120958
Abstract: The most important advancements in the Cardiorenal syndrome (CRS) are its definition and subsequent classifications. When the predominant pathology and pathophysiology is the heart, i.e. chronic heart failure (CHF), and where any renal impairment (RI) subsequent to this is secondary, the classification is type 2 CRS. There are unique differences in the pathophysiology and progression of in idual subclasses. It is important to understand the evolution of CHF and consequences of subsequent RI as they are becoming increasingly prevalent, aggravate morbidity and mortality and limit many therapeutic options. In this paper we discuss the significance of the type 2 CRS patients in the context of the thematic series.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2009
DOI: 10.1097/MOL.0B013E32831F1B18
Abstract: Peroxisome proliferator activated receptors (PPARs) are ligand-dependent transcription factors that mediate a range of important metabolic functions by transactivation, transrepression or corepression of various gene targets. PPAR agonists also have direct antiatherosclerotic effects, independent of their metabolic effects on glucose and lipid homeostasis. The purpose of this review is to evaluate the currently available evidence for a direct vasculoprotective effect of PPAR agonists. Current studies have emphasized PPAR-mediated effects on inflammatory and immune responses, oxidative stress, the renin-angiotensin system and modulation of plaque composition. Furthermore, it has become evident that the relative activation of the different PPAR isoforms and the contribution of transactivation of target genes against transrepression of transcription factors need to be considered when assessing the vasculoprotective effects of PPAR agonists. It is anticipated that the antiatherosclerotic effects of PPAR agonists observed in experimental studies will translate into reduced cardiovascular events. This promise is yet to be realized in short-to-medium term studies. Given the central role of the PPAR in gene regulation, particularly in metabolic states, it is possible that more targeted modulation of PPAR signalling may hold many rewards for the prevention of atherosclerosis.
Publisher: Elsevier BV
Date: 11-2010
Publisher: Wiley
Date: 04-2006
Publisher: Elsevier BV
Date: 04-2003
Publisher: Wiley
Date: 04-2010
Publisher: American Diabetes Association
Date: 04-2008
DOI: 10.2337/DB07-1212
Abstract: OBJECTIVE— The degradation of angiotensin (Ang) II by ACE2, leading to the formation of Ang 1–7, is an important step in the renin-angiotensin system (RAS) and one that is significantly altered in the diabetic kidney. This study examines the role of ACE2 in early renal changes associated with diabetes and the influence of ACE2 deficiency on ACE inhibitor–mediated renoprotection. RESEARCH DESIGN AND METHODS— Diabetes was induced by streptozotocin in male c57bl6 mice and ACE2 knockout (KO) mice. After 5 weeks of study, animals were randomized to receive the ACE inhibitor perindopril (2 mg · kg−1 · day−1). Wild-type mice were further randomized to receive the selective ACE2 inhibitor MLN-4760 (10 mg · kg−1 · day−1) and followed for an additional 5 weeks. Markers of renal function and injury were then assessed. RESULTS— Induction of diabetes in wild-type mice was associated with a reduction in renal ACE2 expression and decreased Ang 1–7. In diabetic mice receiving MLN-4760 and in ACE2 KO mice, diabetes-associated albuminuria was enhanced, associated with an increase in blood pressure. However, renal hypertrophy and fibrogenesis were reduced in diabetic mice with ACE2 deficiency, and hyperfiltration was attenuated. Diabetic wild-type mice treated with an ACE inhibitor experienced a reduction in albuminuria and blood pressure. These responses were attenuated in both diabetic ACE2 KO mice and diabetic mice receiving MLN-4760. However, other renoprotective and antifibrotic actions of ACE inhibition in diabetes were preserved in ACE2-deficient mice. CONCLUSIONS— The expression of ACE2 is significantly modified by diabetes, which impacts both pathogenesis of kidney disease and responsiveness to RAS blockade. These data indicate that ACE2 is a complex and site-specific modulator of diabetic kidney disease.
Publisher: American Diabetes Association
Date: 02-06-2010
DOI: 10.2337/DC10-0324
Abstract: We prospectively examined the relationship between lung function and risk of type-2 diabetes and fatal and nonfatal coronary heart disease (CHD) events and investigated the hypothesis that inflammation may underlie these associations. A prospective study of 4,434 men aged 40–59 years with no history of cardiovascular disease (CHD or stroke) or diabetes drawn from general practices in 24 British towns and followed up for 20 years. There were 680 major CHD events (276 fatal, 404 nonfatal) and 256 incident type 2 diabetes during the 20 years follow-up. Forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) but not FEV1-to-FVC ratio were significantly and inversely associated with incident type 2 diabetes and fatal CHD events (not nonfatal events) after adjustment for age, potential confounders, and metabolic risk factors. The adjusted relative risk (RR) for type 2 diabetes (Quartile 1 vs. Quartile 4) were 1.59 (1.07–2.56) and 1.74 (1.16–2.61) for FVC and FEV1, respectively (P = 0.03 and P = 0.04 for trend). The corresponding RR for fatal CHD were 1.48 (1.00–2.21) and 1.81 (1.19–2.76) (P = 0.002 and P = 0.0003 for trend). Lung function was significantly and inversely associated with C-reactive protein and interleukin-6 the inverse associations with type 2 diabetes for FVC and FEV1 were attenuated after further adjustment for these factors (P = 0.14 and P = 0.11 for trend) but remained significant for fatal CHD (P = 0.03 and P = 0.01, respectively). Restrictive rather than obstructive impairment of lung function is associated with incident type 2 diabetes (and fatal CHD) with both associations partially explained by traditional and metabolic risk factors and inflammation.
