ORCID Profile
0000-0001-9497-927X
Current Organisations
University of Melbourne
,
Royal Melbourne Hospital
,
University of Queensland
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Publisher: Elsevier BV
Date: 08-2009
DOI: 10.1016/J.BBRC.2009.06.040
Abstract: We previously described a putative role for inosine monophosphate dehydrogenase (IMPDH), a rate-limiting enzyme in de novo guanine nucleotide biosynthesis, in lipid accumulation. Here we present data which demonstrate that IMPDH activity is required for differentiation of preadipocytes into mature, lipid-laden adipocytes and maintenance of adipose tissue mass. In 3T3-L1 preadipocytes inhibition of IMPDH with mycophenolic acid (MPA) reduced intracellular GTP levels by 60% (p<0.05) and blocked adipogenesis (p<0.05). Co-treatment with guanosine, a substrate in the salvage pathway of nucleotide biosynthesis, restored GTP levels and adipogenesis demonstrating the specificity of these effects. Treatment of diet-induced obese mice with mycophenolate mofetil (MMF), the prodrug of MPA, for 28 days did not affect food intake or lean body mass but reduced body fat content (by 36%, p=0.002) and adipocyte size (p=0.03) and number. These data suggest that inhibition of IMPDH may represent a novel strategy to reduce adipose tissue mass.
Publisher: Elsevier BV
Date: 05-2009
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2006
DOI: 10.2215/CJN.00210106
Publisher: American Diabetes Association
Date: 12-2004
DOI: 10.2337/DIABETES.53.12.3097
Abstract: Obesity, with its related problems, is recognized as the fastest growing disease epidemic facing the world, yet we still have limited insight into the regulation of adipose tissue mass in humans. We have previously shown that adipose-derived microvascular endothelial cells (MVECs) secrete a factor(s) that increases proliferation of human preadipocytes. We now demonstrate that coculture of human preadipocytes with MVECs significantly increases preadipocyte differentiation, evidenced by dramatically increased triacylglycerol accumulation and glycerol-3-phosphate dehydrogenase activity compared with controls. Subsequent analysis identified fibroblast growth factor (FGF)-1 as an adipogenic factor produced by MVECs. Expression of FGF-1 was demonstrated in MVECs but not in preadipocytes, while preadipocytes were shown to express FGF receptors 1–4. The proliferative effect of MVECs on human preadipocytes was blocked using a neutralizing antibody specific for FGF-1. Pharmacological inhibition of FGF-1 signaling at multiple steps inhibits preadipocyte replication and differentiation, supporting the key adipogenic role of FGF-1. We also show that 3T3-L1 cells, a highly efficient murine model of adipogenesis, express FGF-1 and, unlike human preadipocytes, display no increased differentiation potential in response to exogenous FGF-1. Conversely, FGF-1–treated human preadipocytes proliferate rapidly and differentiate with high efficiency in a manner characteristic of 3T3-L1 cells. We therefore suggest that FGF-1 is a key human adipogenic factor, and these data expand our understanding of human fat tissue growth and have significant potential for development of novel therapeutic strategies in the prevention and management of human obesity.
Publisher: Wiley
Date: 08-12-2014
Publisher: American Diabetes Association
Date: 03-1997
Publisher: Wiley
Date: 26-10-2006
Abstract: We recently established that fibroblast growth factor (FGF)-1 promotes adipogenesis of primary human preadipocytes (phPA). In the current report, we have characterized the adipogenic effects of FGF-1 in phPA and also in a human PA strain derived from an in idual with Simpson-Golabi-Behmel syndrome (SGBS PA), which exhibit an intrinsic capacity to differentiate with high efficiency. In further studies, we compared these models with the well-characterized murine 3T3-L1 preadipocyte cell line (3T3-L1 PA). FGF-1 up-regulated the adipogenic program in phPA, with increased expression of peroxisome proliferator-activated receptor-gamma in confluent PA prior to induction of differentiation and increased expression of adipocyte markers during differentiation. Moreover, phPA differentiated in the presence of FGF-1 were more insulin responsive and secreted increased levels of adiponectin. FGF-1 treatment of SGBS PA further enhanced differentiation. For the most part, the adipogenic program in phPA paralleled that observed in 3T3-L1 PA however, we found no evidence of mitotic clonal expansion in the phPA. Finally, we investigated a role for extracellular regulated kinase 1/2 (ERK1/2) in adipogenesis of phPA. FGF-1 induced robust phosphorylation of ERK1/2 in early differentiation and inhibition of ERK1/2 activity significantly reduced phPA differentiation. These data suggest that FGF-1 treated phPA represent a valuable in vitro model for the study of adipogenesis and insulin action and indicate that ERK1/2 activation is necessary for human adipogenesis in the absence of mitotic clonal expansion.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2005
DOI: 10.1111/J.1572-0241.2005.00311.X
Abstract: Obesity is recognized as a cofactor in hepatitis C (HCV) liver injury. Adipokines may be the link between increasing body mass index (BMI) and disease progression in HCV. Adiponectin is an anti-inflammatory adipokine that is present in serum in a range of multimeric forms that appear to have different metabolic functions. We studied 30 male patients with untreated chronic HCV (15 each with genotypes 1 and 3) and 12 controls. The three groups were matched for age and BMI. Total adiponectin and high (HMW) and low (LMW) molecular weight adiponectin multimers were measured. The relationships between adiponectin, BMI, insulin sensitivity, and liver histology were examined. Genotype 3 was associated with greater hepatic steatosis and inflammation than genotype 1. Patients with genotype 1 were less insulin sensitive than genotype 3, who had similar insulin sensitivity to controls. Insulin resistance was associated with a decrease in total and HMW adiponectin in both HCV and controls, while LMW adiponectin was unchanged. When the effect of genotype was examined, this association was present with genotype 3 but not genotype 1 infection. These data demonstrate that the relationship between insulin resistance and adiponectin is similar in controls and patients with genotype 3 but not genotype 1 infection. The greater degree of insulin resistance in genotype 1 appears to be a genotype-specific effect.
Publisher: Wiley
Date: 17-12-2013
DOI: 10.1111/J.1440-1797.2012.01662.X
Abstract: To assess the impact of vitamin D supplementation (cholecalciferol) on the insulin sensitivity and metabolic health of patients with chronic kidney disease (CKD). Twenty-eight adult patients with CKD stages 3-4 were recruited from the outpatient department of the Princess Alexandra Hospital (Brisbane, Australia) to a double-blind randomized trial of cholecalciferol (vitamin D3) 2000 IU/day or placebo for 6 months. Metabolic parameters at baseline were compared with 20 non-CKD adults. The primary outcome was an improvement in insulin resistance (glucose disposal rate, GDR) at 6 months (quantified by hyperinsulinaemic euglycaemic cl ). Carbohydrate and lipid oxidation rates were assessed by indirect calorimetry. At baseline, patients were significantly insulin-resistant compared with lean younger non-CKD in iduals (n = 9 GDR 3.42 vs. 5.76 mg/kg per minute, P = 0.001), but comparable with their age-, gender- and weight-matched non-CKD counterparts (n = 11 3.42 vs. 3.98 mg/kg per minute, P = 0.4). 25-Hydroxyvitamin D did not change in the placebo group, but rose from 95 ± 37 to 146 ± 25 nmol/L with treatment (P = 0.0001). Post treatment, there was no difference in GDR between groups (GDR 3.38 vs. 3.52 mg/kg per minute, ancova P = 0.4). There was a relative increase in hyperinsulinaemic oxidative disposal of glucose with treatment (within-group P = 0.03). Supplementation with cholecalciferol in CKD 3-4 results in appreciable increases in 25-hydroxyvitamin D concentrations, but does not increase insulin sensitivity. The insulin resistance observed was similar among age-, sex- and body mass index-matched in iduals with and without CKD. Whether renal dysfunction per se has any influence on the insulin sensitivity of an in idual should be the subject of future work.
