ORCID Profile
0000-0002-5595-8174
Current Organisation
Mater Research Institute The University of Queensland
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Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 22-06-2004
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 21-04-2009
DOI: 10.1161/CIRCULATIONAHA.108.843219
Abstract: Background— Low plasma high-density lipoprotein (HDL) is associated with elevated cardiovascular risk and aspects of the metabolic syndrome. We hypothesized that HDL modulates glucose metabolism via elevation of plasma insulin and through activation of the key metabolic regulatory enzyme, AMP-activated protein kinase, in skeletal muscle. Methods and Results— Thirteen patients with type 2 diabetes mellitus received both intravenous reconstituted HDL (rHDL: 80 mg/kg over 4 hours) and placebo on separate days in a double-blind, placebo-controlled crossover study. A greater fall in plasma glucose from baseline occurred during rHDL than during placebo (at 4 hours rHDL=−2.6±0.4 placebo=−2.1±0.3mmol/L P =0.018). rHDL increased plasma insulin (at 4 hours rHDL=3.4±10.0 placebo= −19.2±7.4 pmol/L P =0.034) and also the homeostasis model assessment β-cell function index (at 4 hours rHDL=18.9±5.9 placebo=8.6±4.4% P =0.025). Acetyl-CoA carboxylase β phosphorylation in skeletal muscle biopsies was increased by 1.7±0.3-fold after rHDL, indicating activation of the AMP-activated protein kinase pathway. Both HDL and apolipoprotein AI increased glucose uptake (by 177±12% and 144±18%, respectively P .05 for both) in primary human skeletal muscle cell cultures established from patients with type 2 diabetes mellitus (n=5). The mechanism is demonstrated to include stimulation of the ATP-binding cassette transporter A1 with subsequent activation of the calcium/calmodulin-dependent protein kinase kinase and the AMP-activated protein kinase pathway. Conclusions— rHDL reduced plasma glucose in patients with type 2 diabetes mellitus by increasing plasma insulin and activating AMP-activated protein kinase in skeletal muscle. These findings suggest a role for HDL-raising therapies beyond atherosclerosis to address type 2 diabetes mellitus.
Publisher: American Physiological Society
Date: 2013
DOI: 10.1152/PHYSREV.00045.2011
Abstract: It is increasingly apparent that not only is a cure for the current worldwide diabetes epidemic required, but also for its major complications, affecting both small and large blood vessels. These complications occur in the majority of in iduals with both type 1 and type 2 diabetes. Among the most prevalent microvascular complications are kidney disease, blindness, and utations, with current therapies only slowing disease progression. Impaired kidney function, exhibited as a reduced glomerular filtration rate, is also a major risk factor for macrovascular complications, such as heart attacks and strokes. There have been a large number of new therapies tested in clinical trials for diabetic complications, with, in general, rather disappointing results. Indeed, it remains to be fully defined as to which pathways in diabetic complications are essentially protective rather than pathological, in terms of their effects on the underlying disease process. Furthermore, seemingly independent pathways are also showing significant interactions with each other to exacerbate pathology. Interestingly, some of these pathways may not only play key roles in complications but also in the development of diabetes per se. This review aims to comprehensively discuss the well validated, as well as putative mechanisms involved in the development of diabetic complications. In addition, new fields of research, which warrant further investigation as potential therapeutic targets of the future, will be highlighted.
Publisher: Springer Science and Business Media LLC
Date: 13-08-2014
Publisher: Oxford University Press (OUP)
Date: 10-04-2012
Abstract: The effects of advanced glycation endproducts on cognition and brain structure are poorly understood. We studied associations of the advanced glycation endproduct precursor methylglyoxal (MGO) with cognitive function and brain volumes in older people. Nondemented participants in the Tasmanian Study of Cognition and Gait underwent cognitive testing and brain magnetic resonance imaging scans. Brain volumes were obtained by magnetic resonance imaging scan segmentation and statistical parametric mapping procedures. Serum MGO was measured after derivatization to methylquinoxaline by high pressure liquid chromatography and UV detection. Linear regression was used to examine associations of log-transformed MGO with cognitive scores and brain volumes adjusting for potential confounding by age, sex, education, mood, insulin resistance, history of stroke, vascular risk factors, alcohol intake, and psychoactive medication use. There were 378 participants, mean age 72.1 years (SD 7.1), 55% male. Greater MGO was associated with poorer memory (β = -.12, 95% confidence interval: -0.22, -0.02, p = .02) and executive function, the latter being greater among those with a history of stroke (MGO × stroke β = .48, 95% confidence interval: 0.17, 0.79, p = .002). Greater MGO was associated with lower grey matter volume (β = -6.42, 95% confidence interval -11.82, -1.11, p = .02) but not with white matter volume, white matter lesion volume, or hippoc al volume. These results support the investigation of the role of the advanced glycation endproduct precursor methylglyoxal in cognitive decline and neurodegeneration in older people.
Publisher: Springer Science and Business Media LLC
Date: 13-04-2011
Publisher: Elsevier BV
Date: 09-2009
DOI: 10.1016/J.JVS.2009.05.058
Abstract: Abdominal aortic aneurysms (AAAs) share common risk factors with atherosclerosis, except for diabetes which appears protective. The reason for this is unknown. Although increased circulating concentrations of advanced glycation endproducts (AGEs) such as carboxymethyllysine (CML) are associated with occlusive vascular disease, it is possible that their effects on the aortic wall explain the paradoxically low incidence of AAAs in diabetes. We studied 234 community-dwelling men aged 65 to 79 years. The cases comprised all identifiable diabetic men with AAA (aortic diameter > or =30 mm on ultrasound n = 27) and randomly-selected non-diabetic men with AAA (n = 67). Controls were age-matched randomly-selected diabetic men (n = 69) and age-matched randomly-selected non-diabetic men (n = 71) without AAA (aortic diameter 18 to 22 mm). Serum CML concentrations were measured by validated indirect enzyme-linked immunosorbent assay (ELISA). Serum CML concentrations were significantly lower in men with AAAs than those without (6627 +/- 1544 vs 7309 +/- 1490 nmol/mol lysine P = .001). Variables positively associated with AAA were height, diastolic blood pressure, smoking, a history of coronary heart disease, and serum creatinine (P < or = .040), while serum CML (odds ratio [95% confidence interval] per 1000 nmol/mol lysine 0.80 [0.64-0.98]) and a history of diabetes were inversely associated (P < or = .040). After adjusting, the interaction between diabetes status and serum CML was negatively associated with AAA (P = .016). These cross-sectional data show that circulating concentrations of CML are reduced in diabetic men with AAAs. This is in contrast to studies of the relationship between AGEs and occlusive manifestations of cardiovascular disease and could explain the inverse association between diabetes and AAA.
Publisher: Elsevier BV
Date: 05-2013
DOI: 10.1016/J.METABOL.2012.10.013
Abstract: Plasma Hepatocyte Growth Factor (HGF) is significantly elevated in obesity and may contribute to vascular disease, metabolic syndrome or cancer in obese in iduals. The current studies were done to determine if hyperinsulinemia increases plasma HGF. Twenty-two participants (10 women/12 men, BMI 20.6-34.5 kg/m(2), age 18-49 years) underwent a hyperinsulinemic euglycemic cl with measurement of HGF at baseline and steady state. Relationships between baseline HGF, anthropometrics, triglycerides, liver enzymes, c-reactive protein and adiponectin were also evaluated. Fasting HGF was positively correlated (P<0.050) with weight (r=0.63), BMI (r=0.55), waist circumference (r=0.68), WHR (r=0.48), triglycerides (r=0.44), alanine aminotransferase (r=0.74) and γ-glutamyl transpeptidase (r=0.56), but not c-reactive protein or adiponectin. In stepwise regression, alanine aminotransferase and insulin sensitivity accounted for significant variation in fasting HGF. A significant effect of insulin to suppress HGF during the cl (P=0.029) was found after adjustment for BMI. HGF was reduced 7% at steady state in the lean subjects only (437.1 ±57.8 vs 405.4±72.0 pg/ml P=0.030). The positive correlation of HGF with hepatic enzymes suggests liver may be a significant source of circulating HGF in lean subjects. The strong correlation of plasma HGF with adiposity and the lack of an effect of insulin to increase HGF during the cl in obese subjects suggest that adiposity, rather than elevated insulin levels, may be the major contributor to plasma HGF in obese subjects. Thus, a reduction in plasma HGF through weight loss is likely the best way to decrease comorbidities mediated by this angiogenic and mitogenic factor.
Publisher: Bentham Science Publishers Ltd.
Date: 06-2006
DOI: 10.2174/092986706777452515
Abstract: Diabetic patients have a two- to four-fold increased risk for the development of microvascular (renal, neuronal and retinal) and macrovascular complications. Unfortunately, these complications may develop in both Type 1 and Type 2 diabetic patients even with careful glycaemic, blood pressure and lipid control. With the worldwide increase in the incidence diabetes, new strategies to prevent the complications are urgently needed. Mediators of vascular damage of diabetes include poor glycemic control, lipoprotein abnormalities, hypertension, oxidative stress, inflammation and advanced glycation end-products (AGEs), which are modified proteins formed by non-enzymatic glycation. AGEs are resistant to enzymatic degradation and therefore very stable, thus their accumulation continues throughout aging. AGE accumulation causes arterial stiffening in the vessel wall, glomerulosclerosis in the kidney, and vascular hyperpermeability in the retina. Through their interaction with their putative receptor the so-called receptor for AGEs (RAGE), AGEs activate endothelial cells and macrophages, generate reactive oxygen species (ROS), induce overexpression of vascular endothelial growth factor (VEGF) and vascular cell adhesion molecule-1 (VCAM-1), and quench nitric oxide (NO). The pharmacological treatment currently available for either Type 1 or Type 2 diabetic patients does not directly address the excess accumulation of AGEs. Novel compounds that inhibit AGE formation, cleave AGE cross-links or reverse their interaction with RAGE are now accessible and could prove useful in meeting this challenge. Other strategies such as inhibition of the hexosamine pathway, vitamin therapy to reduce oxidation and AGE accumulation, reduction of the ROS, or blocking the actions of growth factors or intracellular messengers of cell differentiation are also currently under research. This review will recount recent advances in the development of therapeutic approaches for inhibiting and treating the development of diabetic end-organ damage.
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: MDPI AG
Date: 03-04-2020
Abstract: High stage and recurrent ovarian clear cell carcinoma (OCC) are associated with poor prognosis and resistance to chemotherapy. A distinguishing histological feature of OCC is abundant cytoplasmic stores of glucose, in the form of glycogen, that can be mobilized for cellular metabolism. Here, we report the effect on preclinical models of OCC of disrupting glycogen utilization using the glucose analogue 2-deoxy-D-glucose (2DG). At concentrations significantly lower than previously reported for other cancers, 2DG markedly improves the efficacy in vitro of carboplatin chemotherapy against chemo-sensitive TOV21G and chemo-resistant OVTOKO OCC cell lines, and this is accompanied by the depletion of glycogen. Of note, 2DG doses—of more than 10-fold lower than previously reported for other cancers—significantly improve the efficacy of carboplatin against cell line and patient-derived xenograft models in mice that mimic the chemo-responsiveness of OCC. These findings are encouraging, in that 2DG doses, which are substantially lower than previously reported to cause adverse events in cancer patients, can safely and significantly improve the efficacy of carboplatin against OCC. Our results thus justify clinical trials to evaluate whether low dose 2DG improves the efficacy of carboplatin in OCC patients.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2003
DOI: 10.1161/01.HYP.0000060689.38912.CB
Abstract: ACE2, initially cloned from a human heart, is a recently described homologue of angiotensin-converting enzyme (ACE) but contains only a single enzymatic site that catalyzes the cleavage of angiotensin I to angiotensin 1–9 [Ang(1–9)] and is not inhibited by classic ACE inhibitors. It also converts angiotensin II to Ang(1–7). Although the role of ACE2 in the regulation of the renin-angiotensin system is not known, the renin-angiotensin system has been implicated in the pathogenesis of diabetic complications and in particular in diabetic nephropathy. Therefore, the aim of this study was to assess the possible involvement of this new enzyme in the kidney from diabetic Sprague-Dawley rats to compare and contrast it to ACE. ACE2 and ACE gene and protein expression were measured in the kidney after 24 weeks of streptozocin diabetes. ACE2 and ACE mRNA levels were decreased in diabetic renal tubules by ≈50% and were not influenced by ACE inhibitor treatment with ramipril. By immunostaining, both ACE2 and ACE protein were localized predominantly to renal tubules. In the diabetic kidney, there was reduced ACE2 protein expression that was prevented by ACE inhibitor therapy. The identification of ACE2 in the kidney, its modulation in diabetes, and the recent description that this enzyme plays a biological role in the generation and degradation of various angiotensin peptides provides a rationale to further explore the role of this enzyme in various pathophysiological states including diabetic complications.
Publisher: Springer Science and Business Media LLC
Date: 09-09-2016
DOI: 10.1007/S11892-016-0782-Y
Abstract: The receptor for advanced glycation end products (RAGE) is a novel protein increasingly studied in the pathogenesis of type 1 diabetes (T1D). RAGE is expressed by several immune cell types, including T cells, antigen-presenting cells, endothelial cells, and the endocrine cells of the pancreatic islets. RAGE binds various ligands including advanced glycation end products (AGEs), high-mobility group box protein 1 (HMGB1), S100 proteins, β-amyloid, β-sheet fibrils, and lipopolysaccharide. AGEs are a particularly interesting ligand because their exogenous introduction into the body can be accelerated by the consumption of AGE-rich processed foods. This review will detail RAGE isoforms and its ligands and discuss how RAGE binding on the aforementioned cells could be linked to T1D pathogenesis.
Publisher: Springer Science and Business Media LLC
Date: 19-02-2018
Abstract: Globally, diabetes is the leading cause of chronic kidney disease and end-stage renal disease, which are major risk factors for cardiovascular disease and death. Despite this burden, the factors that precipitate the development and progression of diabetic kidney disease (DKD) remain to be fully elucidated. Mitochondrial dysfunction is associated with kidney disease in nondiabetic contexts, and increasing evidence suggests that dysfunctional renal mitochondria are pathological mediators of DKD. These complex organelles have a broad range of functions, including the generation of ATP. The kidneys are mitochondrially rich, highly metabolic organs that require vast amounts of ATP for their normal function. The delivery of metabolic substrates for ATP production, such as fatty acids and oxygen, is altered by diabetes. Changes in metabolic fuel sources in diabetes to meet ATP demands result in increased oxygen consumption, which contributes to renal hypoxia. Inherited factors including mutations in genes that impact mitochondrial function and/or substrate delivery may also be important risk factors for DKD. Hence, we postulate that the diabetic milieu and inherited factors that underlie abnormalities in mitochondrial function synergistically drive the development and progression of DKD.
Publisher: American Diabetes Association
Date: 02-2008
DOI: 10.2337/DB07-1119
Abstract: OBJECTIVE—Excessive production of reactive oxygen species (ROS) via NADPH oxidase has been implicated in the pathogenesis of diabetic nephropathy. Since NADPH oxidase activation is closely linked to other putative pathways, its interaction with changes in protein kinase C (PKC) and increased advanced glycation was examined. RESEARCH DESIGN AND METHODS—Streptozotocin-induced diabetic or nondiabetic Sprague Dawley rats were followed for 32 weeks, with groups randomized to no treatment or the NADPH oxidase assembly inhibitor apocynin (15 mg · kg−1 · day−1 weeks 16–32). Complementary in vitro studies were performed in which primary rat mesangial cells, in the presence and absence of advanced glycation end products (AGEs)-BSA, were treated with either apocynin or the PKC-α inhibitor Ro-32-0432. RESULTS—Apocynin attenuated diabetes-associated increases in albuminuria and glomerulosclerosis. Circulating, renal cytosolic, and skin collagen–associated AGE levels in diabetic rats were not reduced by apocynin. Diabetes-induced translocation of PKC, specifically PKC-α to renal membranes, was associated with increased NADPH-dependent superoxide production and elevated renal, serum, and urinary vascular endothelial growth factor (VEGF) concentrations. In both diabetic rodents and in AGE-treated mesangial cells, blockade of NADPH oxidase or PKC-α attenuated cytosolic superoxide and PKC activation and increased VEGF. Finally, renal extracellular matrix accumulation of fibronectin and collagen IV was decreased by apocynin. CONCLUSIONS—In the context of these and previous findings by our group, we conclude that activation of NADPH oxidase via phosphorylation of PKC-α is downstream of the AGE–receptor for AGE interaction in diabetic renal disease and may provide a novel therapeutic target for diabetic nephropathy.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2010
Publisher: Springer Science and Business Media LLC
Date: 26-05-2016
DOI: 10.1038/SREP26428
Abstract: Blood glucose control is the primary strategy to prevent complications in diabetes. At the onset of kidney disease, therapies that inhibit components of the renin angiotensin system (RAS) are also indicated, but these approaches are not wholly effective. Here, we show that once daily administration of the novel glucose lowering agent, empagliflozin, an SGLT2 inhibitor which targets the kidney to block glucose reabsorption, has the potential to improve kidney disease in type 2 diabetes. In male db / db mice, a 10-week treatment with empagliflozin attenuated the diabetes-induced upregulation of profibrotic gene markers, fibronectin and transforming-growth-factor-beta. Other molecular (collagen IV and connective tissue growth factor) and histological (tubulointerstitial total collagen and glomerular collagen IV accumulation) benefits were seen upon dual therapy with metformin. Albuminuria, urinary markers of tubule damage (kidney injury molecule-1, KIM-1 and neutrophil gelatinase-associated lipocalin, NGAL), kidney growth, and glomerulosclerosis, however, were not improved with empagliflozin or metformin, and plasma and intra-renal renin activity was enhanced with empagliflozin. In this model, blood glucose lowering with empagliflozin attenuated some molecular and histological markers of fibrosis but, as per treatment with metformin, did not provide complete renoprotection. Further research to refine the treatment regimen in type 2 diabetes and nephropathy is warranted.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2005
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: MDPI AG
Date: 10-08-2022
Abstract: Mitochondrial dysfunction is implicated in the pathogenesis of diabetic kidney disease (DKD). Compared to the vast body of evidence from preclinical in vitro and in vivo studies, evidence from human studies is limited. In a comprehensive search of the published literature, findings from studies that reported evidence of mitochondrial dysfunction in in iduals with DKD were examined. Three electronic databases (PubMed, Embase, and Scopus) were searched in March 2022. A total of 1339 articles were identified, and 22 articles met the inclusion criteria. Compared to non-diabetic controls (NDC) and/or in iduals with diabetes but without kidney disease (DC), in iduals with DKD (age ~55 years diabetes duration ~15 years) had evidence of mitochondrial dysfunction. In iduals with DKD had evidence of disrupted mitochondrial dynamics (11 of 11 articles), uncoupling (2 of 2 articles), oxidative damage (8 of 8 articles), decreased mitochondrial respiratory capacity (1 of 1 article), decreased mtDNA content (5 of 6 articles), and decreased antioxidant capacity (3 of 4 articles) compared to ND and/or DC. Neither diabetes nor glycemic control explained these findings, but rather presence and severity of DKD may better reflect degree of mitochondrial dysfunction in this population. Future clinical studies should include in iduals closer to diagnosis of diabetes to ascertain whether mitochondrial dysfunction is implicated in the development of, or is a consequence of, DKD.