Publisher: Elsevier BV
Date: 08-2010
DOI: 10.1038/KI.2010.134
Abstract: The accumulation of advanced glycation end products is thought to be a key factor in the initiation and progression of diabetic nephropathy. Here we determined whether the size of the ligands for the receptor for advanced glycation end products (RAGEs) that were present in the serum of patients with type 2 diabetes modulates their pathogenic potential. Serum was collected from control subjects and patients with type 2 diabetes with varying degrees of renal disease (normo-, micro-, or macroalbuminuria). The titers of the RAGE ligands N-carboxymethyllysine (CML), S100A, S100B, and high-mobility group box 1 (HMGB1) were measured by enzyme-linked immunosorbent assay in serum as well as in pooled size-fractionated serum. We also measured cellular binding of serum fractions to mesangial cells transfected with RAGE and examined the downstream signaling pathways. Circulating CML was increased in patients with type 2 diabetes, whereas HMGB1 was decreased. S100A8, S100BA9, and soluble RAGE were unchanged. The high-molecular-weight (over 50 kDa) serum fraction contained the greatest proportion of RAGE ligands, with all immunoreactivity and cellular binding observed only with serum fractions over 30 kDa. High-molecular-weight serum from macroalbuminuric patients showed greater RAGE binding capacity, modulation of cell-surface RAGE expression, increased phospho-protein kinase C-alpha, and p65 nuclear factor kappaB DNA-binding activity, which were competitively inhibited by soluble RAGE or CML neutralizing antibodies. These data show that ligands that activate RAGE present in the circulation of patients with type 2 diabetes and nephropathy are predominantly of high molecular weight.
Publisher: SAGE Publications
Date: 2019
Abstract: The intestinal vitamin D receptor (VDR) remains poorly characterized in patients with inflammatory bowel disease (IBD). Colonoscopic biopsies and intestinal resection specimens from the terminal ileum, ascending and sigmoid colon, from patients with and without IBD, were analyzed for VDR mRNA quantification by polymerase chain reaction, and protein localization and semi-quantification by immunohistochemistry. The relationship between VDR and intestinal inflammation, serum 25(OH)D and oral vitamin D intake was elicited. A total of 725 biopsies from 20 patients with Crohn’s disease (CD), 15 with ulcerative colitis (UC) and 14 non-IBD controls who underwent colonoscopy were studied. VDR gene expression and protein staining intensity was similar across all three groups, and across the intestinal segments. Sigmoid colon VDR mRNA expression inversely correlated with faecal calprotectin ( r = −0.64, p = 0.026) and histological score ( r = −0.67, p = 0.006) in UC, and histological score ( r = −0.58, p = 0.019) in patients with CD. VDR staining intensity was higher in quiescent than diseased segments. No relationship with serum 25(OH)D or oral vitamin D intake was noted. Immunohistochemical staining of 28 intestinal resection specimens from 15 patients (5 each with CD, UC and non-IBD controls) showed diffuse VDR staining in the mucosa, submucosa and circular muscle. VDR transcript expression and protein staining intensity are inversely related to inflammation in IBD, but unrelated to serum 25(OH)D, and similar to non-IBD controls. Strategies to upregulate intestinal VDR, potentially translating to modulation of disease activity, require investigation.
Publisher: The Endocrine Society
Date: 05-2008
DOI: 10.1210/JC.2007-2177
Abstract: Context: Low testosterone levels are common in men with type 2 diabetes and may be associated with insulin resistance. Objective: We investigated prevalence of testosterone deficiency and the relationship between testosterone and insulin resistance in a large cohort of men with type 2 and type 1 diabetes. Design: The study was a cross-sectional survey of 580 men with type 2 diabetes and 69 men with type 1 diabetes. A subgroup of 262 men with type 2 diabetes was then reassessed after a median of 6 months. Results: Forty-three percent of men with type 2 diabetes had a reduced total testosterone, and 57% had a reduced calculated free testosterone. Only 7% of men with type 1 diabetes had low total testosterone. By contrast, 20.3% of men with type 1 diabetes had low calculated free testosterone, similar to that observed in type 2 diabetes (age-body mass index adjusted odds ratio = 1.4 95% confidence interval = 0.7–2.9). Low testosterone levels were independently associated with insulin resistance in men with type 1 diabetes as well as type 2 diabetes. Serial measurements also revealed an inverse relationship between changes in testosterone levels and insulin resistance. Conclusions: Testosterone deficiency is common in men with diabetes, regardless of the type. Testosterone levels are partly influenced by insulin resistance, which may represent an important avenue for intervention, whereas the utility of testosterone replacement remains to be established in prospective trials.