Publisher: Wiley
Date: 26-05-2006
DOI: 10.1111/J.1463-1326.2006.00604.X
Abstract: The aim of the study was to investigate the relationship between the metabolic syndrome (MS), adiponectin and abnormal liver enzymes in patients with type 2 diabetes. Fasting serum was collected from 189 patients with type 2 diabetes, adiponectin was measure using radioimmunoassay and features of the MS were assessed. Mean ALT was significantly higher in patients with the MS and higher ALT was associated with lower adiponectin levels. As the number of features of MS increased, ALT increased and adiponectin decreased independent of glycaemic control. Hypoadiponectinemia and the MS may be linked with liver injury in patients with type 2 diabetes.
Publisher: BMJ
Date: 23-08-2006
Publisher: American Diabetes Association
Date: 12-12-2012
DOI: 10.2337/DB11-0998
Abstract: Adipose tissue dysfunction underpins the association of obesity with type 2 diabetes. Adipogenesis is required for the maintenance of adipose tissue function. It involves the commitment and subsequent differentiation of preadipocytes and is coordinated by autocrine, paracrine, and endocrine factors. We previously reported that fibroblast growth factor-1 (FGF-1) primes primary human preadipocytes and Simpson Golabi Behmel syndrome (SGBS) preadipocytes and increases adipogenesis through a cascade involving extracellular signal–related kinase 1/2 (ERK1/2). Here, we aimed to use the FGF-1 system to identify novel adipogenic regulators. Expression profiling revealed bone morphogenetic protein (BMP) and activin membrane-bound inhibitor (BAMBI) as a putative FGF-1 effector. BAMBI is a transmembrane protein and modulator of paracrine factors that regulate adipogenesis, including transforming growth factor (TGF) superfamily members (TGF-β and BMP) and Wnt. Functional investigations established BAMBI as a negative regulator of adipogenesis and modulator of the anti- and proadipogenic effects of Wnt3a, TGF-β1, and BMP-4. Further studies showed that BAMBI expression levels are decreased in a mouse model of diet-induced obesity. Collectively, these findings establish BAMBI as a novel, negative regulator of adipogenesis that can act as a nexus to integrate multiple paracrine signals to coordinate adipogenesis. Alterations in BAMBI may play a role in the (patho)physiology of obesity, and manipulation of BAMBI may present a novel therapeutic approach to improve adipose tissue function.
Publisher: Canadian Science Publishing
Date: 06-2013
Abstract: There has been substantial recent interest in using vitamin D to improve insulin sensitivity and preventing/delaying diabetes in those at risk. There is little consensus on the physiological mechanisms and whether the association is direct or indirect through enhanced production of insulin-sensitising chemicals, including adiponectin. We examined cross-sectional associations between serum 25-hydroxyvitamin D (25(OH)D) and insulin sensitivity (Matsuda index), parathyroid hormone (PTH), waist circumference, body mass index (BMI), triglycerides (TG), total and high molecular weight (HMW) adiponectin, HMW : total adiponectin ratio (HMW : total adiponectin), and total cholesterol : HDL cholesterol ratio (TC:HDL cholesterol) in 137 Caucasian adults of mean age 43.3 ± 8.3 years and BMI 38.8 ± 6.9 kg/m 2 . Total adiponectin (standardised β = 0.446 p 0.001), waist circumference (standardised β = –0.216 p 0.05), BMI (standardised β = –0.212 p 0.05), and age (standardised β = –0.298 p 0.001) were independently associated with insulin sensitivity. Serum 25(OH)D (standardised β = 0.114 p = 0.164) was not associated with insulin sensitivity, total or HMW adiponectin, HMW : total adiponectin, or lipids. Our results provide the novel finding that 25(OH)D is not associated with HMW adiponectin or HMW : total adiponectin in nondiabetic, obese adults and support the lack of association between 25(OH)D and lipids noted by others in similar groups of patients.
Publisher: OMICS Publishing Group
Date: 12-2010
DOI: 10.4066/AMJ.2010.466
Publisher: Springer Science and Business Media LLC
Date: 2011
DOI: 10.1186/CC10021
Publisher: The Endocrine Society
Date: 2010
DOI: 10.1210/ME.2009-0133
Abstract: Adiponectin is an adipocyte-secreted, insulin-sensitizing hormone the circulating levels of which are reduced in conditions of insulin resistance and diabetes. Previous work has demonstrated the importance of posttranslational modifications, such as proline hydroxylation and lysine hydroxylation/glycosylation, in adiponectin oligomerization, secretion, and function. Here we describe the first functional characterization of adiponectin sialylation. Using a variety of biochemical approaches we demonstrated that sialylation occurs on previously unidentified O-linked glycans on Thr residues of the variable domain in human adiponectin. Enzymatic removal of sialic acid or its underlying O-linked sugars did not affect adiponectin multimer composition. Expression of mutant forms of adiponectin (lacking the modified Thr residues) or of wild-type adiponectin in cells defective in sialylation did not compromise multimer formation or secretion, arguing against a structural role for this modification. Activity of desialylated adiponectin was comparable to control adiponectin in L6 myotubes and acute assays in adiponectin−/− mice. In contrast, plasma clearance of desialylated adiponectin was accelerated compared with that of control adiponectin, implicating a role for this modification in determining the half-life of circulating adiponectin. Uptake of desialylated adiponectin by isolated primary rat hepatocytes was also accelerated, suggesting a role for the hepatic asialoglycoprotein receptor. Finally, after chronic administration in adiponectin−/− mice steady-state levels of desialylated adiponectin were lower than control adiponectin and failed to recapitulate the improvements in glucose and insulin tolerance tests observed with control adiponectin. These data suggest an important role for sialic acid content in the regulation of circulating adiponectin levels and highlight the importance of understanding mechanisms regulating adiponectin sialylation/desialylation.
Publisher: Springer Science and Business Media LLC
Date: 08-01-2005
DOI: 10.1007/S00125-004-1632-Z
Abstract: Subclinical left ventricular (LV) dysfunction has been shown by tissue Doppler and strain imaging in diabetic patients in the absence of coronary disease or LV hypertrophy, but the prevalence and aetiology of this finding remain unclear. This study sought to identify the prevalence and the determinants of subclinical diabetic heart disease. A group of 219 unselected patients with type 2 diabetes without known cardiac disease underwent resting and stress echocardiography. After exclusion of coronary artery disease or LV hypertrophy, the remaining 120 patients (age 57+/-10 years, 73 male) were studied with tissue Doppler imaging. Peak systolic strain of each wall and systolic (Sm) and diastolic (Em) velocity of each basal segment were measured from the three apical views and averaged for each patient. Significant subclinical LV dysfunction was identified according to Sm and Em normal ranges adjusted by age and sex. Strain and Em were correlated with clinical, therapeutic, echocardiographic and biochemical variables, and significant independent associations were sought using a multiple linear regression model. Significant subclinical LV dysfunction was present in 27% diabetic patients. Myocardial systolic dysfunction by peak strain was independently associated with glycosylated haemoglobin level (p<0.001) and lack of angiotensin-converting enzyme inhibitor treatment (p=0.003). Myocardial diastolic function (Em) was independently predicted by age (p=0.013), hypertension (p=0.001), insulin (p=0.008) and metformin (p=0.01) treatment. In patients with diabetes mellitus, subclinical LV dysfunction is common and associated with poor diabetic control, advancing age, hypertension and metformin treatment ACE inhibitor and insulin therapies appear to be protective.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2006
Publisher: Canadian Science Publishing
Date: 12-2015
Abstract: Intramyocellular lipids (IMCL) are depleted in response to an acute bout of exercise in lean endurance-trained in iduals however, it is unclear whether changes in IMCL content are also seen in response to acute and chronic exercise in obese in iduals. We used magnetic resonance spectroscopy in 18 obese men and 5 normal-weight controls to assess IMCL content before and after an hour of cycling at the intensity corresponding with each participant’s maximal whole-body rate of fat oxidation (Fat max ). Fat max was determined via indirect calorimetry during a graded exercise test on a cycle ergometer. The same outcome measures were reassessed in the obese group after a 16-week lifestyle intervention comprising dietary calorie restriction and exercise training. At baseline, IMCL content decreased in response to 1 h of cycling at Fat max in controls (2.8 ± 0.4 to 2.0 ± 0.3 A.U., –39%, p = 0.02), but not in obese (5.4 ± 2.1 vs. 5.2 ± 2.2 A.U., p = 0.42). The lifestyle intervention lead to weight loss (–10.0 ± 5.4 kg, p 0.001), improvements in maximal aerobic power (+5.2 ± 3.4 mL/(kg·min)), maximal fat oxidation rate (+0.19 ± 0.22 g/min), and a 29% decrease in homeostasis model assessment score (all p 0.05). However, when the 1 h of cycling at Fat max was repeated after the lifestyle intervention, there remained no observable change in IMCL (4.6 ± 1.8 vs. 4.6 ± 1.9 A.U., p = 0.92). In summary, there was no IMCL depletion in response to 1 h of cycling at moderate intensity either before or after the lifestyle intervention in obese men. An effective lifestyle intervention including moderate-intensity exercise training did not impact rate of utilisation of IMCL during acute exercise in obese men.