Publisher: Springer Science and Business Media LLC
Date: 04-07-2014
Publisher: American Diabetes Association
Date: 22-07-2015
DOI: 10.2337/DB14-0506
Abstract: Type 2 diabetes mellitus (T2DM) is associated with brain atrophy, but the mechanisms underlying this link are unknown. Advanced glycation end products (AGEs) accumulate in T2DM, resulting in inflammation, oxidative stress, and protein cross-linking, which are known contributors to neurodegeneration. We aimed to study whether tissue AGE accumulation is associated with T2DM-related brain atrophy. We performed brain magnetic resonance imaging, cognitive tests, and noninvasive skin autofluorescence (SAF a measure of tissue AGE levels) on people aged & years with and without T2DM. Multivariable linear regression was used to study the relationships among T2DM, SAF, and gray matter volume (GMV). There were 486 people included in the study. T2DM was associated with greater SAF. Greater SAF, T2DM, and cognitive impairment were each associated with lower GMV independently of age, sex, and total intracranial volume. SAF partially mediated the association between T2DM and GMV. Longitudinal studies may help confirm whether tissue AGE accumulation is associated with brain atrophy in T2DM.
Publisher: CRC Press
Date: 30-10-2017
Publisher: Elsevier BV
Date: 02-2012
DOI: 10.1016/J.FREERADBIOMED.2011.11.017
Abstract: Cardiovascular benefits of ubiquinone have been previously demonstrated, and we administered it as a novel therapy in an experimental model of type 2 diabetic nephropathy. db/db and dbH mice were followed for 10 weeks, after randomization to receive either vehicle or ubiquinone (CoQ10 10mg/kg/day) orally. db/db mice had elevated urinary albumin excretion rates and albumin:creatinine ratio, not seen in db/db CoQ10-treated mice. Renal cortices from db/db mice had lower total and oxidized CoQ10 content, compared with dbH mice. Mitochondria from db/db mice also contained less oxidized CoQ10(ubiquinone) compared with dbH mice. Diabetes-induced increases in total renal collagen but not glomerulosclerosis were significantly decreased with CoQ10 therapy. Mitochondrial superoxide and ATP production via complex II in the renal cortex were increased in db/db mice, with ATP normalized by CoQ10. However, excess renal mitochondrial hydrogen peroxide production and increased mitochondrial membrane potential seen in db/db mice were attenuated with CoQ10. Renal superoxide dismutase activity was also lower in db/db mice compared with dbH mice. Our results suggest that a deficiency in mitochondrial oxidized CoQ10 (ubiquinone) may be a likely precipitating factor for diabetic nephropathy. Therefore CoQ10 supplementation may be renoprotective in type 2 diabetes, via preservation of mitochondrial function.
Publisher: S. Karger AG
Date: 2010
DOI: 10.1159/000314924
Abstract: i Background/Aims: /i Antihypertensive therapies such as angiotensin-converting enzyme-1 inhibitors (ACEi) slow the decline in renal function seen with diabetic nephropathy, although there is still progression ultimately to end-stage renal disease. The aim of this study was to determine if there were added renoprotective benefits seen by combining ACEi with blockade of NADPH oxidase. i Methods: /i Sprague-Dawley diabetic and non-diabetic rats were randomized to receive intervention therapy with apocynin (15 mg/kg/day, weeks 16–32), apocynin + the ACEi ramipril (1 mg/kg/day, weeks 16–32), or ramipril alone (1 mg/kg). i Results: /i All three treatments retarded the development of albuminuria in the diabetic rats. Apocynin conferred its benefit either as a monotherapy or in combination with ramipril without affecting blood pressure per se. Renal morphological injury was attenuated by all three treatment strategies. Diabetes was associated with increasing renal fibronectin and type IV collagen protein expression, with the combination regimen resulting in the highest decrease in extracellular matrix accumulation. All three treatments prevented the diabetes-associated increases in renal cytosolic superoxide generation as well as urinary isoprostanes. While renal TGF-β1 activation was reduced by ramipril treatment but not by apocynin as a monotherapy, kidney cortical membranous VEGF was reduced by apocynin as monotherapy and dual therapy but not by ramipril alone. i Conclusions: /i Combination of NADPH oxidase blockade with ACE inhibitors is a promising regimen which warrants further investigation as a way to confer additional renoprotection in diabetes.
Publisher: Mary Ann Liebert Inc
Date: 08-2013
Abstract: Defects in the activity of enzyme complexes of the mitochondrial respiratory chain are thought to be responsible for several disorders, including renal impairment. Gene mutations that result in complex I deficiency are the most common oxidative phosphorylation disorders in humans. To determine whether an abnormality in mitochondrial complex I per se is associated with development of renal disease, mice with a knockdown of the complex I gene, Ndufs6 were studied. Ndufs6 mice had a partial renal cortical complex I deficiency Ndufs6gt/gt, 32% activity and Ndufs6gt/+, 83% activity compared with wild-type mice. Both Ndufs6gt/+ and Ndufs6gt/gt mice exhibited hallmarks of renal disease, including albuminuria, urinary excretion of kidney injury molecule-1 (Kim-1), renal fibrosis, and changes in glomerular volume, with decreased capacity to generate mitochondrial ATP and superoxide from substrates oxidized via complex I. However, more advanced renal defects in Ndufs6gt/gt mice were observed in the context of a disruption in the inner mitochondrial electrochemical potential, 3-nitrotyrosine-modified mitochondrial proteins, increased urinary excretion of 15-isoprostane F2t, and up-regulation of antioxidant defence. Juvenile Ndufs6gt/gt mice also exhibited signs of early renal impairment with increased urinary Kim-1 excretion and elevated circulating cystatin C. We have identified renal impairment in a mouse model of partial complex I deficiency, suggesting that even modest deficits in mitochondrial respiratory chain function may act as risk factors for chronic kidney disease. These studies identify for the first time that complex I deficiency as the result of interruption of Ndufs6 is an independent cause of renal impairment.
Publisher: American Diabetes Association
Date: 04-2010
DOI: 10.2337/DB10-ER04A
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: Bentham Science Publishers Ltd.
Date: 30-09-2015
DOI: 10.2174/1389450116666150727123115
Abstract: After the discovery of the db gene in 1966, it was determined that a blood-borne satiety factor was produced excessively, but was not responded to, in db/db mice. This model for type 2 diabetes is widely used since it phenocopies human disease and its co-morbidities including obesity, progressive deterioration in glucose tolerance, hypertension and hyperlipidaemia. Db/db mice, unlike their non-diabetic controls, have consistently elevated levels of liver glycogen, most likely due to hyperphagia. In transmission electron micrographs, liver glycogen usually shows a composite cauliflower-like morphology of large "α particles" (with a wide range of sizes) made up of smaller "β particles" bound together. New studies have explored the size distribution of liver glycogen molecules and found that α particles in db/db mice are more chemically fragile than those in healthy mice, and can readily break apart to smaller β particles. There is evidence that smaller glycogen particles have a higher association with glycogen phosphorylase, a key enzyme involved in glycogen degradation, as well as being degraded more rapidly in vitro therefore the inability to form stable large glycogen α particles is predicted to result in a faster, less controlled degradation into glucose. The implications of this for glycaemic control remain to be fully elucidated. However, "rescuing" the more fragile diabetic glycogen to decrease hepatic glucose output in type 2 diabetes, may provide a potential therapeutic target which is the subject of this review.
Publisher: Wiley
Date: 10-2014
DOI: 10.1111/JGH.12794
Publisher: Wiley
Date: 06-2005
Abstract: Although advanced glycation end products (AGEs) have been postulated to contribute to diabetic nephropathy in their own right, advanced glycation is clearly only one pathway by which renal injury may be induced in diabetes. The interaction between metabolic and hemodynamic factors lifies the deleterious effects of the diabetic milieu, thereby reducing the threshold for microvascular injury via common mechanisms. This includes interactions between AGE-mediated pathways and the renin angiotensin system, oxidative stress, protein kinase C, and growth factors, which play a significant role in the development and progression of diabetic renal disease. As it is likely that the future of preventive therapy will not involve a single "cure-all" agent, it seems that a highly relevant question in diabetic nephropathy should be, which pathogenic pathways are already addressed by currently available therapies? Combination therapies that target multiple pathways may ultimately be more successful than those that modify a single pathway. Therefore, research into synergistic interactions among the various pathogenic pathways leading to diabetic complications is critical in order to develop interventions that confer optimal end-organ protection.
Publisher: Elsevier BV
Date: 10-2013
DOI: 10.1038/KI.2013.89
Abstract: The mechanisms involved in expansion of the tubulointerstitial compartment of the kidney in in iduals with diabetes are not well understood. Given that tubulointerstitial damage is an important predictor of progression to end-stage kidney disease in most forms of chronic kidney disease it is imperative to gain a greater understanding of the processes involved. With this in mind, a very clear objective for the scientific content of this meeting was to spend more than half the program outside the comfort zone of nephrology, gaining insights from sources such as neurodegenerative and mitochondrial diseases, stem cells, cancer and high-level computing to reconstruct organ systems. The meeting also aimed to place the new concepts presented in the context of current knowledge in diabetic kidney disease and the milestones achieved to date in this area. The presenters were all extremely generous, giving not only their time, but also showing a large proportion of unpublished data to stimulate discussions, questions and innovation.
Publisher: Springer Science and Business Media LLC
Date: 10-01-2001
Abstract: ALT-946, an inhibitor of advanced glycation with a minimal inhibitory effect on nitric oxide synthase, was compared with aminoguanidine in experimental diabetic nephropathy. In vitro and in vivo assays were used to assess the ability of ALT-946 to inhibit AGE-protein cross-link formation. Diabetic animals were randomly allocated into groups receiving aminoguanidine for 32 weeks, ALT-946 or vehicle (untreated). As a delayed intervention protocol, an additional diabetic group was treated with ALT-946 from week 16 to week 32 of the study. Non-diabetic rats were studied concurrently. Systolic blood pressure, body weight, plasma glucose, glycated haemoglobin and urinary albumin excretion were measured serially. Accumulation of advanced-glycation end products in the kidney was assessed by immunohistochemistry. The ALT-946 inhibitor was more potent than aminoguanidine in inhibiting AGE-protein cross-linking both in vitro and in vivo. Increased albuminuria observed in diabetic rats was attenuated in all three treatment groups. We found no difference in body weight, blood pressure or glycaemic control with any of the treatments. The untreated diabetic group had a twofold increase in glomerular staining for advanced-glycation end products compared with the diabetic groups which received treatment. ALT-946 is a potent inhibitor of advanced renal glycation end-product accumulation and reproduces the renoprotective effects of aminoguanidine. Therefore, ALT-946 should be considered as a treatment for preventing or retarding diabetic nephropathy.
Publisher: Bentham Science Publishers Ltd.
Date: 05-2008
DOI: 10.2174/092986608784246515
Abstract: Advanced glycation end products (AGEs) are formed from the non-enzymatic reaction between reducing sugars and amine residues on proteins, lipoproteins or nucleic acids. AGEs are found on long-lived proteins and their tissue accumulation is associated with normal ageing. The formation of AGEs can be accelerated in certain pathological conditions such as diabetes where hyperglycaemia is present. AGE modification of proteins can lead to alterations of normal function by binding to intracellular or extracellular cell components, or through receptor binding. This consequently can initiate a cascade of events, which includes the activation of signal transduction pathways, which activate inflammatory responses causing tissue damage. Such tissue injury contributes to the development of microvascular complications and is of particular relevance in diabetes where interventions to reduce the accumulation of AGEs is desirable.
Publisher: Springer Science and Business Media LLC
Date: 21-10-2012
DOI: 10.1007/S00726-010-0771-4
Abstract: The kidney is an extremely complex organ with broad ranging functions in the body, including but not restricted to waste excretion, ion and water balance, maintenance of blood pressure, glucose homeostasis, generation of erythropoietin and activation of vitamin D. With diabetes, many of these integral processes are interrupted via a combination of haemodynamic and metabolic changes including increases in the accumulation of proteins modified by advanced glycation, known as advanced glycation end products (AGEs). Indeed, hyperglycaemia and the redox imbalances seen with diabetes are each independent accelerants for the production of AGEs, which synergistically combine in this disorder. In addition, as kidney function declines, characterised by a loss of glomerular filtration, the excretion of AGEs is decreased, possibly exacerbating renal injury by further elevating the body's tissue and circulating AGE pool. Therefore, it has become apparent that decreasing the accumulation of AGEs or interrupting their downstream effects on the kidney, are desirable therapeutic targets for the treatment of diabetic renal disease.
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: Springer Science and Business Media LLC
Date: 08-06-2021
DOI: 10.1038/S42255-021-00393-9
Abstract: Reduced protein intake, through dilution with carbohydrate, extends lifespan and improves mid-life metabolic health in animal models. However, with transition to industrialised food systems, reduced dietary protein is associated with poor health outcomes in humans. Here we systematically interrogate the impact of carbohydrate quality in diets with varying carbohydrate and protein content. Studying 700 male mice on 33 isocaloric diets, we find that the type of carbohydrate and its digestibility profoundly shape the behavioural and physiological responses to protein dilution, modulate nutrient processing in the liver and alter the gut microbiota. Low (10%)-protein, high (70%)-carbohydrate diets promote the healthiest metabolic outcomes when carbohydrate comprises resistant starch (RS), yet the worst outcomes were with a 50:50 mixture of monosaccharides fructose and glucose. Our findings could explain the disparity between healthy, high-carbohydrate diets and the obesogenic impact of protein dilution by glucose-fructose mixtures associated with highly processed diets.
Publisher: Cold Spring Harbor Laboratory
Date: 22-07-2019
DOI: 10.1101/710558
Abstract: The accumulation of advanced glycation end products (AGEs) have been implicated in the development and progression of diabetic kidney disease (DKD). There has been interest in investigating the potential of AGE clearance receptors, such as oligosaccharyltransferase-48kDa subunit (OST48) to prevent the detrimental effects of excess AGE accumulation seen in the diabetic kidney. Here the objective of the study was to increase the expression of OST48 to examine if this slowed the development of DKD by facilitating the clearance of AGEs. Groups of 8-week-old heterozygous knock-in male mice (n=9-12/group) over-expressing the gene encoding for OST48, dolichyl-diphosphooligosaccharide-protein glycosyltransferase ( DDOST +/-) and litter mate controls were randomised to either (i) no diabetes or (ii) diabetes induced via multiple low-dose streptozotocin and followed for 24 weeks. By the study end, global over expression of OST48 increased glomerular OST48. This facilitated greater renal excretion of AGEs but did not affect circulating or renal AGE concentrations. Diabetes resulted in kidney damage including lower glomerular filtration rate, albuminuria, glomerulosclerosis and tubulointerstitial fibrosis. In diabetic mice, tubulointerstitial fibrosis was further exacerbated by global increases in OST48. There was significantly insulin effectiveness, increased acute insulin secretion, fasting insulin concentrations and AUC insulin observed during glucose tolerance testing in diabetic mice with global elevations in OST48 when compared to diabetic wild-type littermates. Overall, this study suggested that despite facilitating urinaryrenal AGE clearance, there were no benefits observed on kidney functional and structural parameters in diabetes afforded by globally increasing OST48 expression. However, the improvements in insulin secretion seen in diabetic mice with global over-expression of OST48 and their dissociation from effects on kidney function warrant future investigation.
Publisher: Springer Science and Business Media LLC
Date: 02-11-2014
DOI: 10.1038/NM.3705
Abstract: In type 2 diabetes, hyperglycemia is present when an increased demand for insulin, typically due to insulin resistance, is not met as a result of progressive pancreatic beta cell dysfunction. This defect in beta cell activity is typically characterized by impaired insulin biosynthesis and secretion, usually accompanied by oxidative and endoplasmic reticulum (ER) stress. We demonstrate that multiple inflammatory cytokines elevated in diabetic pancreatic islets induce beta cell oxidative and ER stress, with interleukin-23 (IL-23), IL-24 and IL-33 being the most potent. Conversely, we show that islet-endogenous and exogenous IL-22, by regulating oxidative stress pathways, suppresses oxidative and ER stress caused by cytokines or glucolipotoxicity in mouse and human beta cells. In obese mice, antibody neutralization of IL-23 or IL-24 partially reduced beta cell ER stress and improved glucose tolerance, whereas IL-22 administration modulated oxidative stress regulatory genes in islets, suppressed ER stress and inflammation, promoted secretion of high-quality efficacious insulin and fully restored glucose homeostasis followed by restitution of insulin sensitivity. Thus, therapeutic manipulation of immune regulators of beta cell stress reverses the hyperglycemia central to diabetes pathology.
Publisher: Bioscientifica
Date: 30-06-2014
DOI: 10.1530/JOE-13-0517
Abstract: The endoplasmic reticulum (ER) is an organelle that primarily functions to synthesise new proteins and degrade old proteins. Owing to the continual and variable nature of protein turnover, protein synthesis is inherently an error-prone process and is therefore tightly regulated. Fortunately, if this balance between synthesis and degradation is perturbed, an intrinsic response, the unfolded protein response (UPR) is activated to restore ER homoeostasis through the action of inositol-requiring protein 1, activating transcription factor 6 and PKR-like ER kinase transmembrane sensors. However, if the UPR is oversaturated and misfolded proteins accumulate, the ER can shift into a cytotoxic response, a physiological phenomenon known as ER stress. The mechanistic pathways of the UPR have been extensively explored however, the role of this process in such a synthetic organ as the kidney requires further clarification. This review will focus on these aspects and will discuss the role of ER stress in specific resident kidney cells and how this may be integral in the pathogenesis and progression of diabetic nephropathy (DN). Given that diabetes is a perturbed state of protein turnover in most tissues, it is important to understand if ER stress is a secondary or tertiary response to other changes within the diabetic milieu or if it is an independent accelerator of kidney disease. Modulators of ER stress could provide a valuable tool for the treatment of DN and are under active investigation in other contexts.
Publisher: Wiley
Date: 22-06-2021
DOI: 10.1002/EDM2.278
Abstract: The accumulation of advanced glycation end products is implicated in the development and progression of diabetic kidney disease. No study has examined whether stimulating advanced glycation clearance via receptor manipulation is reno‐protective in diabetes. Podocytes, which are early contributors to diabetic kidney disease and could be a target for reno‐protection. To examine the effects of increased podocyte oligosaccharyltransferase‐48 on kidney function, glomerular sclerosis, tubulointerstitial fibrosis and proteome (PXD011434), we generated a mouse with increased oligosaccharyltransferase‐48kDa subunit abundance in podocytes driven by the podocin promoter. Despite increased urinary clearance of advanced glycation end products, we observed a decline in renal function, significant glomerular damage including glomerulosclerosis, collagen IV deposition, glomerular basement membrane thickening and foot process effacement and tubulointerstitial fibrosis. Analysis of isolated glomeruli identified enrichment in proteins associated with collagen deposition, endoplasmic reticulum stress and oxidative stress. Ultra‐resolution microscopy of podocytes revealed denudation of foot processes where there was co‐localization of oligosaccharyltransferase‐48kDa subunit and advanced glycation end‐products. These studies indicate that increased podocyte expression of oligosaccharyltransferase‐48 kDa subunit results in glomerular endoplasmic reticulum stress and a decline in kidney function.