Publisher: Wiley
Date: 04-2006
Publisher: Elsevier BV
Date: 07-2006
Abstract: The abnormal development of the intrarenal renin-angiotensin system (RAS) is thought contribute to adult-onset hypertension in the spontaneously hypertensive rat (SHR). Angiotensin-converting enzyme 2 (ACE2) is a novel enzyme with complementary actions to that of ACE. Recent studies have shown that ACE2 expression is reduced in the adult SHR. However, its regulation in pre-hypertensive animals is unknown. In this study, we examine the developmental expression of ACE2 in the rodent kidney and its temporal expression, as it relates to the development of hypertension in the SHR model. Kidneys from SHR and normotensive Wistar Kyoto (WKY) rats (n=8-12/group) at birth, 6 weeks of age, and adulthood (80 days) were examined. Gene expression and activity of ACE2 were determined by real-time reverse transcription-polymerase chain reaction and quenched fluorescence assays, respectively. Renal expression was localized by in situ hybridization and immunohistochemistry. The expression and ACE2 activity are significantly increased in the SHR kidney at birth. With the onset of hypertension, the tubular expression of ACE2 falls in SHR compared to WKY and remains reduced in the adult SHR kidney. Glomerular expression is paradoxically increased in the SHR glomerulus. The overall developmental pattern of ACE2 expression in the SHR kidney is also modified, with declining expression over the course of renal development. The developmental pattern of ACE2 expression in the SHR kidney is altered before the onset of hypertension, consistent with the key role of the RAS in the pathogenesis of adult-onset hypertension. Further research is required to distinguish the contribution of these changes to the development and progression of hypertension in this model.
Publisher: Springer Science and Business Media LLC
Date: 08-08-2016
Publisher: Springer Science and Business Media LLC
Date: 05-05-2020
Publisher: Elsevier BV
Date: 12-2005
DOI: 10.1111/J.1523-1755.2005.00746.X
Abstract: Advanced glycation end products (AGEs) accumulate in patients with diabetes, particularly at sites of vascular damage and within atherosclerotic lesions, but whether they have direct actions on vascular smooth muscle cells (VSMCs) is controversial. AGEs were constructed and characterized by protein content, level of modification, fluorescence, and molecular size. Human VSMCs were derived from different vascular beds. Glucose consumption, de novo protein synthesis, and proteoglycan biosynthesis were measured using a colorimetric assay and metabolic radiolabeling. Receptor for AGEs (RAGE) expression was assessed by real-time reverse transcription-polymerase chain reaction (RT-PCR) and Western blot. Treatment with AGEs under low or high glucose conditions showed no change in cellular glucose consumption or in cellular protein synthesis under low glucose conditions. Treatment of VSMCs with Nepsilon-(carboxymethyl)lysine in the presence of low glucose increased [35S]-sulfate incorporation into secreted proteoglycans by 72% (P < 0.001) and 67% (P < 0.001) however, the control proteins also increased [35S]-sulfate incorporation into proteoglycans by 56% (P < 0.01), with similar effects observed under high glucose conditions. Human VSMCs showed no difference in response to glycated and non-glycated protein. Protein and gene expression of RAGE in VSMC was approximately 50-fold lower compared to HMEC-1 and U937 cells, consistent with the immunohistochemical staining of RAGE in vivo. VSMCs show very low levels of RAGE expression thus, activation of VSMCs by AGEs does not occur. In diabetes, RAGE expression in VSM may increase to the extent that it becomes activated by AGEs in a manner that would contribute to the process of atherosclerosis.
Publisher: SAGE Publications
Date: 06-2014
Abstract: Diabetes mellitus was originally conceived as a renal disorder. In the last decade, however, there has been renewed interest in role of the kidney in the development and maintenance of high glucose levels. This has led to the development of novel agents to inhibit sodium glucose transporter-2 (SGLT 2 ) as a means to better control glucose levels and at the same time augment calorie wasting and lower insulin, blood pressure and uric acid levels. Such actions, indirectly, may also have benefits for the prevention of diabetic complications including renal disease. However, there are also data to support the potential for direct renoprotective actions arising from inhibition of SGLT 2 , including actions to attenuate diabetes-associated hyperfiltration and tubular hypertrophy, as well as reduce the tubular toxicity of glucose. Some studies have demonstrated significant reductions in albumin excretion in various experimental models, independent of its effects on blood pressure or glucose control. Although promising, such actions remain to be established by comprehensive clinical trials with a renal focus, many of which are currently in progress. This article reviews the clinical and experimental data pertaining to the renal effects of SGLT 2 inhibition with a particular focus on dapaglifozin.