Publisher: Oxford University Press (OUP)
Date: 06-2008
DOI: 10.1038/AJH.2008.166
Abstract: A hypertensive response to exercise has prognostic significance. Patients with type 2 diabetes have vascular abnormalities which may predispose to exaggerated brachial and central blood pressure (BP) during exercise. This study aimed to test this hypothesis and to determine the clinical significance of high exercise BP by examining its relation to left ventricular (LV) mass. Brachial and central BP were recorded at rest and in response to maximal exercise in 73 diabetic patients (aged 54 +/- 10 years) and 73 controls (aged 53 +/- 12 years). Brachial BP was recorded using mercury sphygmomanometry and LV mass using 2D-echocardiography. Central BP was estimated by radial tonometry using an exercise-validated generalized transfer function. At rest there were no significant (P > 0.05) differences between groups in brachial or central BP. The diabetic patients had significantly increased exercise brachial systolic BP (SBP: 199 +/- 25 mm Hg vs. 185 +/- 21 mm Hg P = 0.002) and central SBP (158 +/- 17 mm Hg vs. 149 +/- 15 mm Hg P = 0.002). There was a significantly higher prevalence of an exaggerated exercise BP response (> or =210/105 mm Hg men and > or =190/105 mm Hg women) in the diabetic patients (51% vs. 22% P < 0.01). Compared with those with normal exercise BP, LV relative wall thickness (RWT) was significantly higher (0.41 +/- 0.09 vs. 0.36 +/- 0.08 P < 0.05) and LV hypertrophy was more prevalent (35% vs. 16% P < 0.05) in those with a hypertensive response. After accounting for other confounding variables, exercise central SBP remained independently associated with LV RWT (beta = 0.22 P = 0.006). Diabetic patients are more likely to exhibit exaggerated exercise BP. Regardless of disease status, high exercise central SBP may contribute to cardiovascular risk via adverse cardiac remodeling.
Publisher: Wiley
Date: 04-2022
DOI: 10.14814/PHY2.15257
Publisher: IEEE
Date: 06-2007
Publisher: Wiley
Date: 08-1992
DOI: 10.1111/J.1445-5994.1992.TB02153.X
Abstract: We reported previously that 24-hr moving average ambient air pollution concentrations were positively associated with ventricular arrhythmias detected by implantable cardioverter defibrillators (ICDs). ICDs also detect paroxysmal atrial fibrillation episodes (PAF) that result in rapid ventricular rates. In this same cohort of ICD patients, we assessed the association between ambient air pollution and episodes of PAF. We performed a case-crossover study. Patients who lived in the Boston, Massachusetts, metropolitan area and who had ICDs implanted between June 1995 and December 1999 (n=203) were followed until July 2002. We used conditional logistic regression to explore the association between community air pollution and 91 electrophysiologist-confirmed episodes of PAF among 29 subjects. We found a statistically significant positive association between episodes of PAF and increased ozone concentration (22 ppb) in the hour before the arrhythmia (odds ratio=2.08 95% confidence interval=1.22, 3.54 p=0.001). The risk estimate for a longer (24-hr) moving average was smaller, thus suggesting an immediate effect. Positive but not statistically significant risks were associated with fine particles, nitrogen dioxide, and black carbon. Increased ambient O3 pollution was associated with increased risk of episodes of rapid ventricular response due to PAF, thereby suggesting that community air pollution may be a precipitant of these events.
Publisher: Springer Science and Business Media LLC
Date: 12-10-2009
Abstract: Adiponectin is a major adipocyte-derived protein with insulin-sensitizing, anti-inflammatory and anti-atherogenic properties. Adiponectin levels correlate inversely with renal function and higher levels are predictive of lower cardiovascular disease (CVD) in patients with normal renal function and chronic kidney disease. No data exists on the association between adiponectin and CVD in renal transplant recipients (RTR). Standard biochemistry, clinical data and adiponectin were collected from 137 RTR recruited to the LANDMARK 2 study at baseline. The LANDMARK 2 study is an ongoing randomized controlled study that compares the outcome of aggressive risk factor modification for cardiovascular disease versus standard post-transplant care in renal transplant recipients with impaired glucose tolerance or diabetes mellitus. Mean patient age was 53.4 ± 12 years and the median post-transplantation period was 5 (0.5-31.9) years. Mean serum adiponectin level was 12.3 ± 7.1 μg/mL. On univariate analysis, adiponectin was positively associated with female gender (P = 0.01) and serum high-density lipoprotein (HDL) concentration (P 0.001), and inversely with body mass index (P = 0.009), metabolic syndrome (P = 0.047), abnormal glucose tolerance (P = 0.01), C-reactive protein (P = 0.001) and serum triglyceride (P 0.001). On stepwise multivariate analysis, adiponectin in males was negatively correlated with combined baseline CVD (P = 0.03), waist-hip ratio (P = 0.003) and glomerular filtration rate (P = 0.046), and positively with HDL (P 0.001). In contrast, in females adiponectin was inversely associated with C-reactive protein (P = 0.001) and serum triglyceride. In conclusion, adiponectin is positively correlated with inflammation, dyslipidemia and abnormal glucose tolerance in RTR. Furthermore, hypoadiponectinemia correlated with increased baseline CVD in male RTR.
Publisher: Oxford University Press (OUP)
Date: 2009
DOI: 10.1038/AJH.2008.284
Publisher: Wiley
Date: 07-02-2006
DOI: 10.1111/J.1365-2702.2006.01294.X
Abstract: To review the existing literature on health-promoting schools and put forward recommendations for continuing progress. The World Health Organisation's Ottawa Charter for Health Promotion in 1986 sought to create a framework for health promotion action that conveyed the notion of capacity building as it related to specific settings. It provided the catalyst from which the health-promoting school movement emerged, against the backdrop of health professionals adapting to the changing needs and demands of clients and the evolving social context of the communities in which they live. Since then, the international health-promoting school movement has been one of the most successful of the settings-based projects and has expanded considerably over recent years. An extensive review of available health-promoting school-related literature provides the basis for critical discussion and recommendations. Traditionally, the school nursing movement has provided the backbone of nursing-related health promotion activity in the school setting. The literature, however, is generally critical of its contribution over the years - especially as its role is mainly confined to a 'conventional' health education function and has little to do with health-promoting school projects. There are more and more calls now for the school nursing service to either re-evaluate its function and processes or be devolved back into a broader primary health care practitioner role. Nurses should view the health-promoting school movement as another opportunity to embrace evolving broad-based health promotion concepts truly, as a means to forge and own their own health agenda and also as a means to move beyond a traditional reliance on a limited health education role. Schools also need to adapt and expand their efforts to focus on health promotion activities, in collaboration with the ever-widening community networks of health and social agencies. This requires the commitment of all healthcare professional groups. Nurses who practice in all settings, and not just school nurses, should be aiming to initiate and promote radical health promotion reform as set out in the health-promoting school movement. If health professionals wish to be at the forefront of current health-promoting school strategies they must embrace the radical health promotion reforms that are emerging from the current literature and put forward in this article. Building such group capacity, through developing social interaction, cohesion, participation and political action can only benefit the community at large and further emphasize the health promotion role of nursing. The health-promoting school movement is truly an international concept and, as such, deserves a concerted nursing representation and resourcing well beyond its current commitment.