Publisher: Walter de Gruyter GmbH
Date: 2014
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2016
DOI: 10.2215/CJN.05240515
Publisher: Elsevier BV
Date: 08-2019
DOI: 10.1016/J.CLNU.2018.08.001
Abstract: Extremes of dysglycaemia as well as glycaemic variability are associated with excess mortality in critically ill patients. Glycaemic variability is an increasingly important measure of glucose control in the intensive care unit (ICU) due to this association however, there is limited data pertaining to the relationship between exogenous glucose from nutrition and glycaemic variability and clinical outcomes. The primary aim of this study was to determine if glycaemic variability is associated with an increase in mortality. Secondary objectives were to investigate any factors affecting glycaemic variability, and to characterise the role nutrition, particularly carbohydrate, plays as a contributing factor to glycaemic variability and other clinical outcomes (duration of ventilation and ICU length of stay). Data on patients in a combined medical/surgical tertiary Australian Intensive Care Unit (ICU), ventilated for >24 h and exclusively fed by artificial nutrition support was extracted from a clinical database of prospectively collected information over an 18 month period. Glycaemic variability was defined as the coefficient of variation (GV standard deviation/mean of blood glucose levels x 100). Statistical analysis was performed using logistic regression, zero-truncated negative binomial and linear regression as appropriate to the distribution of the outcome variable using R software. Data on up to 759 subjects was available. The average age of the study cohort was 56.9 years with a mean (standard deviation) APACHE III score of 72 (28). 66% of the study subjects were male. Glycaemic variability was associated with an increase in mortality (odds ratio 1.02 95% CI: 1.00-1.04, p = 0.03). Factors associated with glycaemic variability included Acute Physiology and Chronic Health Evaluation III score (0.09, 0.06-0.11, p < 0.001), being male (-1.67, -2.97 to -0.38), p = 0.01) and mean units of insulin per day (0.08, 0.06-0.09, p < 0.001). There was no effect of any nutritional factor on glycaemic variability. Further exploratory analyses though showed that for those patients who required insulin during ICU admission, increased insulin dose was associated with increasing carbohydrate (incidence rate ratio (IRR) 1.003, 1.001-1.005, p = 0.001). Mean daily carbohydrate provision (grams) was associated with an increase in ventilation hours (IRR, 95% CI: 1.009, 1.008-1.009, p < 0.001) and length of intensive care unit stay (IRR, 95% CI: 1.007, 1.006-1.008, p < 0.001). This study confirms that GV was associated with excess mortality. Furthermore, administration of increasing doses of insulin was associated with increased GV. Increased carbohydrate intake was associated with an increased insulin requirement, as well as increased duration of mechanical ventilation and ICU length of stay. These findings provide important context for further prospective trials investigating the effect of carbohydrate provision in mechanically ventilated critically ill patients requiring artificial nutritional support.
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: Springer Science and Business Media LLC
Date: 25-09-2017
DOI: 10.1038/S41598-017-12548-4
Abstract: The protein oligosaccharyltransferase-48 (OST48) is integral to protein N-glycosylation in the endoplasmic reticulum (ER) but is also postulated to act as a membrane localised clearance receptor for advanced glycation end-products (AGE). Hepatic ER stress and AGE accumulation are each implicated in liver injury. Hence the objective of this study was to increase the expression of OST48 and examine the effects on hepatic function and structure. Groups of 8 week old male mice (n = 10–12/group) over-expressing the gene for OST48, dolichyl-diphosphooligosaccharide-protein glycosyltransferase ( DDOST +/−), were followed for 24 weeks, while randomised to diets either low or high in AGE content. By week 24 of the study, either increasing OST48 expression or consumption of high AGE diet impaired liver function and modestly increased hepatic fibrosis, but their combination significantly exacerbated liver injury in the absence of steatosis. DDOST +/− mice had increased both portal delivery and accumulation of hepatic AGEs leading to central adiposity, insulin secretory defects, shifted fuel usage to fatty and ketoacids, as well as hepatic glycogen accumulation causing hepatomegaly along with hepatic ER and oxidative stress. This study revealed a novel role of the OST48 and AGE axis in hepatic injury through ER stress, changes in fuel utilisation and glucose intolerance.
Publisher: Elsevier BV
Date: 11-2010
DOI: 10.1016/J.METABOL.2010.01.027
Abstract: Decreased gene expression of heat shock protein 72 (HSP72) in skeletal muscle is associated with insulin resistance in humans. We aimed to determine whether HSP72 protein expression in insulin-sensitive tissues is related to criterion standard measures of adiposity and insulin resistance in a young healthy human population free of hyperglycemia. Healthy participants (N = 17 age, 30 ± 3 years) underwent measurement of body composition (dual-energy x-ray absorptiometry), a maximum aerobic capacity test (VO(2max)), an oral glucose tolerance test, and a hyperinsulinemic-euglycemic cl (M) to access insulin sensitivity. Skeletal muscle and subcutaneous adipose tissue biopsies were obtained by percutaneous needle biopsy. HSP72 protein expression in skeletal muscle was inversely related to percentage body fat (r = -0.54, P < .05) and remained significant after adjustment for age and sex (P < .05). Insulin sensitivity was also related to HSP72 protein expression in skeletal muscle (r = 0.52, P < .05) however, this relationship disappeared after adjustment for percentage body fat (P = .2). In adipose tissue, HSP72 protein expression was not related to adiposity or insulin sensitivity. Physical activity and aerobic fitness did not show any association with HSP72 protein expression in either tissue studied. A lower expression of HSP72 protein in human skeletal muscle was associated with increased adiposity and decreased insulin sensitivity in healthy in iduals. These findings are consistent with rodent data suggesting that HSP72 stimulates fat oxidation with consequent reduction in fat storage and adiposity.
Publisher: Wiley
Date: 17-12-2013
DOI: 10.1111/J.1440-1797.2012.01665.X
Abstract: Mouse chow is commonly high in advanced glycation end-products, known contributors to diabetic nephropathy. The aim of this study was to evaluate if targeting of the AGE-RAGE axis was still effective in the context of a diet low in AGE content, which is more comparable to diets consumed by in iduals with type 1 diabetes. C57BL/6J wild-type and mice deficient in the receptor for AGEs (RAGE-KO) consumed a diet low in AGE content. Groups of mice were given (i) vehicle (ii) streptozotocin or (iii) streptozotocin + AGE lowering therapy (alagebrium chloride) and followed for 24 weeks. Diabetic mice had high urinary albumin excretion rates, hyperfiltration and release of urinary Kim-1, not seen in diabetic RAGE-KO mice. Diabetic mice also had renal fibrosis, measured by glomerulosclerosis, tubulointerstitial expansion, TGF-β1 and glomerular collagen-IV deposition which almost all improved by RAGE-KO or alagebium. Diabetic mice had a greater renal burden of AGEs and increased expression of renal specific PKC-α phosphorylation, which was improved in RAGE-KO mice, or those treated with alagebrium. Diabetic mice given a low-AGE diet still developed renal disease, which could be attenuated by targeting of the AGE-RAGE axis.
Publisher: Springer Science and Business Media LLC
Date: 19-07-2017
DOI: 10.1007/S00125-017-4360-X
Abstract: In parallel with the growing diabetes pandemic, there is an increasing burden of micro- and macrovascular complications, occurring in the majority of patients. The identification of a number of synergistic accelerators of disease, providing therapeutic pathways, has stabilised the incidence of complications in most western nations. However, the primary instigators of diabetic complications and, thus, prevention strategies, remain elusive. This has necessitated a refocus on natural history studies, where tissue and plasma s les are sequentially taken to determine when and how disease initiates. In addition, recent Phase III trials, wherein the pleiotropic effects of compounds were arguably as beneficial as their glucose-lowering capacity in slowing the progression of complications, have identified knowledge gaps. Recently the influence of other widely recognised pathological pathways, such as mitochondrial production of reactive oxygen species, has been challenged, highlighting the need for a erse and robust global research effort to ascertain viable therapeutic targets. Technological advances, such as -omics, high-resolution imaging and computational modelling, are providing opportunities for strengthening and re-evaluating research findings. Newer areas such as epigenetics, energetics and the increasing scrutiny of our synergistic inhabitants, the microbiota, also offer novel targets as biomarkers. Ultimately, however, this field requires concerted lobbying to support all facets of diabetes research.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2005
Publisher: Georg Thieme Verlag KG
Date: 22-02-2007
Abstract: Diabetic nephropathy (DN), the most common cause of end stage renal disease in developed nations, is thought to result from interactions between metabolic and haemodynamic factors. Specific metabolically driven, glucose dependent pathways are activated within diabetic renal tissues. These pathways induce oxidative stress, polyol pathway flux, hexosamine flux and accumulation of advanced glycated end-products (AGEs). Haemodynamic factors are also implicated in the pathogenesis of DN and include elevations of systemic and intraglomerular pressure and activation of various vasoactive hormone pathways including the renin-angiotensin aldosterone system (RAAS), endothelin and urotensin. These altered hemodynamics act independently and in concert with metabolic pathways, to activate intracellular second messengers such as protein kinase C (PKC) and MAP kinase (MAPK), nuclear transcription factors such as nuclear factor-kappaB (NF-kappaB) and various growth factors such as the prosclerotic cytokines, transforming growth factor-beta1 (TGF-beta1), connective tissue growth factor (CTGF) and the angiogenic, permeability enhancing growth factor, vascular endothelial growth factor, VEGF. Ultimately these molecular mechanisms lead to increased renal albumin permeability, and extracellular matrix accumulation, which results in increasing proteinuria, glomerulosclerosis and tubulointerstitial fibrosis. In the past, the treatment of diabetic nephropathy has focused on control of hyperglycemia and the interruption of the RAAS with certain anti-hypertensive agents. Newer novel targets, some of which are linked to glucose dependent pathways, appear to be a major focus of new therapies directed against the development and progression of renal damage as a result of diabetes. It is likely that resolution of diabetic nephropathy will require synergistic therapies to target multiple mediators of this disease.
Publisher: American Diabetes Association
Date: 13-11-2013
DOI: 10.2337/DC13-0143
Abstract: Type 2 diabetes (T2DM) is associated with brain atrophy and cerebrovascular disease. We aimed to define the regional distribution of brain atrophy in T2DM and to examine whether atrophy or cerebrovascular lesions are feasible links between T2DM and cognitive function. This cross-sectional study used magnetic resonance imaging (MRI) scans and cognitive tests in 350 participants with T2DM and 363 participants without T2DM. With voxel-based morphometry, we studied the regional distribution of atrophy in T2DM. We measured cerebrovascular lesions (infarcts, microbleeds, and white matter hyperintensity [WMH] volume) and atrophy (gray matter, white matter, and hippoc al volumes) while blinded to T2DM status. With use of multivariable regression, we examined for mediation or effect modification of the association between T2DM and cognitive measures by MRI measures. T2DM was associated with more cerebral infarcts and lower total gray, white, and hippoc al volumes (all P & 0.05) but not with microbleeds or WMH. T2DM-related gray matter loss was distributed mainly in medial temporal, anterior cingulate, and medial frontal lobes, and white matter loss was distributed in frontal and temporal regions. T2DM was associated with poorer visuospatial construction, planning, visual memory, and speed (P ≤ 0.05) independent of age, sex, education, and vascular risk factors. The strength of these associations was attenuated by almost one-half when adjusted for hippoc al and total gray volumes but was unchanged by adjustment for cerebrovascular lesions or white matter volume. Cortical atrophy in T2DM resembles patterns seen in preclinical Alzheimer disease. Neurodegeneration rather than cerebrovascular lesions may play a key role in T2DM-related cognitive impairment.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2009
Publisher: Springer Science and Business Media LLC
Date: 09-2012
DOI: 10.1038/NM0912-1445C
Publisher: Springer Science and Business Media LLC
Date: 24-06-2014
DOI: 10.1007/S00125-014-3291-Z
Abstract: The AGEs and the receptor for AGEs (RAGE) are known contributors to diabetic complications. RAGE also has a physiological role in innate and adaptive immunity and is expressed on immune cells. The aim of this study was to determine whether deletion of RAGE from bone-marrow-derived cells influences the pathogenesis of experimental diabetic nephropathy. Groups (n = 8/group) of lethally irradiated 8 week old wild-type (WT) mice were reconstituted with bone marrow from WT (WT → WT) or RAGE-deficient (RG) mice (RG → WT). Diabetes was induced using multiple low doses of streptozotocin after 8 weeks of bone marrow reconstitution and mice were followed for a further 24 weeks. Compared with diabetic WT mice reconstituted with WT bone marrow, diabetic WT mice reconstituted with RG bone marrow had lower urinary albumin excretion and podocyte loss, more normal creatinine clearance and less tubulo-interstitial injury and fibrosis. However, glomerular collagen IV deposition, glomerulosclerosis and cortical levels of TGF-β were not different among diabetic mouse groups. The renal tubulo-interstitium of diabetic RG → WT mice also contained fewer infiltrating CD68(+) macrophages that were activated. Diabetic RG → WT mice had lower renal cortical concentrations of CC chemokine ligand 2 (CCL2), macrophage inhibitory factor (MIF) and IL-6 than diabetic WT → WT mice. Renal cortical RAGE ligands S100 calgranulin (S100A)8/9 and AGEs, but not high mobility box protein B-1 (HMGB-1) were also decreased in diabetic RG → WT compared with diabetic WT → WT mice. In vitro, bone-marrow-derived macrophages from WT but not RG mice stimulated collagen IV production in cultured proximal tubule cells. These studies suggest that RAGE expression on haemopoietically derived immune cells contributes to the functional changes seen in diabetic nephropathy by promoting macrophage infiltration and renal tubulo-interstitial damage.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2003
DOI: 10.1097/01.ASN.0000099374.58607.C9
Abstract: A link between angiotensin II and cell proliferation has previously been reported. However, there remains controversy as to the role of the in idual angiotensin II receptor subtypes in mediating these effects and their link to angiogenic cytokines and their receptors. Male Sprague-Dawley rats were infused with either angiotensin II or vehicle for 14 d at a dose of 58.3 ng/min. Angiotensin II-infused rats received no treatment, an AT(1) receptor antagonist valsartan (30 mg/kg per d), or an AT(2) receptor antagonist PD123319 (830 ng/min). Gene expression of vascular endothelial growth factor (VEGF) and receptor VEGF-R2, as well as Tie-2 and its ligands angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) were assessed by reverse transcription-PCR. Protein expression was assessed by Western blotting and immunohistochemistry. Gene and protein expression of VEGF, Ang-1, and Ang-2 were increased by angiotensin II infusion. Valsartan and PD123319 attenuated angiotensin II-associated increases in VEGF gene and protein expression. Ang-1 and Ang-2 gene but not protein expression were reduced by both treatments. These changes occurred in the context of attenuation of angiotensin II-induced glomerular cell proliferation by both valsartan and PD123319. In situ hybridization and immunohistochemical studies localized VEGF, Ang-1, and Ang-2 expression to the epithelial cells of the glomerulus, and VEGF-R2 and Tie-2 receptors to the endothelial cells of the kidney. These findings extend the increasing evidence that the AT(2) receptor, in addition to the AT(1) receptor subtype, plays an important role in mediating the proliferative actions of angiotensin II in the kidney.
Publisher: Elsevier BV
Date: 10-2010
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: Elsevier BV
Date: 06-2000
DOI: 10.1046/J.1523-1755.2000.00097.X
Abstract: The cellular infiltration and matrix accumulation accompanying acute renal ischemia and reperfusion have been frequently noted but poorly defined. The long-term consequences of ischemia may irreversibly damage the kidney. Female Sprague-Dawley rats (200 g) underwent unilateral nephrectomy. After five days, the left renal pedicle was occluded for 45 minutes. Animals were sacrificed at 0, 1, 2, 4, 8, 16, 32, 64, and 180 days postischemia (N = 6). Immunohistochemistry for monocytes/macrophages (Mo/Mphi, ED-1), myofibroblasts [alpha-smooth muscle actin (alpha-SMA)], collagen III and IV, matrix metalloproteinase-2 (MMP-2) and proliferating cell nuclear antigen (PCNA) and terminal dUTP nick end labeling (TUNEL) were performed. Kidney weights of postischemic animals were increased at all time points (postischemic to controls, 1.47 +/- 0.21 to 0.94 +/- 0.12 g at day 8 1.49 +/- 0.20 to 1.27 +/- 0.13 g at day 64 and 1.86 +/- 0.1 to 1. 24 +/- 0.2 g at day 180). Serum creatinine values increased to 0.42 +/- 0.10 mmol/L at day 2 but returned to control levels by day 8 (0. 05 mmol/L). Glomerular collagen IV was decreased from 2 to 16 days postischemia, which was accompanied by an increase in MMP-2. The fractional area of the interstitium was greatest at day 8 (19.55 +/- 0.91% compared with day 0 at 8.08 +/- 0.27%), with a second increase observed at day 180 (16.61 +/- 0.70%). Interstitial Mo/Mphi increased postischemia from days 2 through 8 (8.84 +/- 2.12 to 133. 32 +/- 14.04 per 0.91 mm2) and then decreased. Myofibroblasts proliferated locally (PCNA double labeling was demonstrated), and increased numbers were found from days 2 through 16 (maximal at day 8, 26.96 +/- 3.04%, compared with day 0, 0.88 +/- 0.11%). In the postischemic groups, collagen IV increased to day 8 (20.84 +/- 1. 30%), but then decreased to below control values at day 64 (2.22 +/- 0.15%) before returning to normal by day 180. Interstitial collagen III increased to 8 days (0.45 +/- 0.07% to 2.55 +/- 0.36%) and then decreased to control levels by day 32, but showed a marked increase to approximately 6% at days 64 and 180. Cellular proliferation (PCNA) was maximal at days 2 and 4 (affecting tubule cells and myofibroblasts but not macrophages). Apoptosis was maximal at day 8 (in both interstitial and tubule cells) in the postischemic groups. Marked changes in the accumulation of Mo/Mphi, MF, and collagen IV were found in this model of ischemic acute renal failure. The reversibility of functional and structural changes is in marked contrast to that found in progressive disease. The increases observed for collagen III at 64 and 180 days postischemia suggest that in the long term, however, further chronic structural changes may be observed.
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: Springer Science and Business Media LLC
Date: 06-02-2011
DOI: 10.1007/S00125-011-2058-Z
Abstract: This group of studies examines human genetic susceptibility conferred by the receptor for advanced glycation end-products (RAGE) in type 1 diabetes and investigates how this may interact with a western environment. We analysed the AGER gene, using 13 tag SNPs, in 3,624 Finnish in iduals from the FinnDiane study, followed by AGER associations with a high risk HLA genotype (DR3)-DQA1*05-DQB1*02/DRB1*0401-DQB1*0302 (n = 546 HLA-DR3/DR4), matched in healthy newborn infants from the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) Study (n = 373) using allelic analysis. We also studied islets and circulating RAGE in NODLt mice. The rs2070600 and rs17493811 polymorphisms predicted increased risk of type 1 diabetes, whereas the rs9469089 SNP was related to decreased risk, on a high risk HLA background. Children from the DIPP study also showed a decline in circulating soluble RAGE levels, at seroconversion to positivity for type 1 diabetes-associated autoantibodies. Islet RAGE and circulating soluble RAGE levels in prediabetic NODLt mice decreased over time and were prevented by the AGE lowering therapy alagebrium chloride. Alagebrium chloride also decreased the incidence of autoimmune diabetes and restored islet RAGE levels. These studies suggest that inherited AGER gene polymorphisms may confer susceptibility to environmental insults. Declining circulating levels of soluble RAGE, before the development of overt diabetes, may also be predictive of clinical disease in children with high to medium risk HLA II backgrounds and this possibility warrants further investigation in a larger cohort.