Publisher: Springer Science and Business Media LLC
Date: 10-02-2012
DOI: 10.1007/S00125-012-2485-5
Abstract: Hyperfiltration is widely regarded as a contributing factor to the development of microalbuminuria and progressive nephropathy in type 1 diabetes. However, recent studies have questioned this conclusion. To address this conflicting evidence, we examined the association between hyperfiltration and progression to microalbuminuria in 2,318 adults with type 1 diabetes. We also compared the estimated GFR in our diabetic patients with rates observed in 6,247 adults from the Finnish general population, using age- and sex-specific z scores. The distribution of estimated GFR in adults with type 1 diabetes and normoalbuminuria was not significantly different from that expected in the general population (p = 0.51, Mann-Whitney test). Type 1 diabetic patients with a higher estimated GFR were also no more likely to develop microalbuminuria over a median of 5.2 years of follow-up than those with normal estimated GFR. This was the case regardless of whether hyperfiltration was defined by an absolute threshold, deciles of estimated GFR or a z score, using creatinine- or cystatin-based clearance formulas in men or in women. Together with other studies, these data suggest that creatinine- or cystatin-based estimates of GFR do not predict the development of microalbuminuria in patients with type 1 diabetes. Moreover, in the absence of incipient or overt nephropathy, conventionally determined renal function in patients with type 1 diabetes appears no different from that in the general population. This is hardly surprising, given that these in iduals, by all definitions, do not have kidney disease.
Publisher: OMICS Publishing Group
Date: 03-2013
DOI: 10.2217/DMT.13.3
Publisher: Wiley
Date: 04-2006
Publisher: Elsevier BV
Date: 07-2011
DOI: 10.1038/KI.2011.57
Abstract: Obesity is highly prevalent in Western populations and is considered a risk factor for the development of renal impairment. Interventions that reduce the tissue burden of advanced glycation end-products (AGEs) have shown promise in stemming the progression of chronic disease. Here we tested if treatments that lower tissue AGE burden in patients and mice would improve obesity-related renal dysfunction. Overweight and obese in iduals (body mass index (BMI) 26-39 kg/m(2)) were recruited to a randomized, crossover clinical trial involving 2 weeks each on a low- and a high-AGE-containing diet. Renal function and an inflammatory profile (monocyte chemoattractant protein-1 (MCP-1) and macrophage migration inhibitory factor (MIF)) were improved following the low-AGE diet. Mechanisms of advanced glycation-related renal damage were investigated in a mouse model of obesity using the AGE-lowering pharmaceutical, alagebrium, and mice in which the receptor for AGE (RAGE) was deleted. Obesity, resulting from a diet high in both fat and AGE, caused renal impairment however, treatment of the RAGE knockout mice with alagebrium improved urinary albumin excretion, creatinine clearance, the inflammatory profile, and renal oxidative stress. Alagebrium treatment, however, resulted in decreased weight gain and improved glycemic control compared with wild-type mice on a high-fat Western diet. Thus, targeted reduction of the advanced glycation pathway improved renal function in obesity.
Publisher: Wiley
Date: 21-06-2004
Publisher: Elsevier BV
Date: 06-2003
DOI: 10.1046/J.1523-1755.2003.00006.X
Abstract: The renal clearance of organic cations is important for the homeostasis of a number of exogenous and endogenous compounds. The organic cation transporters (OCTs) situated on the basolateral surface of proximal tubular cells mediate active cation excretion. Alterations of cation transport may occur in diabetes, although the role of the OCTs has not been previously assessed. Experimental diabetes was induced in rats with streptozotocin (55 mg/kg) and animals were randomly assigned to receive ramipril (3 mg/mL) in drinking water for 24 weeks. In a second protocol, rats were infused with angiotensin II (Ang II) at a dose of 58.3 ng/kg/min for 2 weeks via an implanted osmotic pump. Expression of the OCTs and renal clearance of the endogenous cation N-methyl-nicotinamide (NMN) was assessed. Diabetes was associated with a reduction in gene and protein expression of both OCT-1 and OCT-2 and a reduction in NMN clearance. These effects were prevented by ramipril, associated with the prevention of albuminuria and tubular injury as demonstrated by the expression of osteopontin and glutathione peroxidase 3 (GPX-3). An infusion of Ang II also reduced NMN clearance but without altering the renal expression of OCTs. We hypothesize that reduced expression of OCTs in diabetes may be a marker of tubular injury. However, Ang II may also directly augment renal cation clearance independent of changes in transporter expression. Together these effects may provide additional mechanism to explain treatment-related improvements in creatinine clearance and renoprotection in diabetes following blockade of the renin-angiotensin system (RAS).
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2006
Publisher: Elsevier BV
Date: 07-2021
DOI: 10.1053/J.ACKD.2021.07.001
Abstract: The pathobiology of diabetic kidney disease (DKD) involves an interplay between all the many different cell types that exist within the kidney and their shared and cumulative dysfunction in response to chronic hyperglycemia. DKD is characteriszed by morphological changes including tubular hypertrophy, podocyte dysfunction, mesangial expansion and mesangiolysis, endothelitis and capillary rarefaction, arteriolar hyalinosis, basement membrane thickening, and ultimately nephron dropout and tubulointerstitial fibrosis. These adaptive but ultimately maladaptive changes accelerate the progression of lesions in the diabetic kidney by increasing mechanical and oxidative stress, hypoxia, fibrogenesis, inflammation, senescence, and apoptosis. In particular, atrophy at the critical junction between Bowman's capsule and the proximal tubule likely represent the leading cause of nephron dropout and kidney function decline in DKD. Preventing, slowing, or reversing these changes should be the target of future "smart" therapies for patients with DKD, many of which are now under development.