Publisher: Bioscientifica
Date: 17-11-2015
DOI: 10.1530/JME-15-0232
Abstract: The inability of pancreatic β-cells to make sufficient insulin to control blood sugar is a central feature of the aetiology of most forms of diabetes. In this review we focus on the deleterious effects of oxidative stress and endoplasmic reticulum (ER) stress on β-cell insulin biosynthesis and secretion and on inflammatory signalling and apoptosis with a particular emphasis on type 2 diabetes (T2D). We argue that oxidative stress and ER stress are closely entwined phenomena fundamentally involved in β-cell dysfunction by direct effects on insulin biosynthesis and due to consequences of the ER stress-induced unfolded protein response. We summarise evidence that, although these phenomenon can be driven by intrinsic β-cell defects in rare forms of diabetes, in T2D β-cell stress is driven by a range of local environmental factors including increased drivers of insulin biosynthesis, glucolipotoxicity and inflammatory cytokines. We describe our recent findings that a range of inflammatory cytokines contribute to β-cell stress in diabetes and our discovery that interleukin 22 protects β-cells from oxidative stress regardless of the environmental triggers and can correct much of diabetes pathophysiology in animal models. Finally we summarise evidence that β-cell dysfunction is reversible in T2D and discuss therapeutic opportunities for relieving oxidative and ER stress and restoring glycaemic control.
Publisher: American Physiological Society
Date: 2009
DOI: 10.1152/AJPENDO.90602.2008
Abstract: Cell number is an important determinant of adipose tissue mass, and the coordinated proliferation and differentiation of preadipocytes into mature lipid-laden adipocytes underpins the increased adipose tissue mass associated with obesity. Despite this, the molecular cues governing such adipose tissue expansion are poorly understood. We previously reported that fibroblast growth factor-1 (FGF-1) promotes both proliferation and differentiation of human preadipocytes and that the major adipogenic effect of FGF-1 occurs during proliferation, priming the cells for adipose conversion. In the current study, we examined whether this effect was linked to the mitogenic action of FGF-1 by investigating the mitogenic and adipogenic potential of other growth factors, platelet-derived growth factor (PDGF AA and BB) and vascular endothelial growth factor. Although PDGF-AA and PDGF-BB showed comparable mitogenic potential to FGF-1, only FGF-1 treatment resulted in priming and subsequent differentiation. Pharmacological inhibition of FGF receptor (FGFR) tyrosine kinase activity, using the FGFR-specific inhibitors PD-173074 and SU-5402, revealed an obligate requirement for FGFR activity in these processes. A combination of biochemical and genetic approaches revealed an important role for FGFR1. Knock down of FGFR1 expression by small-interfering RNA reduced FGF-1-stimulated signaling events, proliferation, and priming. Together these data highlight the unique nature of the role of FGF-1 during the earliest stages of adipogenesis and establish a role for FGFR1 in human adipogenesis, identifying FGFR1 as a potential therapeutic target to reduce obesity.
Publisher: Wiley
Date: 19-06-2003
DOI: 10.1046/J.1365-2362.2003.01178.X
Abstract: Peroxisome proliferator activated receptor gamma (PPARgamma) is a ligand-activated transcription factor known to be central to both adipose tissue development and insulin action. Growth of adipose tissue requires differentiation of preadipocytes with acquisition of specific cellular functions including insulin sensitivity, leptin secretion and the capacity to store triglyceride. Dietary fatty acids and members of the thiazolidinedione class of compounds have been reported to influence adipogenesis at the transcriptional level. Here, we compare the effects of a dietary fatty acid, linoleic acid, and a thiazolidinedione, rosiglitazone, on biochemical and functional aspects of human preadipocyte differentiation in vitro. Human omental and subcutaneous preadipocytes were subcultured 2-3 times and subsequently differentiated for 21 days in the presence of either linoleic acid or rosiglitazone. Differentiation was assessed using a number of biochemical and functional parameters. Omental and subcutaneous preadipocytes differentiated in the presence of linoleic acid showed marked cytoplasmic triacylglycerol accumulation however, no biochemical markers of differentiation (LPL expression, G3PDH gene expression and enzyme activity and leptin expression or secretion) were detected. In contrast, treatment of these cells with rosiglitazone induced full biochemical differentiation as judged by all markers assessed, despite comparatively little lipid accumulation. The rosiglitazone effects were subcutaneous depot-specific. Cells treated with linoleic acid showed decreased glucose uptake cf rosiglitazone-treated cells. A luciferase reporter assay demonstrated that rosiglitazone potently activates h-peroxisome proliferator activated receptor gamma while linoleic acid had no effect. These studies demonstrate that (a) human preadipocytes have the potential to accumulate triacylglycerol irrespective of their stage of biochemical differentiation (b) while omental preadipocytes are refractory to biochemical differentiation in vitro, they are able to accumulate triacylglycerol and (c) rosiglitazone and linoleic acid may exert their effects via different biochemical pathways.
Publisher: Springer Science and Business Media LLC
Date: 2009
DOI: 10.1186/CC7941
Publisher: Elsevier BV
Date: 12-2003
DOI: 10.1016/S0168-8278(03)00463-X
Abstract: Host factors such as increased body mass index (BMI) and genotype-specific viral factors contribute to the development of steatosis in patients with chronic hepatitis C (HCV). We hypothesized that host metabolic factors associated with increased BMI may play a role in disease progression. Fasting serum was collected from 160 patients with chronic HCV at the time of liver biopsy and 45 age, gender and BMI matched controls, and assessed for levels of insulin, c-peptide and leptin. Patients with viral genotype 3 had more severe steatosis (P=0.0001) and developed stages 1 and 2 fibrosis at a younger age (P<0.05) than patients with genotype 1. For both genotypes, overweight patients had significantly more steatosis and increased insulin and leptin levels. In contrast to lean patients, there was a statistically significant increase in circulating insulin levels with increasing fibrosis in overweight patients with chronic HCV (P=0.03). Following multivariate analysis, insulin was independently associated with fibrosis (P=0.046) but not inflammation (P=0.83). There was no association between serum leptin levels and stage of fibrosis. Increasing circulating insulin levels may be a factor responsible for the association between BMI and fibrosis in patients with HCV, irrespective of viral genotype.
Publisher: Elsevier BV
Date: 08-1999
Publisher: BMJ
Date: 13-12-2007
Abstract: Obesity is associated with increased risks of Barrett's oesophagus and oesophageal adenocarcinoma. Alterations in serum leptin and adiponectin, obesity-related cytokines, have been linked with several cancers and have been postulated as potential mediators of obesity-related carcinogenesis however, the relationship with Barrett's oesophagus remains unexplored. Serum leptin and adiponectin concentrations were measured on two subsets of participants within a case-control study conducted in Brisbane, Australia. Cases were people aged 18-79 years with histologically confirmed Barrett's oesophagus newly diagnosed between 2003 and 2006. Population controls, frequency matched by age and sex to cases, were randomly selected from the electoral roll. Phenotype and medical history data were collected through structured, self-completed questionnaires. Odds ratios (OR) and 95% CI were calculated using multivariable logistic regression analysis. In the pilot analysis (51 cases, 67 controls) risks of Barrett's oesophagus were highest among those in the highest quartile of serum leptin (OR 4.6, 95% CI 0.6 to 33.4). No association was seen with adiponectin. In the leptin validation study (306 cases, 309 controls), there was a significant threefold increased risk of Barrett's oesophagus among men in the highest quartile of serum leptin (OR 3.3, 95% CI 1.7 to 6.6) and this persisted after further adjustment for symptoms of gastro-oesophageal reflux (OR 2.4, 95% CI 1.1 to 5.2). In contrast, the risk of Barrett's oesophagus among women decreased with increasing serum leptin concentrations. High serum leptin is associated with an increased risk of Barrett's oesophagus among men but not women. This association is not explained simply by higher body mass or gastro-oesophageal reflux among cases. The mechanism remains to be determined.