Publisher: Springer Science and Business Media LLC
Date: 06-07-2014
DOI: 10.1007/S00726-013-1542-9
Abstract: It has been postulated that chronic exposure to high levels of advanced glycation end products (AGEs), in particular from dietary sources, can impair insulin secretion. In the present study, we investigated the cross-sectional relationship between AGEs and acute insulin secretion during an intravenous glucose tolerance test (IVGTT) and following a 75 g oral glucose tolerance test (OGTT) in healthy humans. We report the cross-sectional association between circulating AGE concentrations and insulin secretory function in healthy humans (17 F: 27 M, aged 30 ± 10 years) with a wide range of BMI (24.6-31.0 kg/m(2)). Higher circulating concentrations of AGEs were related to increased first phase insulin secretion during IVGTT (r = 0.43 p < 0.05) and lower 2-h glucose concentrations during OGTT (r = -0.31 p < 0.05). In addition, fasting (r = -0.36 p < 0.05) and 2-h glucose concentrations were negatively related to circulating levels of soluble receptor for AGE (RAGE) isoforms (r = -0.39 p < 0.01). In conclusion, in healthy humans, we show a cross-sectional association between advanced glycation end products and acute insulin secretion during glucose tolerance testing.
Publisher: Wiley
Date: 04-2008
Abstract: A major common feature of the chemically disparate compounds that inhibit advanced glycation end product (AGE) accumulation or signaling is their ability to show end-organ protection in experimental models of diabetes complications. The mechanisms by which these AGE- lowering therapies confer their benefits remain unsolved. Is it the reduction in tissue AGE levels per se or the inhibition of downstream signal transduction (as has been described with the soluble receptor for AGE)? Possible modes of action that need to be investigated include the ability of some of these agents to stimulate antioxidant defenses, to lower cholesterol and other lipid levels, and to inhibit low-grade inflammation. To understand these novel mechanisms, further examination of the advanced glycation pathway and, in particular, the erse action of these agents in ameliorating the development of diabetic complications is needed.
Publisher: The Endocrine Society
Date: 20-08-2018
Abstract: Diabetes mellitus is associated with increased fracture risk despite preservation of bone density and reduced bone turnover. We tested the hypothesis that circulating advanced glycation end products (AGEs) and endogenous secretory receptor for AGEs (esRAGE) differentially modulate bone turnover and predict fracture risk in older men. A total of 3384 community-dwelling men aged 70 to 89 years. Collagen type I C-terminal cross-linked telopeptide, N-terminal propeptide of type I collagen (P1NP), and total osteocalcin (TOC) were assayed using immunoassay and undercarboxylated osteocalcin (ucOC) following hydroxyapatite binding. Plasma N-carboxymethyllysine (CML) and esRAGE were assayed using immunoassay. Methylglyoxal and glyoxal were assayed using mass spectrometry. Incident hip fractures were ascertained. Median age was 76.3 years (interquartile range, 74.2 to 79.1 years). Plasma CML was measured in 3011 men, methylglyoxal and glyoxal in 766 men, and esRAGE in 748 men. Plasma CML, methylglyoxal, glyoxal, and esRAGE were similar in men without and with diabetes (all P > 0.05). CML was positively associated with fasting glucose (r = 0.06, P < 0.001), and esRAGE was inversely associated (r = -0.08, P = 0.045). esRAGE was positively associated with bone formation (P1NP, r = 0.17, P < 0.001 ucOC, r = 0.11, P = 0.008 TOC, r = 0.16, P < 0.001). Incident hip fractures occurred in 106 men during follow-up. Men with CML in the third quartile of values had reduced incidence of hip fracture compared with men in the lowest quartile (hazard ratio, 0.49 95% CI, 0.24 to 0.99 P = 0.045). Glycemia associates positively with CML and reciprocally with esRAGE in older men. Circulating esRAGE modulates bone turnover in older men, whereas CML predicts incidence of hip fracture.
Publisher: MDPI AG
Date: 04-11-2022
Abstract: Type 1 diabetes (T1D) is an autoimmune disease in which the β-cells of the pancreas are attacked by the host’s immune system, ultimately resulting in hyperglycemia. It is a complex multifactorial disease postulated to result from a combination of genetic and environmental factors. In parallel with increasing prevalence of T1D in genetically stable populations, highlighting an environmental component, consumption of advanced glycation end products (AGEs) commonly found in in Western diets has increased significantly over the past decades. AGEs can bind to cell surface receptors including the receptor for advanced glycation end products (RAGE). RAGE has proinflammatory roles including in host–pathogen defense, thereby influencing immune cell behavior and can activate and cause proliferation of immune cells such as islet infiltrating CD8+ and CD4+ T cells and suppress the activity of T regulatory cells, contributing to β-cell injury and hyperglycemia. Insights from studies of in iduals at risk of T1D have demonstrated that progression to symptomatic onset and diagnosis can vary, ranging from months to years, providing a window of opportunity for prevention strategies. Interaction between AGEs and RAGE is believed to be a major environmental risk factor for T1D and targeting the AGE-RAGE axis may act as a potential therapeutic strategy for T1D prevention.
Publisher: Springer Science and Business Media LLC
Date: 23-06-2017
DOI: 10.1038/S41598-017-04214-6
Abstract: Diets high in advanced glycation end products (AGEs) are thought to be detrimental to cardiovascular health. However, there remains uncertainty about the beneficial effect of a low AGE diet on cardiovascular risk factors and inflammatory markers in overweight in iduals. We thus performed a randomised, double blind, crossover trial to determine whether consumption of low AGE diets reduce inflammation and cardiovascular risks in overweight and obese otherwise healthy adults. All participants (n = 20) consumed low and high AGE diets alternately for two weeks and separated by a four week washout period. Low AGE diets did not change systolic (p = 0.2) and diastolic blood pressure (p = 0.3), mean arterial pressure (p = 0.8) and pulse pressure (p = 0.2) compared to high AGE diets. Change in total cholesterol (p = 0.3), low-density lipoprotein (p = 0.7), high-density lipoprotein (p = 0.2), and triglycerides (p = 0.4) also did not differ and there was no difference in inflammatory markers: interleukin-6 (p = 0.6), monocyte chemoattractant protein-1 (p = 0.9), tumour necrosis factor α (p = 0.2), C-reactive protein (p = 0.6) and nuclear factor kappa beta (p = 0.2). These findings indicate that consumption of low AGE diets for two weeks did not improve the inflammatory and cardiovascular profiles of overweight and obese adults.
Publisher: Springer Science and Business Media LLC
Date: 02-05-2000
Abstract: Advanced glycation is postulated to have a pivotal role in mediating diabetic vascular complications. The emergence of thiazolium compounds such as N-phenacylthiazolium bromide which cleave preformed advanced glycation end products (AGEs) has allowed us to explore the effects of these agents on the vascular AGE accumulation and hypertrophy associated with diabetes. Control and streptozotocin diabetic rats were selected at random for no treatment or treatment with N-phenacylthiazolium bromide (10 mg/kg intraperitoneally) and followed for 3 weeks. In a separate study, intervention with N-phenacylthiazolium bromide was delayed until after 3 weeks of diabetes and then given for 3 weeks (total of 6 weeks). Diabetes was associated with increased mesenteric vascular advanced glycation end products, as assessed by radioimmunoassay and immunohistochemistry. This increase in vascular AGE accumulation was prevented by N-phenacylthiazolium bromide treatment. Diabetes-associated mesenteric vascular hypertrophy was attenuated by treatment with N-phenacylthiazolium bromide only if given from the time of induction of diabetes. Cross-link breakers seem to be effective in preventing or reversing accumulation of advanced glycation end-products in blood vessels and have the potential to play a part in the treatment of diabetic vascular complications.
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: Wiley
Date: 23-02-2012
DOI: 10.1111/J.1440-1797.2011.01547.X
Abstract: Interleukin-6 (IL-6) is secreted from adipose tissue and thought to contribute to obesity-related disorders. The aim of this study was to assess if IL-6-knockout (IL-6-/-) mice would develop obesity-induced renal impairment. Wild-type (WT) and IL-6-/- mice were high-fat fed (HFF) for 16 weeks to induce obesity. At the end of the study, renal function was measured via albumin/creatinine ratio and serum creatinine levels, using enzyme-linked immunosorbent assay (ELISA) and high-performance liquid chromatography (HPLC). Glomerulosclerotic index (GSI) was scored in periodic acid Schiff-stained sections and collagen IV accumulation was assessed by immunohistochemistry. Renal cortical tumour growth factor beta (TGF-β(1) ) activity and monocyte chemotactic protein-1 (MCP-1) levels were measured via ELISA. Renal IL-6 concentrations were increased with obesity. Although both WT HFF and IL-6-/- HFF mice exhibited renal impairment as measured by increased serum creatinine and urinary albumin/creatinine ratios, this was exacerbated in IL-6-/- mice. Obese mice had renal activation of cortical TGF-β(1) , which was also higher in IL-6-/- mice. Collagen IV staining was not affected by obesity. GSI was increased with obesity in both WT and IL-6-/- mice. Obese IL-6-/- mice demonstrated renal functional and structural abnormalities above that seen in obese WT mice. We suggest that absence or low IL-6 levels may be an important accelerating factor implicated in the development and progression of obesity-induced renal disease.
Publisher: MDPI AG
Date: 28-06-2022
DOI: 10.3390/NU14132675
Abstract: Since the 1980s, chronic kidney disease (CKD) affecting all ages has increased by almost 25%. This increase may be partially attributable to lifestyle changes and increased global consumption of a “western” diet, which is typically energy dense, low in fruits and vegetables, and high in animal protein and ultra-processed foods. These modern food trends have led to an increase in the consumption of advanced glycation end products (AGEs) in conjunction with increased metabolic dysfunction, obesity and diabetes, which facilitates production of endogenous AGEs within the body. When in excess, AGEs can be pathological via both receptor-mediated and non-receptor-mediated pathways. The kidney, as a major site for AGE clearance, is particularly vulnerable to AGE-mediated damage and increases in circulating AGEs align with risk of CKD and all-cause mortality. Furthermore, in iduals with significant loss of renal function show increased AGE burden, particularly with uraemia, and there is some evidence that AGE lowering via diet or pharmacological inhibition may be beneficial for CKD. This review discusses the pathways that drive AGE formation and regulation within the body. This includes AGE receptor interactions and pathways of AGE-mediated pathology with a focus on the contribution of diet on endogenous AGE production and dietary AGE consumption to these processes. We then analyse the contribution of AGEs to kidney disease, the evidence for dietary AGEs and endogenously produced AGEs in driving pathogenesis in diabetic and non-diabetic kidney disease and the potential for AGE targeted therapies in kidney disease.
Publisher: Cold Spring Harbor Laboratory
Date: 22-07-2019
DOI: 10.1101/710186
Abstract: The accumulation of advanced glycation end products is implicated in the development and progression of diabetic kidney disease. No study has examined whether stimulating advanced glycation clearance via receptor manipulation is reno-protective in diabetes. Podocytes, which are early contributors to diabetic kidney disease and could be a target for reno-protection. To examine the effects of increased podocyte oligosaccharyltransferase-48 on kidney function, glomerular sclerosis, tubulointerstitial fibrosis and proteome (PXD011434), we generated a mouse with increased oligosaccharyltransferase-48kDa subunit abundance in podocytes driven by the podocin promoter. Despite increased urinary clearance of advanced glycation end products, we observed a decline in renal function, significant glomerular damage including glomerulosclerosis, collagen IV deposition, glomerular basement membrane thickening and foot process effacement and tubulointerstitial fibrosis. Analysis of isolated glomeruli identified enrichment in proteins associated with collagen deposition, endoplasmic reticulum stress and oxidative stress. Ultra-resolution microscopy of podocytes revealed denudation of foot processes where there was co-localization of oligosaccharyltransferase-48kDa subunit and advanced glycation end-products. These studies indicate that increased podocyte expression of oligosaccharyltransferase-48kDa subunit results in glomerular endoplasmic reticulum stress and a decline in kidney function.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2003
DOI: 10.1097/00004872-200312000-00029
Abstract: This study examined the separate and combined effects of hypertension and diabetes on renal cortical expression of protein kinase C (PKC) isoforms -beta 1, -beta 2, -alpha and -epsilon, to determine whether albuminuria is the result of an increase in the expression of one or a combination of PKC isoforms. Corresponding changes in renal microtubules were also assessed. Diabetes (D) was induced in Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) by streptozotocin. After 24 weeks, PKC expression was determined by Western blot and microtubules were assessed by immunohistochemistry for alpha-tubulin protein. Diabetes was characterized by significant increases in glycated haemoglobin (HbA1c) as compared to controls (C). There was a significant increase of three- to four-fold in PKC protein content for all four isoforms in renal cortex from SHR-C and WKY-D, and similar and significant levels of albuminuria (approximately 10 mg/24 h) observed in these groups in comparison to WKY-C (approximately 1 mg/24 h). Interestingly, PKC-alpha and -epsilon but not PKC-beta 1 and -beta 2 protein content was doubled in SHR-D, and albuminuria increased tenfold (approximately 100 mg/24 h) in comparison to SHR-C and WKY-D. These changes were paralleled by a significant decrease in alpha-tubulin protein content of approximately 50% in SHR-C and approximately 33% in WKY-D compared to WKY-C, with a further decrease of approximately 67% in SHR-D compared to WKY-C. These findings indicate that PKC expression can be increased by either diabetes or hypertension, and that there are further specific increases in the expression of PKC isoforms -alpha and -epsilon in the model of combined diabetes and hypertension. In addition, the degree of disruption in microtubular cytoskeleton appears to be correlated with PKC activation and levels of albuminuria.
Publisher: Portland Press Ltd.
Date: 18-03-2016
DOI: 10.1042/CS20150838
Abstract: Oxidative phosphorylation (OXPHOS) drives ATP production by mitochondria, which are dynamic organelles, constantly fusing and iding to maintain kidney homoeostasis. In diabetic kidney disease (DKD), mitochondria appear dysfunctional, but the temporal development of diabetes-induced adaptations in mitochondrial structure and bioenergetics have not been previously documented. In the present study, we map the changes in mitochondrial dynamics and function in rat kidney mitochondria at 4, 8, 16 and 32 weeks of diabetes. Our data reveal that changes in mitochondrial bioenergetics and dynamics precede the development of albuminuria and renal histological changes. Specifically, in early diabetes (4 weeks), a decrease in ATP content and mitochondrial fragmentation within proximal tubule epithelial cells (PTECs) of diabetic kidneys were clearly apparent, but no changes in urinary albumin excretion or glomerular morphology were evident at this time. By 8 weeks of diabetes, there was increased capacity for mitochondrial permeability transition (mPT) by pore opening, which persisted over time and correlated with mitochondrial hydrogen peroxide (H2O2) generation and glomerular damage. Late in diabetes, by week 16, tubular damage was evident with increased urinary kidney injury molecule-1 (KIM-1) excretion, where an increase in the Complex I-linked oxygen consumption rate (OCR), in the context of a decrease in kidney ATP, indicated mitochondrial uncoupling. Taken together, these data show that changes in mitochondrial bioenergetics and dynamics may precede the development of the renal lesion in diabetes, and this supports the hypothesis that mitochondrial dysfunction is a primary cause of DKD.
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: S. Karger AG
Date: 20-02-2003
DOI: 10.1159/000068528
Abstract: Angiotensin II (ANG II) is intimately involved in normal renal function, and is estimated to exist at a normal physiological range of 6–10 n i M /i within the renal tubules. The potential role that intrarenal ANG II may play in renal disease was assessed by perfusing isolated rat kidneys with or without excess intratubular levels of ANG II, which may mimic changes in the intrarenal RAS under pathological conditions. The effects of increased systemic ANG II were also determined by infusing rats with ANG II by osmotic pump. In isolated perfused kidneys, ANG II significantly and specifically increased the fractional clearance of albumin to clinical levels, as determined by using radiolabelled albumin. This effect was reversible, as removing ANG II from the perfusate caused the albumin fractional clearance to decrease to pre-ANG II exposure levels. The increase in fractional clearance of albumin was not correlated with renal hemodynamic changes, nor glomerular permeability alterations as measured by the fractional clearance of 36 Å Ficoll and immunoglobulin G. Immunochemical analysis using anti-α-tubulin antibody of perfused kidney sections revealed that ANG II caused a marked disruption of tubular epithelial cytoskeletal components, through disassembly and reorganization of α-tubulin. This disruption was reversible. In vivo, osmotic pump delivery of ANG II at less potent dosage caused a proteinuria (Biuret) and an albuminuria (radioimmunoassay) in rats, from as early as 2 days after pump implantation. These results demonstrate that ANG II may reversibly induce clinical levels of albuminuria. These data point to an important role for renal tubules and the intratubular lumen concentrations of ANG II in the renal processing of albumin.
Publisher: Elsevier BV
Date: 11-2021
Publisher: The Endocrine Society
Date: 12-2002
Abstract: The aim of this study was to determine whether aminoguanidine (AG), an inhibitor of advanced glycation, prevents expression of the profibrotic cytokine, connective tissue growth factor (CTGF), as well as accumulation of the previously reported CTGF-dependent matrix protein, fibronectin, in a model of experimental diabetic nephropathy. Diabetic animals were randomly allocated into groups receiving 32 wk of AG or vehicle. Diabetic rats showed increases in CTGF mRNA and protein expression as well as in advanced glycation end-product (AGE) and fibronectin immunostaining, compared with nondiabetic rats. In the diabetic kidney, the increase in CTGF gene and protein expression as well as expression of the extracellular matrix protein fibronectin were prevented by AG. To further explore the relationship between AGEs and mesangial CTGF and fibronectin production, cultured human mesangial cells were exposed in vitro to soluble AGE-BSA and carboxymethyl lysine-BSA, and this led to induction of both CTGF and fibronectin. On the basis of our in vitro findings in mesangial cells linking AGEs to CTGF expression, the known prosclerotic effects of CTGF, and the ability of AG to attenuate mesangial expansion, it is postulated that the antifibrotic effects of AG in this animal model may be partially mediated by CTGF.
Publisher: Elsevier
Date: 2018
Publisher: Elsevier BV
Date: 09-2019
Publisher: Bentham Science Publishers Ltd.
Date: 2009
DOI: 10.2174/138945009787122905
Abstract: Diabetes, is a metabolic disorder characterised by chronic hyperglycaemia, hypertension, dyslipidaemia, microalbuminuria and inflammation. Moreover, there are a number of complications associated with this condition including retinopathy, neuropathy and nephropathy. Diabetic nephropathy, is the major cause of end-stage renal disease in Western societies affecting a substantial proportion (25-40%) of patients with diabetes. Advanced glycation end products (AGEs) have been identified as important modulators of the development and progression of diabetic nephropathy, through both receptor dependant and independent interactions. AGEs elicit their receptor mediated effects via their engagement with numerous receptors and binding proteins which are broadly thought to be either inflammatory (RAGE and AGE-R2) or clearance receptors (AGE-R1, AGE-R3, CD36, Scr-II, FEEL-1 and FEEL-2). Modulation of AGE receptor expression is an important potential therapeutic approach worth consideration as a treatment for diabetic nephropathy and likely applicable to other vascular complications.