Publisher: American Diabetes Association
Date: 07-08-2015
DOI: 10.2337/DC15-0925
Abstract: This study explored whether activation of the receptor for advanced glycation end products (RAGE) is implicated in the development of diabetes complications. A case-cohort study was performed in 3,763 participants with prevalent diabetes in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial. The hazard ratios (HRs) for death, major cardiovascular events, and new or worsening nephropathy were derived using Cox regression models, and the ability of sRAGE and AGE levels to reclassify the risk of nephropathy was assessed. After adjustment for a range of possible confounders and other risk factors, sRAGE levels were associated with all-cause mortality (HR 1.11 for a 1-SD increase of log sRAGE [95% CI 1.00–1.22] P = 0.045) and new or worsening nephropathy (HR 1.20 for a 1-SD increase of log sRAGE [95% CI 1.02–1.41] P = 0.032). Circulating AGE levels were also independently associated with new or worsening nephropathy (HR 1.21 for a 1-SD increase [95% CI 1.08–1.36] P = 0.001). Both markers also significantly improved the accuracy with which the 5-year risk of new or worsening nephropathy could be predicted (net reclassification index in continuous model, 0.25 for sRAGE and 0.24 for AGE levels). In adults with type 2 diabetes, increased levels of sRAGE are independently associated with new or worsening kidney disease and mortality over the next 5 years. Higher levels of AGE are also associated with an increased risk of adverse renal outcomes. The AGE/RAGE axis may be of importance in the prevention and management of diabetes complications.
Publisher: American Diabetes Association
Date: 13-04-2018
DOI: 10.2337/DBI18-0010
Abstract: Cardiovascular disease, despite all the recent advances in treatment of the various risk factors, remains the major cause of mortality in both type 1 and type 2 diabetes. Experimental models of diabetes-associated atherosclerosis, despite their limitations in recapitulating the human context, have assisted in the elucidation of molecular and cellular pathways implicated in the development and progression of macrovascular injury in diabetes. Our own studies have emphasized the role of oxidative stress and advanced glycation and identified potential targets for vasoprotective therapies in the setting of diabetes. Furthermore, it has been clearly shown that previous episodes of hyperglycemia play a key role in promoting end-organ injury in diabetes, as shown in clinical trials such as the UK Prospective Diabetes Study (UKPDS), Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation Observational Study (ADVANCE-ON), and the Diabetes Control and Complications Trial/ Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC). The cause of this phenomenon, known as metabolic memory, remains to be elucidated, but it appears that epigenetic pathways, including glucose-induced histone methylation, play a central role. Further delineation of these pathways and their link to not only glucose but also other factors implicated in vascular injury should lead to more rational, potentially more effective therapies to retard diabetes-associated cardiovascular disease.
Publisher: American Diabetes Association
Date: 08-03-2014
DOI: 10.2337/DC13-1947
Publisher: Elsevier BV
Date: 09-1994
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-07-2018
Abstract: 8‐Oxo‐2′‐deoxyguanosine (8‐oxo‐2′‐ dG ) is a biomarker of oxidative DNA damage that is associated with cardiovascular disease and premature mortality in the general population. Although oxidative stress has a proven role in cardiovascular complications in diabetes mellitus, evidence for a relationship between plasma 8‐oxo‐2′‐ dG and major cardiovascular outcomes in diabetes mellitus is weak. A case‐cohort study was performed in 3766 participants with prevalent diabetes mellitus in the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) trial ( ClinicalTrials.gov number NCT 00145925). The hazard ratios for mortality and major acute cardiovascular events were derived using Cox regression models. During a median of 5 years of follow‐up, 695 (18.4%) participants in this enriched cohort died (including 354 deaths from cardiovascular disease). In iduals with higher levels of 8‐oxo‐2′‐ dG were more likely to die. After adjusting for cardiovascular disease risk factors, the hazard ratio for a 1‐SD increase in plasma 8‐oxo‐2′‐ dG was 1.10 (95% confidence interval, 1.01–1.20 P =0.03). This was driven by an independent association between plasma 8‐oxo‐2′‐ dG and cardiovascular death (hazard ratio, 1.23 95% confidence interval, 1.10–1.37 [ P .001]). By contrast, no association was seen between 8‐oxo‐2′‐ dG and noncardiovascular disease death (of which cancer was the major single cause). 8‐Oxo‐2′‐ dG was also not significantly associated with either nonfatal myocardial infarction or nonfatal stroke. In adults with type 2 diabetes mellitus, increased levels of 8‐oxo‐2′‐ dG are independently associated with all‐cause mortality and cardiovascular mortality in adults with longstanding type 2 diabetes mellitus who participated in the ADVANCE trial, consistent with the role of oxidative damage in the development and progression of cardiovascular decompensation in diabetes mellitus. URL : www.clinicaltrials.gov . Unique identifier: NCT 00145925.