Publisher: Wiley
Date: 22-05-2007
DOI: 10.1111/J.1440-1797.2007.00804.X
Abstract: Metabolic syndrome (MS) is a significant risk factor for cardiovascular disease, mortality and chronic kidney disease (CKD) in the general population. However, the prevalence, predictors, prognostic value and treatment of MS in the CKD population have not been rigorously studied. The study involved 200 stages 4 and 5 CKD patients enrolled in a randomized controlled trial of intensive multiple risk factor modification (targeting hypercholesterolaemia, hyperhomocysteinaemia, anaemia and disordered bone mineral metabolism) versus usual care. Participants were followed for a median period of 22 months. The overall prevalence of MS was 30.5%. MS was independently predicted by older age, peritoneal dialysis and Maori/Pacific Islander origin. When laboratory parameters were included as covariates, the only significant predictors of MS were higher serum malondialdehyde and lower serum adiponectin concentrations. MS was an independent predictor of time to composite end-point of cardiovascular death, acute coronary syndrome, revascularization, non-fatal stroke and utation (adjusted hazard ratio 2.46, 95% CI 1.17-5.18). No significant difference in cardiovascular event-free survival was observed in those allocated to intensive risk factor modification compared with usual care. Metabolic syndrome occurs in 30.5% of stages 4 and 5 CKD patients and is associated with older age, peritoneal dialysis, ethnicity, increased oxidative stress, lower serum adiponectin concentrations and a significantly increased risk of future cardiovascular events. Intervention strategies targeting hypercholesterolaemia, hyperhomocysteinaemia, anaemia and disordered bone mineral metabolism may not be effective in ameliorating the heightened cardiovascular risk of CKD patients with MS.
Publisher: Wiley
Date: 14-09-2016
DOI: 10.1111/CEN.12879
Abstract: The optimal management of nonfunctioning pituitary adenomas presenting without symptomatic mass effect remains uncertain. The objective of this study was to elucidate the natural history of nonfunctioning pituitary adenomas managed conservatively. Volumetric evaluation of tumour growth in serial pituitary MRI scans by a single observer and retrospective review of changes in pituitary function. Patients with nonfunctioning pituitary adenomas who underwent at least 2 serial pituitary MRI scans over ≥6 months between 2003 and 2013 prior to any intervention. Primary end-point was a ≥20% increase in volume or surgery. Secondary end-points were rate of pituitary dysfunction and pituitary apoplexy. Fifty nonfunctioning pituitary adenomas (23 macroadenomas and 27 microadenomas, mean age 49, range 17-85 years) were identified. Mean follow-up was 36 months (range 6-79). An increase in volume occurred in macroadenomas (P < 0·01) but not in microadenomas (P = 0·44). A ≥20% increase in volume occurred in nine of 23 macroadenomas compared with two of 27 microadenomas (P < 0·05). Five macroadenomas (one with new visual field defect) and one microadenoma proceeded to surgery (P = 0·08). Hormone deficiency was present in four of 24 macroadenomas vs 0 of 27 microadenomas (P 10 mm Nonfunctioning pituitary macroadenomas have a greater tendency to grow and require surgical intervention while microadenomas rarely progress.
Publisher: Springer New York
Date: 2007
Publisher: Elsevier BV
Date: 12-2005
DOI: 10.1016/J.AJOG.2005.04.058
Abstract: We sought to determine the contribution of adipose tissue to the insulin resistance of pregnancy. We also investigated whether hyperosmolar stress (induced by sorbitol) stimulates glucose uptake in human adipose tissue and, if so, whether this effect is altered in pregnancy and gestational diabetes mellitus. Subcutaneous and omental adipose tissue biopsy specimens were obtained at elective abdominal surgery or cesarean delivery from 16 normal glucose-tolerant pregnant women, 13 pregnant women with gestational diabetes mellitus, and 19 body mass index-matched nonpregnant control subjects. Basal, insulin (100 nmol/L)-, and sorbitol (250 mmol/L)-stimulated glucose uptake levels were measured. Basal and insulin-stimulated glucose uptake into adipose tissue was not impaired in pregnancy or gestational diabetes mellitus compared with control subjects. Hyperosmolarity stimulated glucose uptake in human adipose tissue from the subcutaneous, but not omental depot, and not in adipose tissue from pregnant subjects. There is no significant difference in insulin sensitivity in adipose tissue from pregnant or nonpregnant women hyperosmolarity stimulates glucose uptake in subcutaneous adipose tissue from nonpregnant women, and adipose tissue from pregnant women is sorbitol resistant. These findings suggest the phosphotidylinositol 3-kinase-independent pathway may have pathophysiologic relevance to glucose uptake in human adipose tissue and may be impaired in pregnancy.
Publisher: Elsevier BV
Date: 11-1994
Abstract: Rapid weight loss is frequently seen in malignancy. This weight loss is considered to result from enhanced lipolysis. Here, we show that adipocyte deletion by apoptosis, demonstrated by electron microscopy and DNA gel electrophoresis, occurs in some patients. Adipocyte apoptosis could not be demonstrated in patients without malignancy. These findings suggest that fat cell loss by apoptosis plays a role in malignancy-associated weight loss.
Publisher: The Endocrine Society
Date: 08-2004
DOI: 10.1210/ER.2003-0012
Publisher: American Diabetes Association
Date: 07-2005
DOI: 10.2337/DIACARE.28.7.1643
Abstract: OBJECTIVE—Type 2 diabetes is associated with reduced exercise capacity, but the cause of this association is unclear. We sought the associations of impaired exercise capacity in type 2 diabetes. RESEARCH DESIGN AND METHODS—Subclinical left ventricular (LV) dysfunction was sought from myocardial strain rate and the basal segmental diastolic velocity (Em) of each wall in 170 patients with type 2 diabetes (aged 56 ± 10 years, 91 men), good quality echocardiographic images, and negative exercise echocardiograms. The same measurements were made in 56 control subjects (aged 53 ± 10 years, 29 men). Exercise capacity was calculated in metabolic equivalents, and heart rate recovery (HRR) was measured as the heart rate difference between peak and 1 min after exercise. In subjects with type 2 diabetes, exercise capacity was correlated with clinical, therapeutic, biochemical, and echocardiographic variables, and significant independent associations were sought using a multiple linear regression model. RESULTS—Exercise capacity, strain rate, Em, and HRR were significantly reduced in type 2 diabetes. Exercise capacity was associated with age (r = −0.37, P & 0.001), male sex (r = 0.26, P = 0.001), BMI (r = −0.19, P = 0.012), HbA1c (A1C r = −0.22, P = 0.009), Em (r = 0.43, P & 0.001), HRR (r = 0.42, P & 0.001), diabetes duration (r = −0.18, P = 0.021), and hypertension history (r = −0.28, P & 0.001). Age (P & 0.001), male sex (P = 0.007), BMI (P = 0.001), Em (P = 0.032), HRR (P = 0.013), and A1C (P = 0.0007) were independent predictors of exercise capacity. CONCLUSIONS—Reduced exercise capacity in patients with type 2 diabetes is associated with diabetes control, subclinical LV dysfunction, and impaired HRR.