Publisher: Wiley
Date: 11-2014
DOI: 10.14814/PHY2.12192
Publisher: Informa UK Limited
Date: 22-12-2017
Publisher: JMIR Publications Inc.
Date: 09-04-2018
DOI: 10.2196/RESPROT.9374
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: 29-02-2012
DOI: 10.1007/S00125-012-2495-3
Abstract: An increase in the production of reactive oxygen species is commonly thought to contribute to the development of diabetic cardiomyopathy. This study aimed to assess whether administration of the antioxidant coenzyme Q(10) would protect the diabetic heart against dysfunction and remodelling, using the db/db mouse model of type 2 diabetes. Furthermore, we aimed to compare the efficacy of coenzyme Q(10) to that of the ACE inhibitor ramipril. Six-week-old non-diabetic db/+ mice and diabetic db/db mice received either normal drinking water or water supplemented with coenzyme Q(10) for 10 weeks. Endpoint cardiac function was assessed by echocardiography and catheterisation. Ventricular tissue was collected for histology, gene expression and protein analysis. Untreated db/db diabetic mice exhibited hyperglycaemia, accompanied by diastolic dysfunction and adverse structural remodelling, including cardiomyocyte hypertrophy, myocardial fibrosis and increased apoptosis. Systemic lipid peroxidation and myocardial superoxide generation were also elevated in db/db mice. Coenzyme Q(10) and ramipril treatment reduced superoxide generation, ameliorated diastolic dysfunction and reduced cardiomyocyte hypertrophy and fibrosis in db/db mice. Phosphorylation of Akt, although depressed in untreated db/db mice, was restored with coenzyme Q(10) administration. We postulate that preservation of cardioprotective Akt signalling may be a mechanism by which coenzyme Q(10)-treated db/db mice are protected from pathological cardiac hypertrophy. These data demonstrate that coenzyme Q(10) attenuates oxidative stress and left ventricular diastolic dysfunction and remodelling in the diabetic heart. Addition of coenzyme Q(10) to the current therapy used in diabetic patients with diastolic dysfunction warrants further investigation.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2005
DOI: 10.1097/00004872-200501000-00026
Abstract: It has been postulated that vascular endothelial growth factor (VEGF) plays a role in the progression of renal injury. However, the role of other angiogenic factors and their receptors, such as the angiopoietins and Tie2, and in particular their relation to renoprotective therapies, such as agents that interrupt the renin-angiotensin system, have not been studied in the context of diabetes-related renal injury. Renal expression of VEGF, angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2) and their receptors, VEGF-R2 and Tie-2, were assessed using reverse transcription-polymerase chain reaction, immunohistochemistry and Western blotting, in control and streptozotocin diabetic rats, untreated or receiving the AT1 receptor antagonist, valsartan, or the AT2 receptor antagonist, PD123319. Diabetes was associated with increased gene and protein expression of VEGF, VEGF-R2, Ang-1, Ang-2 and Tie-2. AT1 receptor antagonism attenuated gene expression of these cytokines and receptors, yet PD123319, which had no effect on blood pressure, reduced VEGF-R2 and Ang-1 gene expression and decreased VEGF, Ang-1 and Ang-2 protein levels. In experimental diabetes, there is significant upregulation within the kidney of various angiogenic cytokines and their receptors. Furthermore, the effects of angiotensin II receptor blockade on these parameters is consistent with the VEGF-VEGF-R2 and angiopoietin-Tie-2 axes being modulated in the kidney by haemodynamic factors in the diabetic context.
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: Springer Science and Business Media LLC
Date: 09-07-2016
DOI: 10.1007/S10719-016-9691-1
Abstract: Advanced glycation end products (AGEs) are the final products of the Maillard reaction, a complex process that has been studied by food chemists for a century. Over the past 30 years, the biological significance of advanced glycation has also been discovered. There is mounting evidence that advanced glycation plays a homeostatic role within the body and that food-related Maillard products, intermediates such as reactive α-dicarbonyl compounds and AGEs, may influence this process. It remains to be understood, at what point AGEs and their intermediates become pathogenic and contribute to the pathogenesis of chronic diseases that inflict current society. Diabetes and its complications have been a major focus of AGE biology due to the abundance of excess sugar and α-dicarbonyls in this family of diseases. While further temporal information is required, a number of pharmacological agents that inhibit components of the advanced glycation pathway have already showed promising results in preclinical models. These therapies appear to have a wide range of mechanistic actions to reduce AGE load. Some of these agents including Alagebrium, have translated successfully to clinical trials, while others such as aminoguanidine, have had undesirable side-effect profiles. This review will discuss different pharmacological agents that have been used to reduce AGE burden in preclinical models of disease with a focus on diabetes and its complications, compare outcomes of those therapies that have reached clinical trials, and provide further rationale for the use of inhibitors of the glycation pathway in chronic diseases.
Publisher: Springer Science and Business Media LLC
Date: 20-09-2019
DOI: 10.1038/S41598-019-50221-0
Abstract: The accumulation of advanced glycation end products (AGEs) have been implicated in the development and progression of diabetic kidney disease (DKD). There has been interest in investigating the potential of AGE clearance receptors, such as oligosaccharyltransferase-48 kDa subunit (OST48) to prevent the detrimental effects of excess AGE accumulation seen in the diabetic kidney. Here the objective of the study was to increase the expression of OST48 to examine if this slowed the development of DKD by facilitating the clearance of AGEs. Groups of 8-week-old heterozygous knock-in male mice (n = 9–12/group) over-expressing the gene encoding for OST48, dolichyl-diphosphooligosaccharide-protein glycosyltransferase ( DDOST +/−) and litter mate controls were randomised to either (i) no diabetes or (ii) diabetes induced via multiple low-dose streptozotocin and followed for 24 weeks. By the study end, global over expression of OST48 increased glomerular OST48. This facilitated greater renal excretion of AGEs but did not affect circulating or renal AGE concentrations. Diabetes resulted in kidney damage including lower glomerular filtration rate, albuminuria, glomerulosclerosis and tubulointerstitial fibrosis. In diabetic mice, tubulointerstitial fibrosis was further exacerbated by global increases in OST48. There was significantly insulin effectiveness, increased acute insulin secretion, fasting insulin concentrations and AUC insulin observed during glucose tolerance testing in diabetic mice with global elevations in OST48 when compared to diabetic wild-type littermates. Overall, this study suggested that despite facilitating urinary-renal AGE clearance, there were no benefits observed on kidney functional and structural parameters in diabetes afforded by globally increasing OST48 expression. However, the improvements in insulin secretion seen in diabetic mice with global over-expression of OST48 and their dissociation from effects on kidney function warrant future investigation.
Publisher: Public Library of Science (PLoS)
Date: 11-11-2015
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: Wiley
Date: 20-07-2016
Abstract: In experimental studies, moderate to high concentrations of sCD14 (serum cluster of differentiation 14 protein) prevent lipopolysaccharide (LPS)-induced systemic inflammation, while low concentrations may promote inflammation. Given that metabolic endotoxemia is thought to initiate high-fat diet-induced insulin resistance, we explored the association between sCD14 concentrations and insulin sensitivity in humans. Healthy non-obese (n = 12, BMI 26 ± 5y), obese (n = 11, BMI 33.45 ± 3.2) and morbidly obese participants (n = 38, BMI 45 ± 7) underwent measurement of body composition (dual energy X-ray absorptiometry) and a hyperinsulinemic-euglycemic cl to measure insulin sensitivity (M value). Circulating sCD14 concentrations were measured by ELISA. Non-obese participants had lower circulating sCD14 concentrations compared to obese (p = 0.03). Circulating sCD14 concentrations were positively associated with percent body fat, waist circumference and white blood cell count and negatively associated with insulin sensitivity. In contrast, circulating sCD14 were positively associated with insulin sensitivity in morbidly obese participants. In regression analysis, insulin sensitivity (r = 0.52, p = 0.004) and fasting triglycerides (r = 0.49, p = 0.005) contributed independently to circulating sCD14 variance after controlling for age, sex and BMI in these morbidly obese subjects. These findings suggest that circulating sCD14 concentrations, through its compensatory (in non-obese subjects) or buffering role (in morbidly obese subjects), could exert an important role in modulating insulin sensitivity.
Publisher: Elsevier BV
Date: 08-2007
Abstract: The biochemical process of advanced glycation appears to play a central role in the development and progression of diabetic vascular complications. A number of strategies to influence this pathway have been designed, one of which involves the putative advanced glycation end-product (AGE) crosslink breaker, alagebrium which has been shown in in vitro studies to cleave preformed AGE crosslinks. This agent has been studied in various models of diabetic complications and has been shown to attenuate diabetic renal disease, cardiac dysfunction, and atherosclerosis. In addition to the ability of alagebrium to reduce tissue levels of AGEs, this drug appears to inhibit activation of certain protein kinase C isoforms. Planned clinical studies in diabetic subjects at risk of complications should assist in determining the role of alagebrium in the prevention, retardation, and reversal of diabetic micro- and macrovascular disease.
Publisher: JMIR Publications Inc.
Date: 09-11-2017
Publisher: Public Library of Science (PLoS)
Date: 04-02-2013
Publisher: American Diabetes Association
Date: 16-09-2011
DOI: 10.2337/DB10-1033
Abstract: Excess accumulation of advanced glycation end products (AGEs) contributes to aging and chronic diseases. We aimed to obtain evidence that exposure to AGEs plays a role in the development of type 1 diabetes (T1D). The effect of AGEs was examined on insulin secretion by MIN6N8 cells and mouse islets and in vivo in three separate rodent models: AGE-injected or high AGE–fed Sprague-Dawley rats and nonobese diabetic (NODLt) mice. Rodents were also treated with the AGE-lowering agent alagebrium. β-Cells exposed to AGEs displayed acute glucose-stimulated insulin secretory defects, mitochondrial abnormalities including excess superoxide generation, a decline in ATP content, loss of MnSOD activity, reduced calcium flux, and increased glucose uptake, all of which were improved with alagebrium treatment or with MnSOD adenoviral overexpression. Isolated mouse islets exposed to AGEs had decreased glucose-stimulated insulin secretion, increased mitochondrial superoxide production, and depletion of ATP content, which were improved with alagebrium or with MnTBAP, an SOD mimetic. In rats, transient or chronic exposure to AGEs caused progressive insulin secretory defects, superoxide generation, and β-cell death, ameliorated with alagebrium. NODLt mice had increased circulating AGEs in association with an increase in islet mitochondrial superoxide generation, which was prevented by alagebrium, which also reduced the incidence of autoimmune diabetes. Finally, at-risk children who progressed to T1D had higher AGE concentrations than matched nonprogressors. These findings demonstrate that AGEs directly cause insulin secretory defects, most likely by impairing mitochondrial function, which may contribute to the development of T1D.
Publisher: Springer Science and Business Media LLC
Date: 23-12-2008
Publisher: Baishideng Publishing Group Inc.
Date: 2016
Publisher: Springer Science and Business Media LLC
Date: 13-05-2012
DOI: 10.1038/NM.2750
Abstract: This study establishes a mechanism for metabolic hyperalgesia based on the glycolytic metabolite methylglyoxal. We found that concentrations of plasma methylglyoxal above 600 nM discriminate between diabetes-affected in iduals with pain and those without pain. Methylglyoxal depolarizes sensory neurons and induces post-translational modifications of the voltage-gated sodium channel Na(v)1.8, which are associated with increased electrical excitability and facilitated firing of nociceptive neurons, whereas it promotes the slow inactivation of Na(v)1.7. In mice, treatment with methylglyoxal reduces nerve conduction velocity, facilitates neurosecretion of calcitonin gene-related peptide, increases cyclooxygenase-2 (COX-2) expression and evokes thermal and mechanical hyperalgesia. This hyperalgesia is reflected by increased blood flow in brain regions that are involved in pain processing. We also found similar changes in streptozotocin-induced and genetic mouse models of diabetes but not in Na(v)1.8 knockout (Scn10(-/-)) mice. Several strategies that include a methylglyoxal scavenger are effective in reducing methylglyoxal- and diabetes-induced hyperalgesia. This previously undescribed concept of metabolically driven hyperalgesia provides a new basis for the design of therapeutic interventions for painful diabetic neuropathy.
Publisher: Elsevier BV
Date: 03-2015
DOI: 10.1016/J.CARBPOL.2014.11.005
Abstract: Liver glycogen, a highly branched polymer, acts as our blood-glucose buffer. While past structural studies have extracted glycogen from fresh or frozen tissue using a cold-water, sucrose-gradient centrifugation technique, a method for the extraction of glycogen from formalin-fixed liver would allow the analysis of glycogen from human tissues that are routinely collected in pathology laboratories. In this study, both sucrose-gradient and formalin-fixed extraction techniques were carried out on piglet livers, with the yields, purities and size distributions (using size exclusion chromatography) compared. The formalin extraction technique, when combined with a protease treatment, resulted in higher yields (but lower purities) of glycogen with size distributions similar to the sucrose-gradient centrifugation technique. This formalin extraction procedure was also significantly faster, allowing glycogen extraction throughput to increase by an order of magnitude. Both extraction techniques were compatible with mass spectrometry proteomics, with analysis showing the two techniques were highly complementary.
Publisher: American Diabetes Association
Date: 17-10-2019
DOI: 10.2337/DB19-0043
Abstract: The sequelae of diabetes include microvascular complications such as diabetic kidney disease (DKD), which involves glucose-mediated renal injury associated with a disruption in mitochondrial metabolic agility, inflammation, and fibrosis. We explored the role of the innate immune complement component C5a, a potent mediator of inflammation, in the pathogenesis of DKD in clinical and experimental diabetes. Marked systemic elevation in C5a activity was demonstrated in patients with diabetes conventional renoprotective agents did not therapeutically target this elevation. C5a and its receptor (C5aR1) were upregulated early in the disease process and prior to manifest kidney injury in several erse rodent models of diabetes. Genetic deletion of C5aR1 in mice conferred protection against diabetes-induced renal injury. Transcriptomic profiling of kidney revealed diabetes-induced downregulation of pathways involved in mitochondrial fatty acid metabolism. Interrogation of the lipidomics signature revealed abnormal cardiolipin remodeling in diabetic kidneys, a cardinal sign of disrupted mitochondrial architecture and bioenergetics. In vivo delivery of an orally active inhibitor of C5aR1 (PMX53) reversed the phenotypic changes and normalized the renal mitochondrial fatty acid profile, cardiolipin remodeling, and citric acid cycle intermediates. In vitro exposure of human renal proximal tubular epithelial cells to C5a led to altered mitochondrial respiratory function and reactive oxygen species generation. These experiments provide evidence for a pivotal role of the C5a/C5aR1 axis in propagating renal injury in the development of DKD by disrupting mitochondrial agility, thereby establishing a new immunometabolic signaling pathway in DKD.
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: American Diabetes Association
Date: 17-06-2022
DOI: 10.2337/DB22-0177
Abstract: Type 1 diabetes is an autoimmune disease with no cure, where clinical translation of promising therapeutics has been h ered by the reproducibility crisis. Here, short-term administration of an antagonist to the receptor for advanced glycation end products (sRAGE) protected against murine diabetes at two independent research centers. Treatment with sRAGE increased regulatory T cells (Tregs) within the islets, pancreatic lymph nodes, and spleen, increasing islet insulin expression and function. Diabetes protection was abrogated by Treg depletion and shown to be dependent on antagonizing RAGE with use of knockout mice. Human Tregs treated with a RAGE ligand downregulated genes for suppression, migration, and Treg homeostasis (FOXP3, IL7R, TIGIT, JAK1, STAT3, STAT5b, CCR4). Loss of suppressive function was reversed by sRAGE, where Tregs increased proliferation and suppressed conventional T-cell ision, confirming that sRAGE expands functional human Tregs. These results highlight sRAGE as an attractive treatment to prevent diabetes, showing efficacy and reproducibility at multiple research centers and in human T cells.
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: American Diabetes Association
Date: 08-01-2015
DOI: 10.2337/DC14-1186
Abstract: Dietary advanced glycation end products (AGEs) and their interactions with the receptor for AGEs (RAGE) may play a role in the pathogenesis of type 1 diabetes. This study set out to assess whether there is any association of circulating concentrations of soluble RAGE (sRAGE), AGEs, and their ratio with the appearance of diabetes-associated autoantibodies in children progressing to clinical diabetes. Serum concentrations of sRAGE, N-ε(carboxymethyl)lysine (CML) adducts, and the sRAGE/CML ratio were analyzed in children who progressed to type 1 diabetes. The s les were taken at four time points: before seroconversion, at the time of the first autoantibody-positive s le, at the time of the first s le positive for multiple (& ) autoantibodies, and close to the disease diagnosis. S les of autoantibody-negative controls matched for age, sex, and HLA-conferred diabetes risk were analyzed at corresponding time points. The prediabetic children had higher sRAGE concentrations before seroconversion (Pc = 0.03), at the appearance of multiple autoantibodies (Pc = 0.008), and close to diagnosis (Pc = 0.04). Close to diagnosis, the cases had lower CML concentrations than the controls (Pc = 0.004). Prediabetic children had a higher sRAGE/CML ratio than the controls before seroconversion (Pc = 0.008) and at diagnosis (Pc & 0.001). Prediabetic children have higher concentrations of sRAGE and a higher sRAGE/CML ratio than healthy controls. Circulating sRAGE concentrations seem to decline with the appearance of diabetes-predictive autoantibodies in children progressing to type 1 diabetes. The higher sRAGE/CML ratio in prediabetic children may reflect a higher AGE scavenger capacity.
Publisher: Elsevier BV
Date: 04-2001
DOI: 10.1046/J.1523-1755.2001.0590041333.X
Abstract: There is growing evidence of long-term pathological consequences following renal ischemia. Endothelin (ET) receptor antagonists have proved beneficial in the treatment of ischemic acute renal failure (IARF) however, the long-term outcomes have not been assessed in this disease. Experimental IARF was induced in uninephrectomized female Sprague-Dawley rats (N = 8) by cl ing of the renal pedicle. At 24-hours postischemia, a once-only administration of drug or vehicle was given. One ischemic group received saline only (saline ischemic), and two other ischemic groups received either SB 234551 (ETA receptor antagonist, ETA group) or SB 209670 (ETA and ETB receptor antagonist, ETA/ETB group). A uninephrectomized control group was sham operated to simulate operative conditions without ischemia and was given a once-only saline infusion (sham ischemic). All groups were sacrificed at six-months postischemia. Serum creatinine was assessed daily for one week and then every four weeks. Glomerular filtration rates (GFRs), systolic blood pressure, 24-hour urine collection, and creatinine clearance were performed just prior to sacrifice. Immunohistochemistry for monocytes and macrophages (Mo and Mphi), myofibroblasts (MF, alpha-SMA), collagen IV, and collagen III was also evaluated. Cell kinetics were studied by immunostaining for proliferating cell nuclear antigen (PCNA) and by TUNEL. Urinalysis revealed significant increases in urinary protein and albumin in the ETA/ETB group when compared with all other groups. GFRs and creatinine clearance were also decreased significantly in the ETA/ETB group. Urine albumin, protein, GFR, and creatinine clearance in the ETA group, however, were not different from the sham ischemic and saline ischemic groups. Systolic blood pressure was increased in the saline ischemic group as compared with all other groups. Kidney weights were increased in all ischemic groups, but no differences were observed between the saline ischemic group and ETR antagonist-treated groups. Immunohistochemistry revealed relationships between Mo and Mphi, MF, and tubulointerstitial collagen III, where the saline ischemic and ETA/ETB groups were increased as compared with the sham ischemic and ETA groups. There was no change observed in tubulointerstitial collagen IV accumulation. The largest number of proliferating cells was demonstrated in the ETA/ETB group, whereas apoptotic cells were identified in small amounts in all groups, with the largest number being found in the saline ischemic group. Renal ischemia appears to have long-term functional and pathological consequences that can be prevented by treatment with ETA receptor antagonists. Blockade of both ETA and ETB receptors, however, appears to be detrimental to long-term kidney function.