Publisher: Wiley
Date: 04-2006
Publisher: American Physiological Society
Date: 06-2010
DOI: 10.1152/AJPRENAL.00049.2010
Abstract: The extent to which a reduced nephron endowment contributes to hypertension and renal disease is confounded in models created by intrauterine insults that also demonstrate other phenotypes. Furthermore, recent data suggest that a reduced nephron endowment provides the “first hit” and simply increases the susceptibility to injurious stimuli. Thus we examined nephron number, glomerular volume, conscious mean arterial pressure (MAP), and renal function in a genetic model of reduced nephron endowment before and after a high-salt (5%) diet. One-yr-old glial cell line-derived neurotrophic factor wild-type (WT) mice, heterozygous (HET) mice born with two kidneys (HET2K), and HET mice born with one kidney (HET1K) were used. Nephron number was 25% lower in HET2K and 65% lower in HET1K than WT mice. Glomeruli hypertrophied in both HET groups by 33%, resulting in total glomerular volumes that were similar between HET2K and WT mice but remained 50% lower in HET1K mice. On a normal-salt diet, 24-h MAP was not different between WT, HET2K, and HET1K mice (102 ± 1, 103 ± 1, and 102 ± 2 mmHg). On a high-salt diet, MAP increased 9.1 ± 1.9 mmHg in HET1K mice ( P 0.05) and 5.4 ± 0.9 mmHg in HET2K mice ( P 0.05) and did not change significantly in WT mice. Creatinine clearance was 60% higher in WT mice but 30% lower in HET2K and HET1K mice fed a high-salt diet than in controls maintained on a normal-salt diet. Thus a reduction in nephron number (or total glomerular volume) alone does not lead to hypertension or kidney disease in aged mice, but exposure to high salt uncovers a hypertensive and renal phenotype.
Publisher: Elsevier BV
Date: 08-2014
DOI: 10.1016/J.ATHEROSCLEROSIS.2014.05.945
Abstract: Both the renin-angiotensin system (RAS) and the receptor for advanced glycation end products (RAGE) potentiate diabetes-associated atherosclerosis (DAA). We assessed the effectiveness of concomitant RAS and RAGE inhibition on DAA. Diabetic (5 × 55 mg/kg streptozotocin daily) and non-diabetic male RAGE/apolipoprotein E double knockout (RAGE/apoE DKO) mice were treated with quinapril (30 mg/kg/day) for 20 weeks. At the end of the study aortic plaques were assessed. Diabetic RAGE/apoE DKO showed significantly less plaque area than diabetic apoE KO mice. Plaque deposition was almost abolished in quinapril treated diabetic RAGE/apoE DKOs, with significant attenuation of vascular collagen deposition, nitrotyrosine staining, and reduced macrophage infiltration. Expression of the advanced glycation end product receptor 3 (galectin 3) was also significantly reduced. Concomitant inhibition of RAS and RAGE signalling almost completely inhibited the development of experimental DAA. A dual therapeutic approach may be a superior strategy for the treatment of diabetic macrovascular disease..
Publisher: Wiley
Date: 04-2006
Publisher: American Chemical Society (ACS)
Date: 14-12-2006
DOI: 10.1021/JA056797H
Abstract: Ozonolysis of double bonds is observed during the negative ion electrospray ionization of unsaturated phospholipids under conditions that produce a corona discharge. Ionic products of the ozonolysis are detected and characterized by mass spectrometry, and the mass-to-charge ratio of these species can be used to unambiguously assign the double bond position within the unsaturated fatty acid radyls. The reaction products are consistent with the gas-phase ozonolysis of desolvated phospholipid ions in an atmosphere rich in volatilized solvent. Reactions may be carried out in a conventional electrospray ionization mass spectrometer and provide a new method for the structural characterization of phospholipids.
Publisher: Bentham Science Publishers Ltd.
Date: 15-07-2016
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2004
Publisher: Informa UK Limited
Date: 2004
DOI: 10.1080/02713680490517944
Abstract: An active renin-angiotensin system has been found in the retina of rats and humans. Angiotensin-converting enzyme 2 (ACE2) is a recently discovered enzymatic homologue of Angiotensin-converting enzyme (ACE) that may be an important new component of the renin-angiotensin system (RAS). This study assesses the involvement of ACE2 in the normal and diabetic rodent retina and its modulation by ACE inhibition. Sprague-Dawley rats were randomised into three groups, control, diabetes, and diabetes plus ramipril, with diabetes induced with the cell toxin streptozocin and the study run for 24 weeks. ACE2 and ACE gene levels were measured using quantitative real-time polymerase chain reaction (QRT-PCR), ACE2 protein expression was confirmed by Western blotting, and ACE and ACE2 catalytic activity were measured using specific activity assays in the rat retina. Localisation of ACE2 mRNA and protein were determined by in situ hybridisation and immunohistochemistry, respectively. ACE mRNA levels were decreased to approximately 50% in the diabetic retina, but ACE2 mRNA levels were not significantly changed. ACE but not ACE2 gene expression was influenced by ramipril treatment. Following immunostaining, both ACE2 and ACE protein were localised predominantly to the inner nuclear layer (INL) but also to photoreceptors. In the diabetic retina, ACE enzyme activity was decreased, whereas ACE2 enzyme activity was increased. This study has identified ACE2 gene and catalytically active protein in the rodent retina. In diabetes, the major changes were a decrease in ACE but an increase in ACE2 enzymatic activity. The ACE inhibitor ramipril did not reduce ACE2 enzymatic activity.