Publisher: BMJ
Date: 03-2004
Abstract: Obesity is a risk factor for progression of fibrosis in chronic liver diseases such as non-alcoholic fatty liver disease and hepatitis C. The aim of this study was to investigate the longer term effect of weight loss on liver biochemistry, serum insulin levels, and quality of life in overweight patients with liver disease and the effect of subsequent weight maintenance or regain. Thirty one patients completed a 15 month diet and exercise intervention. On completion of the intervention, 21 patients (68%) had achieved and maintained weight loss with a mean reduction of 9.4 (4.0)% body weight. Improvements in serum alanine aminotransferase (ALT) levels were correlated with the amount of weight loss (r = 0.35, p = 0.04). In patients who maintained weight loss, mean ALT levels at 15 months remained significantly lower than values at enrollment (p = 0.004), while in regainers (n = 10), mean ALT levels at 15 months were no different to values at enrollment (p = 0.79). Improvements in fasting serum insulin levels were also correlated with weight loss (r = 0.46, p = 0.04), and subsequent weight maintenance sustained this improvement. Quality of life was significantly improved after weight loss. Weight maintainers sustained recommended levels of physical activity and had higher fasting insulin levels (p = 0.03) at enrollment than weight regainers. In summary, these findings demonstrate that maintenance of weight loss and exercise in overweight patients with liver disease results in a sustained improvement in liver enzymes, serum insulin levels, and quality of life. Treatment of overweight patients should form an important component of the management of those with chronic liver disease.
Publisher: Elsevier BV
Date: 04-2008
DOI: 10.1016/J.DIABRES.2007.11.016
Abstract: Raised liver enzymes are common in type 2 diabetes (T2DM) but often considered benign. Non-alcoholic fatty liver was the cause in 65% of cases but other causes included alcoholic liver disease and viral hepatitis. Cirrhosis was identified in 11 patients. There is a significant burden of advanced liver diseases from a variety of aetiologies in patients with T2DM.
Publisher: Elsevier BV
Date: 12-2014
DOI: 10.1016/J.CGH.2014.02.024
Abstract: Nonalcoholic fatty liver disease (NAFLD), characterized by accumulation of hepatic triglycerides (steatosis), is associated with abdominal obesity, insulin resistance, and inflammation. Although weight loss via calorie restriction reduces features of NAFLD, there is no pharmacologic therapy. Resveratrol is a polyphenol that prevents high-energy diet-induced steatosis and insulin resistance in animals by up-regulating pathways that regulate energy metabolism. We performed a placebo-controlled trial to assess the effects of resveratrol in patients with NAFLD. Overweight or obese men diagnosed with NAFLD were recruited from hepatology outpatient clinics in Brisbane, Australia from 2011 through 2012. They were randomly assigned to groups given 3000 mg resveratrol (n = 10) or placebo (n = 10) daily for 8 weeks. Outcomes included insulin resistance (assessed by the euglycemic-hyperinsulinemic cl ), hepatic steatosis, and abdominal fat distribution (assessed by magnetic resonance spectroscopy and imaging). Plasma markers of inflammation, as well as metabolic, hepatic, and antioxidant function, were measured transcription of target genes was measured in peripheral blood mononuclear cells. Resveratrol pharmacokinetics and safety were assessed. Eight-week administration of resveratrol did not reduce insulin resistance, steatosis, or abdominal fat distribution when compared with baseline. No change was observed in plasma lipids or antioxidant activity. Levels of alanine and aspartate aminotransferases increased significantly among patients in the resveratrol group until week 6 when compared with the placebo group. Resveratrol did not significantly alter transcription of NQO1, PTP1B, IL6, or HO1 in peripheral blood mononuclear cells. Resveratrol was well-tolerated. Eight weeks administration of resveratrol did not significantly improve any features of NAFLD, compared with placebo, but it increased hepatic stress, based on observed increases in levels of liver enzymes. Further studies are needed to determine whether agents that are purported to mimic calorie restriction, such as resveratrol, are safe and effective for complications of obesity. Clinical trials registration no: ACTRN12612001135808.
Publisher: Elsevier BV
Date: 10-2011
DOI: 10.1016/J.BEEM.2011.04.008
Abstract: Metabolic support in intensive care is a rapidly evolving field with new information being gathered almost on a daily basis. In endocrine practice, over the last 20 years, researchers have focussed on a new entity, termed the "metabolic syndrome". This describes the constellation of abnormalities which include central adiposity, insulin resistance and inflammation. All of these predispose the in idual to a greater risk of cardiovascular events. Of interest is the observation that some of the metabolic abnormalities in sepsis and multiple organ dysfunction syndrome of critical illness share several common features with that of the metabolic syndrome. In this chapter we describe the features of the metabolic syndrome as is understood in endocrine parlance, the metabolic abnormalities of critical illness and explore the common threads underlying the pathophysiology and the treatment of the two syndromes. The role of adiponectin in the metabolic abnormalities in both the metabolic syndrome and in sepsis are reviewed. The potential role of the pleiotropic effects of statins in the therapy of sepsis is also discussed.
Publisher: Wiley
Date: 12-2005
Publisher: BMJ
Date: 2005
Publisher: The Endocrine Society
Date: 10-2001
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: Wiley
Date: 09-06-2011
Publisher: Elsevier BV
Date: 2012
DOI: 10.1016/J.JSAMS.2011.04.005
Abstract: Type 2 diabetes mellitus (T2DM) and pre-diabetic conditions such as impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) are rapidly increasing in prevalence. There is compelling evidence that T2DM is more likely to develop in in iduals who are insufficiently active. Exercise training, often in combination with other lifestyle strategies, has beneficial effects on preventing the onset of T2DM and improving glycaemic control in those with pre-diabetes. In addition, exercise training improves cardiovascular risk profile, body composition and cardiorespiratory fitness, all strongly related to better health outcomes. Based on the evidence, it is recommended that patients with T2DM or pre-diabetes accumulate a minimum of 210 min per week of moderate-intensity exercise or 125 min per week of vigorous intensity exercise with no more than two consecutive days without training. Vigorous intensity exercise is more time efficient and may also result in greater benefits in appropriate in iduals with consideration of complications and contraindications. It is further recommended that two or more resistance training sessions per week (2-4 sets of 8-10 repetitions) should be included in the total 210 or 125 min of moderate or vigorous exercise, respectively. It is also recommended that, due to the high prevalence and incidence of comorbid conditions in patients with T2DM, exercise training programs should be written and delivered by in iduals with appropriate qualifications and experience to recognise and accommodate comorbidities and complications.
Publisher: Springer Science and Business Media LLC
Date: 31-10-2014
DOI: 10.1007/S12020-013-0083-Z
Abstract: Androgen deprivation therapy (ADT), which is used in the treatment of prostate cancer (PCa), is associated with increased morbidity. Severe bone loss is a major consequence of androgen ablation and with an increasing number of patients undergoing this treatment, the incidence of osteoporosis and fractures can be expected to increase with a significant impact on healthcare. To evaluate the prevalence of osteoporosis, we conducted a review of the literature on bone health in men with PCa undergoing ADT. A meta-analysis was conducted using the quality effects model, and sources of heterogeneity were further explored by consideration of discordant effect sizes of included studies in the meta-analysis and examining reasons thereof. Our analyses indicate that the prevalence of osteoporosis varies between 9 and 53 % with this variation partially explained by treatment duration, disease stage, ethnicity and site of osteoporosis measurement. While it is well known that a rapid decline in bone health amongst men with PCa on ADT occurs, this meta-analysis documents the high prevalence of osteoporosis in this population and reinforces the need of preventative approaches as part of usual care of PCa patients.