Publisher: Elsevier BV
Date: 06-2016
Abstract: The consumption of advanced glycation end products (AGEs) has increased because of modern food processing and has been linked to the development of type 2 diabetes in rodents. We determined whether changing dietary AGE intake could modulate insulin sensitivity and secretion in healthy, overweight in iduals. We performed a double-blind, randomized, crossover trial of diets in 20 participants [6 women and 14 men mean ± SD body mass index (in kg/m(2)): 29.8 ± 3.7]. Isoenergetic- and macronutrient-matched diets that were high or low in AGE content were alternately consumed for 2 wk and separated by a 4-wk washout period. At the beginning and end of each dietary period, a hyperinsulinemic-euglycemic cl and an intravenous glucose tolerance test were performed. Dietary, plasma and urinary AGEs N(€)-(carboxymethyl)lysine (CML), N(€)-(carboxyethyl)lysin (CEL), and methylglyoxal-derived hydroimadazolidine (MG-H1) were measured with the use of mass spectrometry. Participants consumed less CML, CEL, and MG-H1 during the low-AGE dietary period than during the high-AGE period (all P < 0.05), which was confirmed by changes in urinary AGE excretion. There was an overall difference in insulin sensitivity of -2.1 mg · kg(-1) · min(-1) between diets (P = 0.001). Insulin sensitivity increased by 1.3 mg · kg(-1) · min(-1) after the low-AGE diet (P = 0.004), whereas it showed a tendency to decrease by 0.8 mg · kg(-1) · min(-1) after the high-AGE diet (P = 0.086). There was no difference in body weight or insulin secretion between diets (P = NS). A diet that is low in AGEs may reduce the risk of type 2 diabetes by increasing insulin sensitivity. Hence, a restriction in dietary AGE content may be an effective strategy to decrease diabetes and cardiovascular disease risks in overweight in iduals. This trial was registered at clinicaltrials.gov as NCT00422253.
Publisher: Wiley
Date: 23-01-2017
DOI: 10.1002/DMRR.2872
Abstract: Advanced glycation end products (AGEs) and their interaction with the receptor for AGEs (RAGE) have been studied for their role in the pathogenesis and complications of type 1 diabetes. Decreased concentrations of soluble RAGE (sRAGE) have been reported in acute autoimmune inflammation. We set out to analyze the changes in sRAGE concentration during preclinical diabetes in children seroconverting to islet autoantibody positivity. We measured serum concentrations of sRAGE in 168 children who progressed to clinical disease and 43 children who turned positive for at least 2 diabetes-associated autoantibodies but remained nondiabetic. We analyzed the sRAGE before seroconversion in the first autoantibody-positive s le and annually thereafter until the diagnosis of type 1 diabetes or end of follow-up. Both groups had similar sRAGE before seroconversion, but subsequently, sRAGE concentrations were lower (P < .001) in the progressors. The progressors had significantly higher sRAGE concentrations before than after seroconversion (P < .001). The nonprogressors did not experience a similar decrease. The sRAGE concentrations remained stable after seroconversion in both groups. These data indicate that sRAGE may be involved in the initiation of beta-cell autoimmunity but not in the progression from beta-cell autoimmunity to clinical disease.
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: Springer Science and Business Media LLC
Date: 06-10-0012
DOI: 10.1007/S10719-016-9693-Z
Abstract: Diabetic patients are postulated to be in a perpetual state of oxidative stress and inflammation at sites where chronic complications occur. The accumulation of AGEs derived from both endogenous and exogenous sources (such as the diet) have been implicated in the development and progression of diabetic complications, particularly nephropathy. There has been some interest in investigating the potential for reducing the AGE burden in chronic disease, through the action of AGE "clearance" receptors, such as the advanced glycation end-product receptor 1 (AGE-R1). Reducing the burden of AGEs has been linked to attenuation of inflammation, slower progression of diabetic complications (in particular vascular and renal complications) and has been shown to extend lifespan. To date, however, there have been no direct investigations into whether AGE-R1 has any role in modulating normal kidney function, or specifically during the development and progression of diabetes. This mini-review will focus on the recent advances in knowledge around the mechanistic function of AGE-R1 and the implications of this for the pathogenesis of diabetic kidney disease.
Publisher: Mary Ann Liebert Inc
Date: 03-2007
Abstract: Diabetic nephropathy remains a major cause of morbidity and mortality in the diabetic population and is the leading cause of end-stage renal failure in the Western World. Despite current therapeutics including intensified glycemic control and blood pressure lowering agents, renal disease continues to progress relentlessly in diabetic patients, albeit at a lower rate. It is well recognized that metabolic and hemodynamic factors play a central role in accelerating renal disease in diabetes. However, recent experimental studies have suggested that increased generation of reactive oxygen species (ROS) as a result of the diabetic milieu may play a central role in the progression of diabetic microvascular complications. These ROS appear to be generated primarily from mitochondrial sources and via the enzyme, NADPH oxidase. This review focuses on how ROS play a deleterious role in the diabetic kidney and how they are involved in crosstalk among various signaling pathways, ultimately leading to renal dysfunction and structural injury.
Publisher: JMIR Publications Inc.
Date: 09-11-2017
Publisher: Springer Science and Business Media LLC
Date: 15-07-2010
Publisher: The Endocrine Society
Date: 22-10-2018
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: The Endocrine Society
Date: 02-2007
DOI: 10.1210/EN.2006-1300
Abstract: Blockade of advanced glycation end product (AGE) accumulation with alagebrium with concomitant angiotensin converting enzyme inhibition was tested for effects on renal function and on other postulated mediators of diabetic renal disease including the renin-angiotensin system, AGEs, mitochondrial and cytosolic oxidative stress, and intracellular signaling molecules. Sprague Dawley rats were rendered diabetic with streptozocin and followed consecutively for 32 wk with nondiabetic controls. Groups were treated with ramipril (1 mg/kg.d wk 0-32) alagebrium (10 mg/kg.d wk 16-32) or a combination of both. Although in idual treatments had significant effects on albuminuria, no further improvements were seen with combination therapy. Changes in urinary vascular endothelial growth factor excretion mirrored those seen in albuminuria. Diabetes was associated with suppression of circulating angiotensin II in the context of increased circulating and renal levels of the AGE, carboxymethyllysine. All treatments attenuated circulating but not renal carboxymethyllysine levels. The renal gene expression of AGE receptor 1 and soluble receptor for advanced glycation end products were markedly reduced by diabetes and normalized with alagebrium. Diabetes induced renal mitochondrial oxidative stress, which was reduced with alagebrium. In the cytosol, both therapies were equally effective in reducing reactive oxygen species production. Increases in membranous protein kinase C activity in diabetes were attenuated by all treatments, whereas diabetes-associated increases in nuclear factor-kappaB p65 translocation remained unaltered by any therapy. It is evident that renin-angiotensin system blockade and AGE inhibition have specific effects. However, many of their downstream effects appear to be similar, suggesting that their renoprotective benefits may ultimately involve common pathways and key points of convergence, which could be important targets for new therapies in diabetic nephropathy.
Publisher: Bentham Science Publishers Ltd.
Date: 03-08-2016
DOI: 10.2174/1389450116666150727114410
Abstract: Mitochondria produce the majority of cellular energy via the "slow burn" of substrates such as glucose, free fatty acids and ketones. In diabetes, altered mitochondrial energetics and substrate utilisation may explain, in part, an organ's susceptibility to complications. This is particularly evident at sites such as the kidney, heart, neurons and retina, which have high energy demands and oxygen consumption rates to meet functional requirements. Within this review we highlight the recent research implicating mitochondrial dysfunction, with particular focus on the contribution of mitochondrial reactive oxygen species, on the development and progression of diabetes complications. Finally, we discuss the current strategies which are being assessed to combat mitochondrial dysfunction in diabetes complications.
Publisher: Elsevier BV
Date: 07-2016
DOI: 10.1016/J.TEM.2016.05.002
Abstract: A recent study has highlighted the relationship between mitochondrial ATP generation and protection against organ injury following ischaemia-reperfusion injury in the kidney. Kidneys are fuel-hungry organs and only second to the heart in mitochondrial number and oxygen consumption. This article speculates on why this might be so.
Publisher: American Diabetes Association
Date: 18-03-2021
DOI: 10.2337/DB20-1081
Abstract: Half of the mortality in diabetes is seen in in iduals & years of age and commonly predicted by the early onset of diabetic kidney disease (DKD). In type 1 diabetes, increased urinary albumin-to-creatinine ratio (uACR) during adolescence defines this risk, but the pathological factors responsible remain unknown. We postulated that early in diabetes, glucose variations contribute to kidney injury molecule-1 (KIM-1) release from circulating T cells, elevating uACR and DKD risk. DKD risk was assigned in youth with type 1 diabetes (n = 100 20.0 ± 2.8 years males/females, 54:46 HbA1c 66.1 [12.3] mmol/mol diabetes duration 10.7 ± 5.2 years and BMI 24.5 [5.3] kg/m2) and 10-year historical uACR, HbA1c, and random blood glucose concentrations collected retrospectively. Glucose fluctuations in the absence of diabetes were also compared with streptozotocin diabetes in apolipoprotein E−/− mice. Kidney biopsies were used to examine infiltration of KIM-1–expressing T cells in DKD and compared with other chronic kidney disease. In iduals at high risk for DKD had persistent elevations in uACR defined by area under the curve (AUC uACRAUC0–10yrs, 29.7 ± 8.8 vs. 4.5 ± 0.5 P & 0.01 vs. low risk) and early kidney dysfunction, including ∼8.3 mL/min/1.73 m2 higher estimated glomerular filtration rates (modified Schwartz equation Padj & 0.031 vs. low risk) and plasma KIM-1 concentrations (∼15% higher vs. low risk P & 0.034). High-risk in iduals had greater glycemic variability and increased peripheral blood T-cell KIM-1 expression, particularly on CD8+ T cells. These findings were confirmed in a murine model of glycemic variability both in the presence and absence of diabetes. KIM-1+ T cells were also infiltrating kidney biopsies from in iduals with DKD. Healthy primary human proximal tubule epithelial cells exposed to plasma from high-risk youth with diabetes showed elevated collagen IV and sodium–glucose cotransporter 2 expression, alleviated with KIM-1 blockade. Taken together, these studies suggest that glycemic variations confer risk for DKD in diabetes via increased CD8+ T-cell production of KIM-1.
Publisher: American Diabetes Association
Date: 06-2008
DOI: 10.2337/DB08-0057
Abstract: It is postulated that localized tissue oxidative stress is a key component in the development of diabetic nephropathy. There remains controversy, however, as to whether this is an early link between hyperglycemia and renal disease or develops as a consequence of other primary pathogenic mechanisms. In the kidney, a number of pathways that generate reactive oxygen species (ROS) such as glycolysis, specific defects in the polyol pathway, uncoupling of nitric oxide synthase, xanthine oxidase, NAD(P)H oxidase, and advanced glycation have been identified as potentially major contributors to the pathogenesis of diabetic kidney disease. In addition, a unifying hypothesis has been proposed whereby mitochondrial production of ROS in response to chronic hyperglycemia may be the key initiator for each of these pathogenic pathways. This postulate emphasizes the importance of mitochondrial dysfunction in the progression and development of diabetes complications including nephropathy. A mystery remains, however, as to why antioxidants per se have demonstrated minimal renoprotection in humans despite positive preclinical research findings. It is likely that the utility of current study approaches, such as vitamin use, may not be the ideal antioxidant strategy in human diabetic nephropathy. There is now an increasing body of data to suggest that strategies involving a more targeted antioxidant approach, using agents that penetrate specific cellular compartments, may be the elusive additive therapy required to further optimize renoprotection in diabetes.
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: Springer Science and Business Media LLC
Date: 09-08-2023
DOI: 10.1038/S41598-023-39243-X
Abstract: Hypoglycemia in type 1 diabetes associates with changes in the pancreatic islet α cells, where the receptor for advanced glycation end products (RAGE) is highly expressed. This study compared islet RAGE expression in donors without diabetes, those at risk of, and those with type 1 diabetes. Laser-dissected islets were subject to RNA bioinformatics and adjacent pancreatic tissue were assessed by confocal microscopy. We found that islets from type 1 diabetes donors had differential expression of the RAGE gene ( AGER ) and its correlated genes, based on glucagon expression. Random forest machine learning revealed that AGER was the most important predictor for islet glucagon levels. Conversely, a generalized linear model identified that glucagon expression could be predicted by expression of RAGE signaling molecules, its ligands and enzymes that create or clear RAGE ligands. Confocal imaging co-localized RAGE, its ligands and signaling molecules to the α cells. Half of the type 1 diabetes cohort comprised of adolescents and a patient with history of hypoglycemia—all showed an inverse relationship between glucagon and RAGE. These data confirm an association between glucagon and islet RAGE, its ligands and signaling pathways in type 1 diabetes, which warrants functional investigation into a role for RAGE in hypoglycemia.
Publisher: Elsevier BV
Date: 03-2018
DOI: 10.1016/J.JSBMB.2017.07.013
Abstract: Vitamin D has been reported to have anti-inflammatory properties in in vitro and animal studies, which are thought to occur via inhibition of the nuclear factor kappa-B (NFκB) pathway. However, the association between vitamin D and in vivo NFκB activity in humans has not previously been reported. The aim of the present study was to examine the associations between circulating 25-hydroxyvitamin D (25(OH)D) concentrations and NFκB activity in peripheral blood mononuclear cells (PBMCs) as well as plasma inflammatory markers in healthy in iduals. We hypothesized that 25(OH)D concentrations would be negatively associated with NFκB activity and pro-inflammatory markers downstream of NFκB, and positively associated with anti-inflammatory markers. We measured circulating 25(OH)D (chemiluminescent immunoassay) anthropometry: body mass index (BMI), waist-to-hip ratio (WHR), and % body fat (dual X-ray absorptiometry) plasma pro- and anti-inflammatory markers: high sensitivity C-reactive protein (hsCRP), tumor necrosis factor (TNF), monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6), and IL-10 (ELISA) and NFκB activity in PBMCs (DNA-binding assay). Forty-nine participants were included in the study (21M/28F age=31.6±10.2years (mean±SD) BMI=28.4±4.6kg/m
Publisher: Elsevier BV
Date: 11-2003
DOI: 10.1016/J.ABB.2003.08.017
Abstract: Advanced glycation endproducts (AGEs) have been postulated to play a role in the development of both nephropathy and large vessel disease in diabetes. However, it is still not clear which AGE subtypes play a pathogenetic role and which of several AGE receptors mediate AGE effects on cells. This review summarises the renoprotective effect of inhibitors of AGE formation, including aminoguanidine, and of cross-link breakers, including ALT-711, on experimental diabetic nephropathy and on mesenteric vascular hypertrophy. It also demonstrates similar effects of aminoguanidine and ramipril (an angiotensin converting enzyme inhibitor) on fluorescent and immunoassayable AGE levels, renal protein kinase C activity, nitrotyrosine expression, lysosomal function, and protein handling in experimental diabetes. These findings indicate that inhibition of the renin angiotensin system blocks both upstream and downstream pathways leading to tissue injury. We postulate that the chemical pathways leading to advanced glycation endproduct formation and the renin angiotensin systems may interact through the generation of free radicals, induced both by glucose and angiotensin II. There is also evidence to suggest that AGE-dependent pathways may play a role in the development of tubulointerstitial fibrosis in the diabetic kidney. This effect is mediated through RAGE and is TGF-beta and CTGF-dependent.
Publisher: American Physiological Society
Date: 12-2008
DOI: 10.1152/AJPRENAL.90234.2008
Abstract: Heat shock protein (HSP) HSP27, HSP60, HSP70, and HSP90 are induced by cellular stresses and play a key role in cytoprotection. Both hyperglycemia and glomerular hypertension are crucial determinants in the pathogenesis of diabetic nephropathy and impose cellular stresses on renal target cells. We studied both the expression and the phosphorylation state of HSP27, HSP60, HSP70, and HSP90 in vivo in rats made diabetic with streptozotocin and in vitro in mesangial cells and podocytes exposed to either high glucose or mechanical stretch. Diabetic and control animals were studied 4, 12, and 24 wk after the onset of diabetes. Immunohistochemical analysis revealed an overexpression of HSP25, HSP60, and HSP72 in the diabetic outer medulla, whereas no differences were seen in the glomeruli. Similarly, exposure neither to high glucose nor to stretch altered HSP expression in mesangial cells and podocytes. By contrast, the phosphorylated form of HSP27 was enhanced in the glomerular podocytes of diabetic animals, and in vitro exposure of podocytes to stretch induced HSP27 phosphorylation via a P38-dependent mechanism. In conclusion, diabetes and diabetes-related insults differentially modulate HSP27, HSP60, and HSP70 expression hosphorylation in the glomeruli and in the medulla, and this may affect the ability of renal cells to mount an effective cytoprotective response.
Publisher: Springer Science and Business Media LLC
Date: 08-01-2013
Abstract: Glycaemic control, reduction of blood pressure using agents that block the renin-angiotensin system and control of dyslipidaemia are the major strategies used in the clinical management of patients with diabetes mellitus. Each of these approaches interrupts a number of pathological pathways, which directly contributes to the vascular complications of diabetes mellitus, including renal disease, blindness, neuropathy and cardiovascular disease. However, research published over the past few years has indicated that many of the pathological pathways important in the development of the vascular complications of diabetes mellitus are equally relevant to the initiation of diabetes mellitus itself. These pathways include insulin signalling, generation of cellular energy, post-translational modifications and redox imbalances. This Review will examine how the development of diabetes mellitus has come full circle from initiation to complications and suggests that the development of diabetes mellitus and the progression to chronic complications both require the same mechanistic triggers.