Publisher: Elsevier BV
Date: 03-2011
DOI: 10.1016/J.BIOTECHADV.2011.07.015
Abstract: The complex and erse nature of the post-translational modification (PTM) of proteins represents an efficient and cost-effective mechanism for the exponential ersification of the genome. PTMs have been shown to affect almost every aspect of protein activity, including function, localisation, stability, and dynamic interactions with other molecules. Although many PTMs are evolutionarily conserved there are also important kingdom-specific modifications which should be considered when expressing recombinant proteins. Plants are gaining increasing acceptance as an expression system for recombinant proteins, particularly where eukaryotic-like PTMs are required. Glycosylation is the most extensively studied PTM of plant-made recombinant proteins. However, other types of protein processing and modification also occur which are important for the production of high quality recombinant protein, such as hydroxylation and lipidation. Plant and/or protein engineering approaches offer many opportunities to exploit PTM pathways allowing the molecular farmer to produce a humanised product with modifications functionally similar or identical to the native protein. Indeed, plants have demonstrated a high degree of tolerance to changes in PTM pathways allowing recombinant proteins to be modified in a specific and controlled manner, frequently resulting in a homogeneity of product which is currently unrivalled by alternative expression platforms. Whether a recombinant protein is intended for use as a scientific reagent, a cosmetic additive or as a pharmaceutical, PTMs through their presence and complexity, offer an extensive range of options for the rational design of humanised (biosimilar), enhanced (biobetter) or novel products.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2012
Publisher: Wiley
Date: 20-04-2006
DOI: 10.1111/J.1464-5491.2006.01829.X
Abstract: Anaemia is a common finding in patients with diabetic nephropathy. Impaired production of erythropoietin is thought to be the predominant cause, as a result of renal microvascular disease. This study aims to determine the prevalence of functional erythropoietin deficiency in a cross-sectional survey of patients with Type 2 diabetes. Clinical data on 604 patients with Type 2 diabetes were obtained, including a full blood count, iron indices and detailed history of diabetic complications. Erythropoietin levels were correlated with the presence of anaemia, iron deficiency and renal dysfunction. Functional erythropoietin deficiency was defined by erythropoietin levels in the normal range despite the presence of anaemia. Nineteen per cent of patients (n = 112) were anaemic, among whom erythropoietin deficiency (76%) and reduced iron availability (58%) were common findings. Over 90% of patients had erythropoietin deficiency, once those with reduced iron stores or availability were excluded. Most of these patients had moderate renal impairment (60%, n = 67). However, even in the absence of renal impairment, 71% of anaemic patients (n = 32/45) had functional erythropoietin deficiency, although most had other evidence of nephropathy. In addition, two-thirds of patients with reduced iron availability were unable to increase erythropoietin above the normal range. These findings confirm the failure of the kidney to produce erythropoietin in response to a falling haemoglobin is a key component to anaemia in diabetes. The likelihood of functional erythropoietin deficiency as a cause of anaemia is not dependent on the severity of renal impairment or excluded in diabetic patients with reduced iron stores or availability.
Publisher: AMPCo
Date: 09-2006
Publisher: Oxford University Press (OUP)
Date: 17-01-2005
DOI: 10.1093/QJMED/HCI017
Abstract: Retinopathy is the clinical hallmark of generalized microangiopathy in diabetes. To examine the relation of this abnormality to end-stage renal disease (ESRD) and death in type 2 diabetes. Retrospective analysis. Of 1513 type 2 diabetic patients with nephropathy participating in the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study, 1456 (96.5%) were assessed at baseline by ophthalmoscopy or fundus photography. RENAAL was a multinational double masked, randomized, placebo-controlled intervention study, whose primary end-point was the composite of a doubling of the baseline serum creatinine concentration, end-stage renal disease (ESRD) or death. Of those assessed at baseline, 65% had diabetic retinopathy. Patients with retinopathy had higher systolic blood pressure, albuminuria and lower glomerular filtration rate (GFR), haemoglobin and serum albumin values than those without. In univariate analyses, the presence of retinopathy was associated with a 44% increase in the primary composite end-point (hazard ratio 1.44, 95%CI 1.22-1.70, p < 0.001). Patients with retinopathy had a 52% increase in doubling of serum creatinine (p < 0.001), a 47% increased risk of ESRD (p = 0.002) and a 33% increase in risk of death (p = 0.026) compared to those without. In multivariate analyses, the presence of retinopathy was associated with a 23% increase (p = 0.015) in the primary composite end-point and a 22% increase in ESRD or death (p = 0.038). The presence of diabetic retinopathy at baseline is associated with more proteinuria, lower GFR, and a higher risk for ESRD and death in type 2 diabetic patients.