Publisher: Springer Science and Business Media LLC
Date: 28-10-2016
Publisher: Elsevier BV
Date: 04-2009
DOI: 10.1016/J.MCE.2008.10.020
Abstract: Excess glucocorticoids induce insulin resistance and reduce glucose uptake although the underlying mechanisms are unclear. Here we demonstrate that Dex (1 microM for 24h) inhibits basal and insulin (1 nM) stimulated glucose uptake in human and murine adipocytes by 50% with a concomitant reduction in the levels of GLUT1/4 at the plasma membrane but no change in total GLUT1/4 levels. Expression and phosphorylation of proximal insulin signalling molecules (IRS1, PI3K, AKT) was unaffected by Dex as was phosphorylation of mTOR and FOXO1. In contrast, phosphorylation of AKT substrate 160kDa (AS160) at T642, which is essential for 14-3-3 recruitment and GLUT4 translocation, was reduced by 50% in basal and insulin-stimulated cells and this was mirrored by decreased 14-3-3 association. Co-treatment with the glucocorticoid receptor antagonist RU486 (10 microM) abrogated the Dex effect on AS160-T642 phosphorylation and restored glucose uptake by 80%. These data suggest Dex inhibits glucose uptake in adipocytes, at least in part, by reducing AS160 phosphorylation and interaction with 14-3-3.
Publisher: Elsevier BV
Date: 12-2006
DOI: 10.1016/J.AMJCARD.2006.07.037
Abstract: Subclinical myocardial and vascular dysfunctions occur in subjects with obesity. We investigated whether these changes were reversible with weight loss due to lifestyle intervention. Quantitative assessment of myocardial and vascular functions was performed at baseline and after a minimum of 8 weeks of a lifestyle intervention program in 106 subjects with significant risk factors but no history of cardiovascular disease and normal ejection fractions. Myocardial function was assessed using strain rate, strain, regional myocardial systolic velocity, and diastolic velocity (e(m)). Myocardial reflectivity was assessed by calibrated integrated backscatter. Vascular function was assessed using brachial arterial reactivity and arterial compliance. Exercise capacity was measured by peak oxygen consumption per unit time (VO(2)). Weight loss (-4.5 +/- 2.0%) was achieved by 48 subjects, and 58 maintained or increased weight (+1 +/- 1.5%, p <0.001). Compared with the stable weight group, the weight loss group showed significant improvement in brachial arterial reactivity (8.6 +/- 4.9% vs 6.7 +/- 4.9%, p <0.05), e(m) (6.4 +/- 1.9 vs 5.5 +/- 1.9 cm/s, p <0.01), and reflectivity (calibrated integrated backscatter, 18.3 +/- 4.9 vs 16.2 +/- 5.2 dB, p <0.01). The magnitude of weight change correlated with changes in e(m) (r = 0.36) and calibrated integrated backscatter (r = 0.33). The change in e(m) correlated with peak VO(2) (r = 0.38, p <0.001) and was an independent predictor for peak VO(2) even after adjustment for age and body mass index in a multivariate model (R(2) = 0.45, p <0.001). Weight loss was not associated with a significant change in systolic parameters (regional myocardial systolic velocity, global strain, and strain rate) or arterial compliance.
Publisher: Oxford University Press (OUP)
Date: 02-2016
DOI: 10.1530/EJE-15-0964
Abstract: Thrombospondin-1 (TSP1) is a matricellular protein whose gene expression has previously been shown to increase acutely after exposure to dexamethasone in vitro . The aim of this study was to determine if TSP1 is altered by acute and chronic states of glucocorticoid excess in human subjects. Three studies have been undertaken to assess the difference or change in TSP1 in response to altered glucocorticoid activity: i) an acute interventional study assessed the effects of a single 4 mg dose of dexamethasone in 20 healthy volunteers ii) a cross-sectional study compared plasma TSP1 in 20 healthy volunteers and eight patients with Cushing's syndrome iii) an interventional study assessed the effect on plasma TSP1 of an increase in hydrocortisone dose from ≤20 mg/day to 30 mg/day for 7 days in 16 patients with secondary adrenal insufficiency. In healthy volunteers, 4 mg dexamethasone significantly increased peripheral blood mononuclear cell (PBMC) TSP1 mRNA levels ( P .0001) and plasma TSP1 concentrations ( P .0001), peaking at 12 h. Median (interquartile range) plasma TSP1 was higher in Cushing's, 638 (535–756) ng/ml, than in healthy volunteers, 272 (237–336) ng/ml ( P .0001). Plasma TSP1 ng/ml diagnosed Cushing's syndrome with sensitivity of 100% and specificity of 85%. The higher hydrocortisone dose increased plasma TSP1 from 139 (86–199) to 256 (133–516) ng/ml, ( P .01) in patients with secondary adrenal insufficiency. TSP1 is a glucocorticoid responsive protein in humans. Further research is required to determine if plasma TSP1 has a role as a glucocorticoid biomarker.
Publisher: Springer Science and Business Media LLC
Date: 12-2009
Publisher: Elsevier BV
Date: 06-1994
Abstract: Large increases in fat stores involve an increase in adipocyte number via the replication and differentiation of preadipocytes, with the resultant cell gain widely regarded as irreversible. To date, there has been no clearly defined process or mechanism reported by which adipocyte deletion may occur. Here, we show that human adipocytes undergo apoptosis following growth factor deprivation or mild heat injury in vitro, thus demonstrating a cellular mechanism by which normal adipocyte loss could occur in vivo. The findings have implications for the understanding of adipose tissue kinetics and its derangement as well as for the potential development of methods for modifying fat store size.
Publisher: BMJ
Date: 02-05-2015
DOI: 10.1136/HEARTJNL-2014-307391
Abstract: New imaging techniques have permitted the detection of subclinical LV dysfunction (LVD) in up to half of patients with type 2 diabetes mellitus (DM) with a normal EF. However, the connection between early LVD and prognosis is unclear. This study aimed to define the long-term outcome of LVD associated with type 2 DM. In this prospective cohort study, 230 asymptomatic patients with type 2 DM underwent measurement of global longitudinal 2D strain (GLS) for detection of LVD and were followed for up to 10 years. All subjects had normal EF (≥50%) and no evidence of coronary artery disease at recruitment. Outcome data were obtained through centralised state-wide death and hospital admission registries. The primary endpoint was all-cause mortality and hospitalisation. On study entry, almost half (45%) of the cohort had evidence of LVD as detected by GLS. Over a median follow-up of 7.4±2.6 years (range 0.6-9.7 years), 68 patients (30%) met the primary endpoint (LVD: 37% normal LV function: 24%). GLS was independently associated with the primary endpoint (HR=1.10 p=0.04), as was systolic blood pressure (HR=1.02 p<0.001) and levels of glycosylated haemoglobin (HR=1.28 p=0.011). Patients with LVD had significantly worse outcome than those without (χ(2)=4.73 p=0.030). Subclinical LVD is common in asymptomatic patients with type 2 DM, is readily detectable by GLS imaging and is independently associated with adverse outcome. Australian and New Zealand Clinical Trials Registry (ACTRN12612001178831).
Publisher: American Chemical Society (ACS)
Date: 28-04-2015
DOI: 10.1021/CR5002832
Publisher: Springer Science and Business Media LLC
Date: 04-2008
Publisher: Elsevier BV
Date: 12-2002
Abstract: Adipose tissue is a highly active endocrine organ secreting a range of soluble products with both local and distant actions. These hormones have important roles in metabolism, reproduction, cardiovascular function and immunity. It is now evident that adipose endocrine function directly influences other organ systems, including the brain, liver and skeletal muscle. The endocrine function of adipose tissue is significantly regulated by nutritional status, and both are inextricably linked to the energy storage role of adipose tissue. This chapter highlights the endocrinology of adipose tissue by concentrating on functional aspects of the secreted products. The data of particular relevance to humans are highlighted, and areas in need of future research are suggested.