Publisher: Informa Healthcare
Date: 03-2005
DOI: 10.1517/13543784.14.3.279
Abstract: Diabetic nephropathy is a leading cause of end-stage renal disease, and accounts for significant morbidity and mortality in patients with diabetes. Diabetic nephropathy seems to occur as a result of an interaction between metabolic and haemodynamic factors, which activate common pathways that lead to renal damage. In the past, the treatment of diabetic nephropathy has focused on the control of hyperglycaemia. Newer targets, some of which are linked to glucose-dependent pathways, appear to be a major focus of new treatments directed against the development and progression of renal damage as a result of diabetes. It is anticipated that additional therapeutic approaches that inhibit both metabolic and haemodynamic pathways will include strategies that target growth factors, cytokines and intracellular second messengers. Such an approach is expected to lead to improved therapies for the treatment of diabetic nephropathy.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2004
Publisher: Elsevier BV
Date: 08-2013
DOI: 10.1016/J.COPH.2013.06.009
Abstract: Cardiovascular disease (CVD) is a leading cause of mortality in the Western World. The development and onset of disease can be attributed to many risk factors including genetic susceptibility, diabetes, obesity and atherosclerosis. Numerous studies highlight the production of advanced glycation endproducts (AGEs) and interaction with their receptor (RAGE) as playing a key pathogenic role. The AGEs-RAGE axis is thought to contribute to a proinflammatory environment inducing cellular dysfunction which cascades towards pathology. Mitochondrial dysfunction concurrently plays a role in these proinflammatory responses presenting excess reactive oxygen species (ROS) production under pathological conditions. This ROS release can exacerbate the production of AGEs fuelling the fire somewhat. However, the AGEs-RAGE axis may influence mitochondrial function independently of inflammation. Therefore instigation of the AGEs-RAGE axis may facilitate spiralling towards pathology on many fronts including CVD development.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-07-2013
DOI: 10.1161/CIRCRESAHA.113.300689
Abstract: High-density lipoprotein cholesterol elevation via cholesteryl ester transfer protein (CETP) inhibition represents a novel therapy for atherosclerosis, which also may have relevance for type 2 diabetes mellitus. The current study assessed the effects of a CETP inhibitor on postprandial insulin, ex vivo insulin secretion, and cholesterol efflux from pancreatic β-cells. Healthy participants received a daily dose of CETP inhibitor (n=10) or placebo (n=15) for 14 days in a randomized double-blind study. Insulin secretion and cholesterol efflux from MIN6N8 β-cells were determined after incubation with treated plasma. CETP inhibition increased plasma high-density lipoprotein cholesterol, apolipoprotein AI, and postprandial insulin. MIN6N8 β-cells incubated with plasma from CETP inhibitor–treated in iduals (compared with placebo) exhibited an increase in both glucose-stimulated insulin secretion and cholesterol efflux over the 14-day treatment period. CETP inhibition increased postprandial insulin and promoted ex vivo β-cell glucose-stimulated insulin secretion, potentially via enhanced β-cell cholesterol efflux.
Publisher: JMIR Publications Inc.
Date: 29-07-2015
DOI: 10.2196/RESPROT.4552
Publisher: Informa UK Limited
Date: 02-05-2017
DOI: 10.1080/09637486.2017.1319468
Abstract: We have previously shown that an isoenergetic low advanced glycation end products (AGEs) diet matched for macronutrient content improved insulin sensitivity compared to high AGE diet. Here, we evaluated the differences in micronutrient intake of these two dietary patterns and if they could explain differences in insulin sensitivity. Participants consumed the intervention diets each for 2 weeks with 4 weeks of habitual dietary intake (washout) in-between. Dietary analysis revealed that the high AGE diet contained greater levels of retinol equivalents (RE) (478.9 + 151.3 μg/day versus 329.0 + 170.0 μg/day p < .006), vitamin A (806.3 + 223.5 (μg RE)/day versus 649.1 + 235.8 (μg RE)/day p .1) therefore are unlikely to explain observed changes in insulin sensitivity. (clinicaltrials.gov:NCT00422253).
Publisher: American Diabetes Association
Date: 06-2008
DOI: 10.2337/DB08-0406
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: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2002
DOI: 10.1097/00004872-200205000-00034
Abstract: Nephrin, a cytoskeletal protein which localizes to the slit pore of podocytes, may play a role in proteinuria. This study examines the possible relationship between nephrin expression and albuminuria in normotensive and hypertensive diabetic rats. Streptozotocin diabetes was induced in both Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats. Diabetic and control animals were sacrificed and the kidneys obtained after 8, 16 and 24 weeks. The glomerular filtration rate (GFR) and albuminuria were also measured. Glycaemic control was assessed by measurement of plasma glucose and glycated haemoglobin (HbA1c). Nephrin gene expression was quantitated by real-time polymerase chain reaction (PCR) and localized by in situ hybridization. Nephrin protein expression was localized by immunohistochemistry and quantitated. Following a transient rise at 8 weeks in the diabetic SHR (P < 0.05 versus control SHRs), nephrin gene expression, as determined by real-time PCR, was significantly decreased at 16 and 24 weeks (P < 0.05 versus control SHRs). In situ hybridization confirmed similar changes in nephrin gene expression, which were confined to the glomeruli. This reduction in glomerular nephrin gene expression was associated with increasing albuminuria at 16 and 24 weeks in diabetic SHRs. There were no significant changes in nephrin gene expression, either by real-time reverse transcription polymerase chain reaction or in situ hybridization, observed in normotensive diabetic WKY rats, in the context of much less albuminuria in this group. Immunohistochemistry for nephrin protein revealed a greater depletion in renal nephrin content in SHR than in WKY rats after 24 weeks of diabetes. Reduction in renal nephrin gene and protein expression is closely associated with the development of albuminuria, as observed in an experimental model of diabetes and hypertension.
Publisher: Mary Ann Liebert Inc
Date: 08-2011
Abstract: Advanced glycation end products (AGEs) are involved in age-related diseases, including the complications of diabetes and chronic renal impairment with arterial stiffening. Alagebrium chloride (ALT-711) is an AGE-lowering agent with beneficial effects in renal structural and functional parameters in diabetes, decreased diabetes-accelerated atherosclerosis, and age-related myocardial stiffening. ALT-711 exhibits a structural homology to thiamine, and it was suggested to interfere with thiamine metabolism. Thiamine is converted to thiamine diphosphate (TDP) by thiamine diphosphokinase (TDPK). TDP is a cofactor for pyruvate dehydrogenase, α-ketoglutarate dehydrogenase and transketolase. A decreased activity of these enzymes due to TDP deficiency results in disorders such as beriberi and Wernicke-Korsakoff syndrome. Therefore, we investigated whether ALT-711 is an inhibitor of TDPK. Molecular modeling studies showed that ALT-711 fits into the thiamine-binding pocket of TDPK, and there are three interactions between the thiazolium ring and the enzyme, as well as parallel stacking between the phenyl ring and the indole ring of Trp222B. Enzyme kinetic experiments also showed that ALT-711 dose-dependently decreased TDPK activity with K(i)s, calculated by different experiments and fitting models ranging from 0.88 to 1.09 mM. Fitting of the kinetic data favored mixed-mode inhibition with a major role for competitive inhibition. In summary, our results suggest that ALT-711 is a low-affinity inhibitor of TDPK, but is unlikely to interfere with thiamine metabolism at therapeutic concentrations. However, when new AGE-crosslink breakers based on thiamine are designed, care should be taken that they do not act as more potent competitive inhibitors than ALT-711.
Publisher: Elsevier BV
Date: 07-2013
DOI: 10.1016/J.JNUTBIO.2012.09.009
Abstract: Chronic overconsumption of a Western diet has been identified as a major risk factor for diabetes, yet precisely how each in idual component contributes to defects in glucose homeostasis independent of consumption of other macronutrients remains unclear. Eight-week-old male Sprague Dawley rats were randomized to feeding with one of six semi-pure diets: control, processed (high advanced glycation end products/AGE), high protein, high dextrose (glucose polymer), high in saturated fat (plant origin), or high in saturated fat (animal origin). After chronic feeding for 24 weeks, body composition was determined by bioelectrical impedance spectroscopy and glucose homeostasis was assessed. When compared to the control and high AGE diets, excess consumption of the diet high in saturated fat (animal source) increased body weight and adiposity, and decreased insulin sensitivity, as defined by HOMA IR, impaired skeletal muscle insulin signaling and insulin hypersecretion in the context of increased circulating glucagon-like peptide (GLP-1). Compared to the control diet, chronic consumption of the high AGE, protein or dextrose diet increased fasting plasma glucose, decreased fasting plasma insulin and insulin secretion. These diets also reduced circulating GLP-1 concentrations. These data suggest that in idual components of a western diet have differential effects in modulating glucose homeostasis and adiposity. These data provide clear evidence of a link between over-consumption of a western diet and the development of diabetes.
Publisher: Elsevier BV
Date: 1999
Publisher: Wiley
Date: 19-12-2011
DOI: 10.1111/J.1464-5491.2010.03138.X
Abstract: To determine fasting and postprandial metabolism of apolipoprotein B48 (apoB48) remnant lipoproteins in subjects with Type 1 diabetes and the relationship to progressive cardiovascular disease, and to investigate the impact of remnant lipoprotein cholesterol accumulation associated with arterial wall biglycan using a rodent model of Type 1 diabetes. Normolipidaemic subjects (n = 9) with long-standing Type 1 diabetes (and advanced cardiovascular disease) and seven healthy control subjects were studied. Fasting and postprandial apoB48 concentration was determined following a sequential meal challenge. A rodent model of streptozotocin-induced diabetes was used to investigate the ex vivo retention of fluorescent-conjugated remnants. Binding of remnant lipoproteins to human recombinant biglycan was assessed in vitro. A significantly higher concentration of fasting plasma apoB48 remnants was observed in patients with Type 1 diabetes compared with control subjects. Patients with Type 1 diabetes exhibited a greater total plasma apoB48 area under the curve (AUC) and an increased incremental AUC following a second sequential meal compared with control subjects. The arterial retention of remnants ex vivo and associated cholesterol was increased sevenfold in Type 1 diabetes rats relative to controls. Remnants were shown to bind with significant affinity to human biglycan in vitro and a further 2.3-fold increased binding capacity was observed with glycated biglycan. Remnants were shown to colocalize with both arterial biglycan and glycated matrix proteins in the Type 1 diabetes rodent model. Impaired metabolism of remnant lipoproteins associated with enhanced binding to proteoglycans appears to contribute to the arterial cholesterol deposition in Type 1 diabetes. Our findings support the hypothesis that impaired remnant metabolism may contribute to accelerated progression of atherosclerosis in the hyperglycaemic and insulin-deficient state.
Publisher: Hindawi Limited
Date: 2010
DOI: 10.1155/2010/974681
Abstract: Background . Advanced glycation end-products (AGEs) and their receptors are prominent contributors to diabetic kidney disease. Methods . Flow cytometry was used to measure the predictive capacity for kidney impairment of the AGE receptors RAGE, AGE-R1, and AGE-R3 on peripheral blood mononuclear cells (PBMCs) in experimental models of type 2 diabetes (T2DM) fed varied AGE containing diets and in obese type 2 diabetic and control human subjects. Results . Diets high in AGE content fed to diabetic mice decreased cell surface RAGE on PBMCs and in type 2 diabetic patients with renal impairment (RI). All diabetic mice had elevated Albumin excretion rates (AERs), and high AGE fed dbdb mice had declining Glomerular filtration rate (GFR). Cell surface AGE-R1 expression was also decreased by high AGE diets and with diabetes in dbdb mice and in humans with RI. PBMC expression of AGE R3 was decreased in diabetic dbdb mice or with a low AGE diet. Conclusions . The most predictive PBMC profile for renal disease associated with T2DM was an increase in the cell surface expression of AGE-R1, in the context of a decrease in membranous RAGE expression in humans, which warrants further investigation as a biomarker for progressive DN in larger patient cohorts.
Publisher: Wiley
Date: 22-01-2013
DOI: 10.1111/JGH.12042
Abstract: Advanced glycation end products (AGEs) are nonenzymatic modifications of proteins by reducing sugars. These compounds accumulate in a number of chronic disease states, contributing to tissue injury via several mechanisms, including activation of the receptor for advanced glycation end products (RAGE). We aimed to investigate whether AGEs can exacerbate chronic liver injury and contribute to hepatic fibrosis. We initially studied the effects of chronic hepatic exposure to high levels of AGEs given intraperitoneally as AGE-rat serum albumin. In a separate experiment, we examined the impact of high AGE exposure in rats following bile duct ligation (BDL). In normal rats, chronic AGE-rat serum albumin administration induced significant increases in α-smooth muscle actin gene and protein expression but did not induce fibrosis or biochemical evidence of liver injury. However, in BDL animals, AGE-bovine serum albumin administration significantly increased hepatic fibrosis as evidenced by increased collagen content and α-smooth muscle actin expression, compared with BDL alone. Furthermore, AGEs increased hepatic oxidative stress and receptor for advanced glycation end products gene expression. These findings suggest that AGEs may contribute to the pathogenesis of chronic liver injury and fibrosis.
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: American Diabetes Association
Date: 16-11-2020
DOI: 10.2337/DBI20-0037
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: 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: Wiley
Date: 24-07-2003
DOI: 10.1046/J.1440-1797.2003.00159.X
Abstract: This study has investigated the microtubular cytoskeleton in rat glomerular and proximal tubule cells in experimental diabetes. The effect of treatment with ramipril on the relationship between microtubule organization and albuminuria in diabetes has also been examined. Diabetes was induced in male Sprague-Dawley rats by administration of streptozotocin (50 mg/kg, i.v.). Rats were treated with or without ramipril in their drinking water for 12 weeks. Diabetes was characterized by an increase in blood glucose level, glomerular filtration rate, and albumin excretion rate. Treatment of diabetic rats with ramipril did not affect glycaemic control, but reduced systolic blood pressure and prevented the rise in albuminuria and glomerular filtration rate. Immunohistochemistry was performed by using the ARK Peroxidase method with alpha-tubulin antibody. The regular, grainy staining pattern of the microtubules present in the renal proximal tubules from control kidneys was altered in diabetic animals, and appeared fragmented and striated. This was prevented by treatment with ramipril. Quantitative morphometric analysis revealed an increase in the percent proportional staining for alpha-tubulin in the proximal tubules of untreated diabetic rats (33.3 +/- 3.3%, n = 8, P < 0.05 vs control) compared with control rats (11.7 +/- 1.7%, n = 6), which was reduced by ramipril treatment (26.7 +/- 2.1%, n = 6, P < 0.05 vs untreated diabetic). Staining for alpha-tubulin in glomerular cells was unchanged in all groups. There was no significant difference in renal alpha-tubulin expression among all groups, as determined by real-time reverse transcription-polymerase chain reaction. These results raise the possibility that diabetes-induced changes in microtubules in the renal proximal tubules may contribute, in part, to the increase in albuminuria observed in diabetes.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2006
Publisher: Elsevier BV
Date: 04-2014
DOI: 10.1016/J.JHEP.2013.11.033
Abstract: Advanced glycation end-products (AGEs) levels are high in western diets and contribute to tissue injury via activation of RAGE (receptor for AGEs) and generation of reactive oxygen species (ROS). Here, we determined if high dietary AGE intake worsens progression of non-alcoholic fatty liver disease (NAFLD). Male Sprague Dawley rats were fed a methionine choline deficient (MCD) diet for 6 weeks before 6 weeks of a high AGE MCD diet through baking. They were compared with animals on MCD diet or a methionine choline replete (MCR) diet alone for 12 weeks. Hepatic ROS, triglycerides, biochemistry, picro-sirius morphometry, hepatic mRNA expression and immunohistochemistry were determined. Primary hepatic stellate cells (HSCs) from both MCR and MCD animals were exposed to AGEs. ROS, proliferation and mRNA expression were determined. The high AGE MCD diet increased hepatic AGE content and elevated triglycerides, NADPH dependent superoxide production, HNE adducts, steatosis, steatohepatitis (CD43, IL-6, TNF-α) and fibrosis (α-SMA, CTGF, COL1A, picrosirius) compared to MCD alone. In HSCs, AGEs significantly increased ROS production, bromodeoxyuridine proliferation and MCP-1, IL-6, α-SMA, and RAGE expression in HSCs from MCD but not MCR animals. These effects were abrogated by RAGE or NADPH oxidase blockade. In the MCD model of NAFLD, high dietary AGEs increases hepatic AGE content and exacerbates liver injury, inflammation, and liver fibrosis via oxidative stress and RAGE dependent profibrotic effects of AGEs on activated HSCs. This suggests that pharmacological and dietary strategies targeting the AGE/RAGE pathway could slow the progression of NAFLD.
Publisher: American Diabetes Association
Date: 09-03-2016
DOI: 10.2337/DB15-1418
Abstract: Islet-specific memory T cells arise early in type 1 diabetes (T1D), persist for long periods, perpetuate disease, and are rapidly reactivated by islet transplantation. As memory T cells are poorly controlled by “conventional” therapies, memory T cell–mediated attack is a substantial challenge in islet transplantation, and this will extend to application of personalized approaches using stem cell–derived replacement β-cells. New approaches are required to limit memory autoimmune attack of transplanted islets or replacement β-cells. Here, we show that transfer of bone marrow encoding cognate antigen directed to dendritic cells, under mild, immune-preserving conditions, inactivates established memory CD8+ T-cell populations and generates a long-lived, antigen-specific tolerogenic environment. Consequently, CD8+ memory T cell–mediated targeting of islet-expressed antigens is prevented and islet graft rejection alleviated. The immunological mechanisms of protection are mediated through deletion and induction of unresponsiveness in targeted memory T-cell populations. The data demonstrate that hematopoietic stem cell–mediated gene therapy effectively terminates antigen-specific memory T-cell responses, and this can alleviate destruction of antigen-expressing islets. This addresses a key challenge facing islet transplantation and, importantly, the clinical application of personalized β-cell replacement therapies using patient-derived stem cells.
Publisher: Springer Science and Business Media LLC
Date: 14-08-2013
Abstract: The incidence of type 1 diabetes has increased worldwide, particularly in younger children and those with lower genetic susceptibility. These observations suggest factors in the modern environment promote pancreatic islet autoimmunity and destruction of insulin-producing beta cells. The Environmental Determinants of Islet Autoimmunity (ENDIA) Study is investigating candidate environmental exposures and gene-environment interactions that may contribute to the development of islet autoimmunity and type 1 diabetes. ENDIA is the only prospective pregnancy/birth cohort study in the Southern Hemisphere investigating the determinants of type 1 diabetes in at-risk children. The study will recruit 1,400 unborn infants or infants less than six months of age with a first-degree relative (i.e. mother, father or sibling) with type 1 diabetes, across five Australian states. Pregnant mothers/infants will be followed prospectively from early pregnancy through childhood to investigate relationships between genotype, the development of islet autoimmunity (and subsequently type 1 diabetes), and prenatal and postnatal environmental factors. ENDIA will evaluate the microbiome, nutrition, bodyweight/composition, metabolome-lipidome, insulin resistance, innate and adaptive immune function and viral infections. A systems biology approach will be used to integrate these data. Investigation will be by 3-monthly assessments of the mother during pregnancy, then 3-monthly assessments of the child until 24 months of age and 6-monthly thereafter. The primary outcome measure is persistent islet autoimmunity, defined as the presence of autoantibodies to one or more islet autoantigens on consecutive tests. Defining gene-environment interactions that initiate and/or promote destruction of the insulin-producing beta cells in early life will inform approaches to primary prevention of type 1 diabetes. The strength of ENDIA is the prospective, comprehensive and frequent systems-wide profiling from early pregnancy through to early childhood, to capture dynamic environmental exposures that may shape the development of islet autoimmunity. Australia New Zealand Clinical Trials Registry ACTRN12613000794707 .