Publisher: Elsevier BV
Date: 02-2002
Abstract: Hypothyroidism is common in the renal failure population and is both influenced by the onset of renal failure and its correction with renal transplantation. We report a series of 20 consecutive patients on oral thyroxine, in which restoration of renal function following transplantation resulted in reduced thyroxine requirements. We speculate that iodide excess, reduced bioavailability, and drug interactions may have contributed both to their hypothyroidism and the increased requirements for thyroxine in these patients while on dialysis. Failure to recognize the changes following renal transplantation may result in significant morbidity.
Publisher: Oxford University Press (OUP)
Date: 08-1999
Publisher: Informa UK Limited
Date: 18-01-2021
DOI: 10.1080/07391102.2021.1873186
Abstract: Glyoxalase I (GLO1) is a dimeric esterase of the glyoxalase system. Phosphorylation of the residue T106 has been found to inhibit GLO1 activity, and contribute to the onset of oxidative stress and cellular damage. This research uses multiple molecular dynamics simulations and automated docking of both GLO1 and dimerically phosphorylated GLO1 (p2-GLO1) to predict the initial structural differences induced by phosphorylation, and their interaction with the intermediate substrate Hemimercaptal. This research indicates that immediately following phosphorylation, GLO1 exhibits reduced sphericity, partly caused by outward splaying of the loop region surrounding T106. Phosphorylation induces enhanced concerted motions in the loop composed of residues immediately surrounding T106, which are correlated with motions at the active site pocket at the distant, opposite end of the dimer. These T106 region loop motions result in the distortion of the shape of the active site, and potentially alter its accessibility. Phosphorylation alters the manner in which GLO1 interacts with Hemimercaptal. For GLO1, Hemimercaptal is predicted to bind to T106, which we propose constitutes a novel, highly accessible 'capture site' responsible for initial contact with the substrate. In contrast, for p2-GLO1, Hemimercaptal is unable to bind favourably to (phosphorylated) position T106, suggesting that this proposed transient 'capture site' is abolished upon phosphorylation of GLO1. Hence, a novel physiological role is here proposed for the known essential GLO1 residue T106. These results may further contribute to understanding the inhibition mechanism of GLO1 upon phosphorylation.Communicated by Ramaswamy H. Sarma.
Publisher: Wiley
Date: 18-07-2003
Publisher: The Endocrine Society
Date: 14-09-2019
Abstract: The long-term natural history of diabetic ketoacidosis (DKA) and its risk factors are poorly understood. To determine the long-term incidence and predictors of DKA in adults with longstanding type 1 diabetes (T1D). All hospitalizations and deaths due to DKA between 1996 and 2016 were identified in 4758 adults with T1D from the Finnish Diabetic Nephropathy Study (FinnDiane), and a cohort of 16 224 adults with T1D from the Finnish general population. Between 1996 and 2015, there were 1228 DKA events in the FinnDiane participants (1.4/100 person-years) and 4914 DKA events (1.8/100 person-years) in adults with T1D from the general population. The majority were hospitalized only once. There was a modest increase in the frequency of DKA in the FinnDiane over the follow-up (~2.4%/year [95% CI, 0.3–4.5%] P = 0.03). Predictors of DKA were glucose control, CSII, smoking and alcohol consumption, and raised high-density lipoprotein cholesterol and triacylglycerides. Diabetic nephropathy and renal impairment were associated with DKA patients with end-stage renal disease, macroalbuminuria, and microalbuminuria had 2.09-fol (95% CI, 1.40–3.12), 1.65-fold (95% CI, 1.23–2.19), and 0.87-fold (95% CI, 0.61–1.24) risk of DKA compared with patients with normal albumin excretion rate, respectively. Patients with an estimated glomerular filtration rate & mL/min/1.73 m2 were also more likely to be hospitalized for DKA (HR 1.71 [95% CI, 1.26–2.67]). DKA remains a common cause of hospitalization in in iduals with longstanding T1D. These data suggest that the goal to use SGLT2 inhibitors for their vasculo- and renoprotective actions may be problematic, as those most likely to benefit may also have the highest risk for DKA.
Start Date: 2009
End Date: 2011
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2016
End Date: 2020
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2013
End Date: 2015
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2006
End Date: 2008
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2009
End Date: 2011
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2013
End Date: 2013
Funder: National Heart Foundation of Australia
View Funded ActivityStart Date: 2016
End Date: 2021
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2008
End Date: 2009
Funder: Juvenile Diabetes Research Foundation
View Funded ActivityStart Date: 2013
End Date: 2015
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2010
End Date: 2012
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2014
End Date: 2019
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2016
End Date: 2018
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2008
End Date: 2011
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2012
End Date: 2014
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2015
End Date: 2017
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2017
End Date: 2019
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2006
End Date: 2010
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2001
End Date: 2003
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2010
End Date: 2015
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2016
End Date: 2018
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2015
End Date: 2017
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2010
End Date: 2012
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2020
End Date: 12-2022
Amount: $605,000.00
Funder: Australian Research Council
View Funded Activity