Publisher: American Diabetes Association
Date: 11-2004
DOI: 10.2337/DIABETES.53.11.2921
Abstract: This study investigated the role of advanced glycation end products (AGEs) in mediating protein kinase C (PKC) isoform expression in diabetic nephropathy. In vitro, vascular smooth muscle cells incubated in a high-glucose (25-mmol/l) medium demonstrated translocation and increased expression of PKC-α as compared with those from a low-glucose (5-mmol/l) environment. Coincubation with the cross-link breaker ALT-711 and, to a lesser extent, with aminoguanidine, an inhibitor of AGE formation, attenuated the increased expression and translocation of PKC-α. Streptozotocin-induced diabetic rats were randomized to no treatment, treatment with ALT-711, or treatment with aminoguanidine. Diabetes induced increases in PKC-α as well as in the -βI, -βII, and -ε isoforms. Treatment with ALT-711 and aminoguanidine, which both attenuate renal AGE accumulation, abrogated these increases in PKC expression. However, translocation of phosphorylated PKC-α from the cytoplasm to the membrane was reduced only by ALT-711. ALT-711 treatment attenuated expression of vascular endothelial growth factor and the extracellular matrix proteins, fibronectin and laminin, in association with reduced albuminuria. Aminoguanidine had no effect on VEGF expression, although some reduction of fibronectin and laminin was observed. These findings implicate AGEs as important stimuli for the activation of PKC, particularly PKC-α, in the diabetic kidney, which can be directly inhibited by ALT-711.
Publisher: Bentham Science Publishers Ltd.
Date: 04-2012
DOI: 10.2174/138945012799499758
Abstract: The globally rising incidence of Type 1 diabetes (T1D) is no longer restricted to in iduals with higher risk genotypes, but is now significantly increasing in a population with lower risk genotypes, likely as the result of environmental factors. In this review, we discuss the potential of advanced glycation end products (AGEs) as environmental contributors to the development of T1D. AGEs are nonenzymatically formed protein modifications found in the body, as well as, consumed in our daily diets. To date, many studies have provided evidence of AGE involvement in β cell dysfunction, whether by AGE modification itself or via interaction with AGE receptors. The receptor for AGE (RAGE) and AGE-receptor-1 (AGE-R1) are of particular interest, given that studies have demonstrated the deleterious effects of RAGE modulation and the protection afforded by AGE-R1 in the context of diabetes. More interestingly, we have recently found that two RAGE polymorphism are predictive of T1D in humans while the third is protective. Moreover, soluble RAGE (sRAGE) levels (a circulating competitive inhibitor of RAGE) were greatly reduced at seroconversion to autoantibodies in both children on high risk of T1D background and in an animal model of autoiummune diabetes. Taken together with the fact that AGEs have also shown to be involved in immunomodulation, it is tempting to postulate that dietary AGEs, RAGE and even AGE-R1 could be working synergistically or independently to breach the tightly regulated immune system, providing a missing link in the development of T1D.
Publisher: Wiley
Date: 04-2008
Abstract: Nephropathy remains a significant cause of morbidity and mortality in the diabetic population and is the leading cause of end-stage renal failure in the Western World. As a result of the diabetic milieu, increased generation of reactive oxygen species (ROS) is thought to play a key role in the progression of diabetic nephropathy. Recent experimental studies have suggested that the receptor for advanced glycation end products (RAGE), which is central to the advanced glycation pathway, may mediate renal structural and functional damage via oxidative stress. This review focuses on how RAGE and subsequent ROS generation play a deleterious role in the diabetic kidney, promoting cross-talk among signaling pathways, ultimately leading to renal dysfunction.
Publisher: Springer Science and Business Media LLC
Date: 03-07-2019
DOI: 10.1038/S41598-017-15589-X
Abstract: Mitochondrial dysfunction is a pathological mediator of diabetic kidney disease (DKD). Our objective was to test the mitochondrially targeted agent, MitoQ, alone and in combination with first line therapy for DKD. Intervention therapies (i) vehicle (D) (ii) MitoQ (DMitoQ .6 mg/kg/day) (iii) Ramipril (DRam mg/kg/day) or (iv) combination (DCoAd) were administered to male diabetic db / db mice for 12 weeks ( n = 11–13/group). Non-diabetic (C) db / m mice were followed concurrently. No therapy altered glycaemic control or body weight. By the study end, both monotherapies improved renal function, decreasing glomerular hyperfiltration and albuminuria. All therapies prevented tubulointerstitial collagen deposition, but glomerular mesangial expansion was unaffected. Renal cortical concentrations of ATP, ADP, AMP, cAMP, creatinine phosphate and ATP:AMP ratio were increased by diabetes and mostly decreased with therapy. A higher creatine phosphate:ATP ratio in diabetic kidney cortices, suggested a decrease in ATP consumption. Diabetes elevated glucose 6-phosphate, fructose 6-phosphate and oxidised (NAD+ and NADP+) and reduced (NADH) nicotinamide dinucleotides, which therapy decreased generally. Diabetes increased mitochondrial oxygen consumption (OCR) at complex II-IV. MitoQ further increased OCR but decreased ATP, suggesting mitochondrial uncoupling as its mechanism of action. MitoQ showed renoprotection equivalent to ramipril but no synergistic benefits of combining these agents were shown.
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: American Diabetes Association
Date: 03-03-2009
DOI: 10.2337/DB08-1725
Abstract: Chronic low-grade activation of the immune system (CLAIS) predicts type 2 diabetes via a decrease in insulin sensitivity. Our study investigated potential relationships between nuclear factor-κB (NF-κB) and c-Jun NH2-terminal kinase (JNK) pathways—two pathways proposed as the link between CLAIS and insulin resistance. Adiposity (dual-energy X-ray absorptiometry), waist-to-hip ratio (WHR), and insulin sensitivity (M, hyperinsulinemic-euglycemic cl ) were measured in 22 healthy nondiabetic volunteers (aged 29 ± 11 years, body fat 28 ± 11%). NF-κB activity (DNA-binding assay) and JNK1/2 activity (phosphorylated JNK) were assessed in biopsies of the vastus lateralis muscle and subcutaneous adipose tissue and in peripheral blood mononuclear cell (PBMC) lysates. NF-κB activities in PBMCs and muscle were positively associated with WHR after adjustment for age, sex, and percent body fat (both P & 0.05). NF-κB activity in PBMCs was inversely associated with M after adjustment for age, sex, percent body fat, and WHR (P = 0.02) and explained 16% of the variance of M. There were no significant relationships between NF-κB activity and M in muscle or adipose tissue (both NS). Adipose-derived JNK1/2 activity was not associated with obesity (all P& 0.1), although it was inversely related to M (r = −0.54, P & 0.05) and explained 29% of its variance. When both NF-κB and JNK1/2 were examined statistically, only JNK1/2 activity in adipose tissue was a significant determinant of insulin resistance (P = 0.02). JNK1/2 activity in adipose tissue but not NF-κB activity in PBMCs is an independent determinant of insulin resistance in healthy in iduals.
Publisher: American Diabetes Association
Date: 12-06-2014
DOI: 10.2337/DC13-3049
Abstract: We analyzed the relationship among soluble receptor for advanced glycation end products (sRAGEs), the clinical phenotype, HLA genotype, and risk-associated single nucleotide polymorphisms (SNPs) in the AGER gene in a large population of Finnish children with newly diagnosed type 1 diabetes. S les from 2,115 clinically phenotyped children & years of age in whom type 1 diabetes was diagnosed and 316 control subjects were analyzed for sRAGEs. Three SNPs of AGER, previously associated with HLA-DR/DQ haplotype independent diabetes risk (rs2070600, rs9469089, and rs17493811), were analyzed in 1,390 affected subjects. Children with type 1 diabetes and control subjects had similar sRAGE concentrations (1,171 vs. 1,153 pg/mL, P = 0.48). There was a correlation between age at diagnosis and serum sRAGE concentrations (r = 0.10, P & 0.001) among the patients but not among the control subjects. Children & years of age had the lowest concentrations in the diabetic population (1,027 vs. 1,181 pg/mL, P & 0.001) and the highest among the control subjects (1,329 vs. 1,140 pg/mL, P = 0.04). Ketoacidosis at diagnosis was associated with reduced concentrations (1,086 vs. 1,190 pg/mL, P & 0.001). HLA DR3/DR4 heterozygosity and the DR3 allele were associated with reduced sRAGE concentrations. The predisposing AA genotype of rs2070600 was associated with decreased sRAGE concentrations, while the protective CC genotype of rs9469089 was linked to increased concentrations. Age and AGER polymorphisms are associated with the circulating sRAGE concentration among children with type 1 diabetes. The observations of reduced sRAGE concentrations in young children, in those with ketoacidosis, and in carriers of the high-risk HLA DR3/DR4 genotype suggest that decreased sRAGE concentration reflects a more aggressive disease phenotype.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2004
Publisher: AME Publishing Company
Date: 12-2017
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: S. Karger AG
Date: 2011
DOI: 10.1159/000328581
Abstract: i Background/Aims: /i Advanced glycation end products (AGEs) mediate progressive tissue damage in diabetic nephropathy however, their utility as a noninvasive reliable biomarker of progressive diabetic nephropathy remains to be determined. In this study, we investigated the temporal accumulation of the AGE carboxymethyllysine (CML) at various sites in a model of experimental diabetic nephropathy. i Methods: /i Diabetic rats were followed for 1, 4, 8, 16 and 32 weeks. Glomerular filtration rate and urinary albumin excretion were measured. CML was determined in the plasma, urine, renal cortical mitochondria and cytosol by an in-house ELISA. Gene expression of AGE receptors were quantified by real-time PCR and urinary excretion of 8-hydroxy-2′-deoxyguanosine (8-OHdG) was determined by EIA. i Results: /i Four weeks after diabetes induction, urinary CML excretion was increased, which preceded the excretion of urinary albumin and continued to rise progressively until 32 weeks. Circulating, mitochondrial and cytosolic CML content and urinary excretion of 8-OHdG were increased 4 weeks after diabetes induction, but did not increase further with diabetes duration. Renal gene expression of AGE receptors was transiently upregulated at 1 week of diabetes, but this was not a sustained phenomenon. i Conclusions: /i The most informative marker of progressive renal damage linked to the AGE pathway in experimental diabetic nephropathy is urinary excretion of CML, which now warrants clinical investigation as a potential noninvasive sensitive marker of progressive diabetic nephropathy.
Publisher: S. Karger AG
Date: 2009
DOI: 10.1159/000226586
Abstract: A commonality among the chemically disparate compounds that inhibit the formation and accumulation of advanced glycation end products (AGEs) or their signalling pathways is their end organ protection in experimental models of diabetes complications. Although this group of therapeutics are structurally and functionally distinct with numerous mechanisms of action, the most important factor governing their therapeutic capability is clearly their ability to alleviate the tissue burden of advanced glycation, rather than the biochemical mechanism by which this is achieved. However, it remains to be determined if it is the reduction in tissue AGE levels per se or inhibition of downstream signal pathways which is ultimately required for end organ protection. For ex le, a number of these agents stimulate antioxidant defences, modify lipid profiles and inhibit low-grade inflammation. These novel actions emphasise the importance of further examination of the advanced glycation pathway and in particular the erse action of these agents in ameliorating the development of diabetic complications such as nephropathy.
Publisher: Wiley
Date: 06-2005
Publisher: American Society for Clinical Investigation
Date: 15-12-2001
DOI: 10.1172/JCI11951
Publisher: S. Karger AG
Date: 2011
DOI: 10.1159/000331064
Abstract: i Background/Aims: /i The formation of advanced glycation end products (AGEs) is accelerated in patients with diabetic nephropathy. The aim of this study was to ascertain if the urinary excretion of proteins modified by advanced glycation can be used as biomarkers for albuminuria in in iduals with type 1 or type 2 diabetes. i Methods: /i Community-based patients with type 1 (n = 68) or type 2 diabetes (n = 216) attending a diabetes clinic of a tertiary referral hospital were classified as having normoalbuminuria (Normo, albumin excretion rate (AER) µg/min), microalbuminuria (Micro, AER 20–200 µg/min) or macroalbuminuria (Macro, AER ≧200 µg/min). Serum and urine AGE-modified proteins were measured. i Results: /i In patients with both type 1 diabetes and type 2 diabetes, there was a clear association between the degree of albuminuria and urinary AGE-modified proteins (p 0.0001). Exclusive to patients with type 1 diabetes, urinary excretion of the AGE carboxymethyllysine correlated with AER, whereas patients with type 2 diabetes and macroalbuminuria had an increase in urinary methylglyoxal, an AGE intermediate. These changes were independent of isotopic glomerular filtration rate levels. Serum concentrations of AGEs or soluble receptor for AGEs were not consistently associated with albuminuria in either type 1 or type 2 diabetes. i Conclusions: /i Urinary excretion of proteins modified by AGEs may be useful biomarkers of albuminuria in in iduals with type 1 and type 2 diabetes, warranting prospective investigation in larger diabetic cohorts.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 02-04-2021
Abstract: This study shows how highly processed foods can cause innate immune inflammation that promotes chronic microvascular disease.
Publisher: Elsevier BV
Date: 12-2000
DOI: 10.1046/J.1523-1755.2000.00427.X
Abstract: Angiotensin II (Ang II) is associated with cell proliferation and apoptosis. The role of the angiotensin type 2 receptor (AT2R) in these processes remains controversial. Conventional radioligand binding of 125I-Sar1, Ile8 Ang II in adult kidney has failed to demonstrate the binding for the AT2R. The presence of the AT2R was explored in adult rat kidney by in vitro and in vivo autoradiography using the selective AT2R radioligand 125I-CGP 42112B. The roles of the angiotensin type 1 receptor (AT1R) and the AT2R in mediating cellular proliferation and apoptosis were assessed using selective AT1R or AT2R antagonists in Ang II-infused Sprague-Dawley (SD) rats. 125I-CGP 42112B binding was demonstrated by in vitro and in vivo autoradiography techniques in the glomeruli and proximal tubules of SD rats. This binding could be displaced by Ang II and the AT2R antagonist PD123319 but not by the AT1R antagonist valsartan. Subcutaneous infusion of Ang II for 14 days in eight-week-old SD rats induced proliferation of proximal tubular epithelial cells, as assessed by a twofold increase in proliferating cell nuclear antigen (PCNA)-positive cells and apoptosis, as assessed by a threefold increase in terminal dUTP nick end labeling (TUNEL)-positive cells. The administration of the AT2R antagonist PD123319 or the AT1R antagonist valsartan was associated with attenuation of the increases in both PCNA- and TUNEL-positive cells following Ang II infusion. Ang II infusion was associated with increased osteopontin gene and protein expression, which could be reduced by treatment with either valsartan or PD123319. These findings indicate that there is significant expression of the AT2R in the adult kidney, and that the AT2R has a role in mediating Ang II-induced proliferation and apoptosis in proximal tubular epithelial cells and expression of osteopontin.
Publisher: Wiley
Date: 28-02-2020
DOI: 10.1002/MED.21654
Publisher: Elsevier BV
Date: 03-2007
DOI: 10.1016/J.SEMNEPHROL.2007.01.006
Abstract: Diabetic nephropathy is a major cause of morbidity and mortality in diabetic patients. Two key mechanisms implicated in the development of diabetic nephropathy include advanced glycation and oxidative stress. Advanced glycation is the irreversible attachment of reducing sugars onto amino groups of proteins to form advanced glycation end products (AGEs). AGE modification of proteins may lead to alterations in normal function by inducing cross-linking of extracellular matrices. Intracellular formation of AGEs also can cause generalized cellular dysfunction. Furthermore, AGEs can mediate their effects via specific receptors, such as the receptor for AGE (RAGE), activating erse signal transduction cascades and downstream pathways, including generation of reactive oxygen species (ROS). Oxidative stress occurs as a result of the imbalance between ROS production and antioxidant defenses. Sources of ROS include the mitochondria, auto-oxidation of glucose, and enzymatic pathways including nicotinamide adenine dinucleotide phosphate reduced (NAD[P]H) oxidase. Beyond the current treatments to treat diabetic complications such as the optimization of blood pressure and glycemic control, it is predicted that new therapies designed to target AGEs, including AGE formation inhibitors and cross-link breakers, as well as targeting ROS using novel highly specific antioxidants, will become part of the treatment regimen for diabetic renal disease.
Publisher: Elsevier BV
Date: 04-2008
DOI: 10.1038/LABINVEST.2008.10
Abstract: In vitro studies have implicated activation of the p38 mitogen-activated protein kinase (MAPK) signalling pathway in cytokine-mediated pancreatic beta-cell injury. Activation of the p38 MAPK occurs through two different upstream kinases, mitogen-activated protein kinase kinase 3 (MKK3) and MKK6. This study examined the role of MKK3 signalling in an in vivo model of cytokine-dependent pancreatic injury induced by multiple low doses of streptozotocin (MLD-STZ). Groups of wild-type (WT) or Mkk3-/- C57BL/6J mice received 5 daily injections of STZ (40 mg/kg) and were killed on day 5, week 2 or week 4. MLD-STZ in WT mice exhibited two distinct phases of pancreatic damage: islet cell apoptosis (immunostaining for cleaved caspase-3) on day 5 in the absence of leukocyte infiltration, and this was followed by islet inflammation (leukocyte infiltration and cytokine production) and further islet cell apoptosis on day 14 resulting in a loss of insulin-producing beta-cells and an 80% incidence of hyperglycaemia. Mkk3-/- mice were not protected from the initial phase of STZ-induced islet cell apoptosis day 5. However, Mkk3-/- mice were completely protected from the induction of hyperglycaemia. This was attributed to inhibition of leukocyte infiltration, production of pro-inflammatory cytokines and islet cell apoptosis at day 14 of MLD-STZ. In vitro studies showed that cultured islets from Mkk3-/- and WT mice are equally susceptible to STZ and cytokine-induced apoptosis. In conclusion, MKK3 signalling plays an essential role in the development of islet inflammation leading to destruction of beta-cells and hyperglycaemia in MLD-STZ-induced pancreatic injury.
Publisher: Elsevier BV
Date: 03-2018
DOI: 10.1016/J.SEMNEPHROL.2018.01.001
Abstract: The kidneys are highly metabolic organs that produce vast quantities of adenosine triphosphate via oxidative phosphorylation and, as such, contain many mitochondria. Although mitochondrial reactive oxygen species are involved in many physiological processes in the kidneys, there is a plethora of evidence to suggest that excessive production may be a pathologic mediator of many chronic kidney diseases, including diabetic kidney disease. Despite this, results from clinical testing of antioxidant therapies have been generally underwhelming. However, given the many roles of mitochondria in cellular functioning, pathways other than reactive oxygen species production may prevail as pathologic mediators in diabetic kidney disease. Accordingly, in this review, mitochondrial dysfunction in a broader context is discussed, specifically focusing on mitochondrial respiration and oxygen consumption, intrarenal hypoxia, oxidative stress, mitochondrial uncoupling, and networking.
Location: Australia
No related grants have been discovered for Josephine Forbes.