Publisher: BMJ
Date: 07-05-2009
Abstract: To identify the effects of a 1-year exercise intervention on myocardial dysfunction in patients with type 2 diabetes mellitus (T2DM). Randomised controlled trial, the Diabetes Lifestyle Intervention Study. University hospital. 223 T2DM patients without occult coronary artery disease, aged 18-75 were randomised to an exercise training group (n = 111) or a usual care group (n = 112). Complete follow-up data were available in 176 (88 exercise, 88 usual care). Exercise training consisted of gym, followed by telephone-monitored home-based exercise training. Tissue Doppler-derived myocardial velocities, strain-rate and strain, body composition, glycated haemoglobin (HbA(1c)), maximum oxygen consumption (VO(2max)) and physical activity. Overall changes in myocardial function were not different between groups despite improvements in waist circumference, fat mass, blood glucose, HbA(1c), insulin sensitivity, VO(2max) and 6-minute walk distance in the intervention group (p<0.05). The latter also spent significantly more time in vigorous activity (p<0.05). A post-hoc analysis revealed that intervention patients who spent more time in both moderate and vigorous activity showed a significant improvement in myocardial tissue velocity (p<0.01), HbA(1c) (p = 0.03) and VO(2max) (p = 0.03) compared to controls. Myocardial strain rate (p = 0.03) and HbA(1c) improved in intervention patients with the greatest increase in moderate activity (p = 0.03). In patients with T2DM, current exercise recommendations led to an improvement in metabolic function, but failed to improve myocardial function in the overall group. Patients with greater increases in both moderate and vigorous activity showed improvements in myocardial function, glycaemic control and cardiorespiratory fitness. ACTRN12607000060448.
Publisher: Wiley
Date: 22-03-2016
Publisher: Springer Science and Business Media LLC
Date: 09-06-2007
DOI: 10.1007/S00134-007-0727-7
Abstract: Changes in cortisol metabolism due to altered activity of the enzyme 11beta-hydroxysteroid dehydrogenase (11beta-HSD) have been implicated in the pathogenesis of hypertension, obesity and the metabolic syndrome. No published data exist on the activity of this enzyme in critical illness. To investigate cortisol metabolism in critically ill patients utilising plasma cortisol: cortisone ratio as an index of 11beta-HSD activity. Tertiary level intensive care unit. Three cohorts of critically ill patients: sepsis (n = 13) multitrauma (n = 20) and burns (n = 19). Serial plasma cortisol: cortisone ratios. Plasma total cortisol cortisone ratios were determined serially after admission to the intensive care unit. As compared with controls, the plasma cortisol:cortisone ratio was significantly elevated in the sepsis and trauma cohorts on day 1 (22 +/- 9, p = 0.01, and 23 +/- 19, p = 0.0003, respectively) and remained elevated over the study period. Such a relationship was not demonstrable in burns. The ratio was significantly correlated with APACHE II (r = 0.77, p = 0.0008) and Simplified Acute Physiology Score (r = 0.7, p = 0.003) only on day 7 and only in the burns cohort. There were no significant correlations observed between total plasma cortisol or cortisone and sickness severity in the sepsis and trauma cohorts. In critically ill patients, there is evidence of altered cortisol metabolism due to an increase in 11beta-HSD activity as demonstrated by an elevation of plasma cortisol: cortisone ratios. Further studies with larger s le sizes specifically designed to examine altered tissue 11beta-HSD activity and its clinical significance and correlation with outcome are warranted.
Publisher: Elsevier BV
Date: 06-2011
DOI: 10.1016/J.MCE.2011.04.012
Abstract: The defining characteristic of obesity is increased adipose tissue (AT) mass following chronic positive energy supply. AT mass is determined by adipocyte number and size, which reflect proliferation and differentiation of preadipocytes and hypertrophy of pre-existing adipocytes. The molecular pathways governing AT expansion are incompletely defined. We previously reported that FGF-1 primes proliferating primary human preadipocytes (phPA), thereby increasing adipogenesis. Here we examined whether FGF-1's adipogenic actions were due to modulation of other FGFs. Treatment of phPA with FGF-1 reduced FGF-2 mRNA rotein by 80%. To examine a putative functional role we performed siRNA knockdown studies. Following FGF-2 knockdown preadipocyte proliferation was decreased and expression of adipogenic genes (PPARγ, G3PDH and adiponectin) was increased at day 1 of differentiation. These results suggest that changes in endogenous FGF-2 levels contribute to FGF-1's early adipogenic effects and highlight the complexity of the paracrine interplay between FGFs within human AT.
Publisher: Cambridge University Press (CUP)
Date: 11-1997
DOI: 10.1079/PNS19970096
Publisher: Springer Science and Business Media LLC
Date: 29-01-2008
Abstract: To measure adherence to a specific exercise prescription (1500 kcal week(-1)) by objectively quantifying unsupervised exercise energy expenditure (ExEE) in obese women. The 16-week lifestyle intervention consisted of weekly meetings with research staff and promotion of increased ExEE (1500 kcal week(-1)) and a decreased dietary intake (-500 kcal day(-1)). Twenty-nine obese females (body mass index=36.8+/-5.0 kg m(-2), body fat=49.6+/-3.7%) from a hospital-based lifestyle intervention were included in the analysis. ExEE was estimated and monitored weekly using heart rate monitoring, and body composition was measured before and after the intervention by dual-energy X-ray absorptiometry. Free-living adherence to the exercise prescription was variable and, on average, modest such that 14% achieved 1500 kcal week(-1), and the average weekly ExEE (768 kcal week(-1)) represented 51.2% of the total amount prescribed. ExEE was correlated with changes in body weight (r=0.65, P<0.001) and fat mass (r=0.65, P<0.001). Achievement of a 5% weight loss target was dependent on the achievement of an ExEE level of 1000 kcal week(-1) (P 1000 kcal week(-1)) lost more weight (-9.9 vs -4.1 kg), more fat mass (-6.8 vs -3.0 kg) and more waist circumference (-9.8 vs -5.6 cm) when compared to 'non-adherers' (<1000 kcal week(-1)). Exercise is an integral component of lifestyle interventions aimed at reducing obesity and its complications. However, without accurate and objective measures of ExEE, it is difficult for relationships between exercise and health outcomes to be elucidated. The present study suggests an alternative to self-report to increase the confidence with which conclusions are drawn regarding the role of exercise within lifestyle interventions.
Publisher: Wiley
Date: 30-10-2012
DOI: 10.1002/IJC.27887
Publisher: Oxford University Press (OUP)
Date: 2009
DOI: 10.1038/AJH.2008.263
Abstract: There is evidence that the subgroup of patients with essential hypertension who are also insulin resistant is at increased risk of cardiovascular disease (CVD). We are unaware of the frequency of insulin resistance in patients with essential hypertension as well as the CVD risk in this subgroup of patients. This analysis was aimed at providing the prevalence of insulin resistance and associated CVD risk factors in treated and untreated patients with essential hypertension. The study population consisted of 126 patients with hypertension: 56 untreated and 70 in a stable treatment program. Body mass index (BMI), blood pressure, plasma glucose and insulin responses to an oral glucose challenge, lipid and lipoprotein concentrations, and steady-state plasma glucose (SSPG) concentration during the insulin suppression test were measured. Insulin resistance was defined operationally as a SSPG concentration >180 mg/dl. Demographic characteristics and metabolic CVD risk factors were comparable in both groups, with 30-50% of both treated and untreated patients having abnormalities of all risk factors measured. Approximately 50% of patients met the criteria for insulin resistance in both groups, and the prevalence of abnormal CVD risk factors in this group was increased two to threefold as compared to the other half of the subjects. Approximately 50% of patients with essential hypertension, both treated and untreated, appear to be insulin resistant, and CVD risk factors are greatly accentuated in this subset of patients.
Publisher: Elsevier BV
Date: 03-2007
DOI: 10.1016/J.AMJCARD.2006.10.045
Abstract: Left ventricular (LV) diastolic dysfunction and increased arterial stiffness are prevalent in patients with type 2 diabetes mellitus (DM). Because the systemic vasculature plays a pivotal role in myocardial loading, this study aimed to determine the effect of arterial characteristics on LV diastolic function in patients with type 2 DM. Conventional echocardiography and tissue Doppler imaging were performed in 155 patients with type 2 DM (88 men mean age 55 +/- 11 years) with preserved LV ejection fractions (>50%). Patients were stratified into groups on the basis of LV diastolic function (normal, n = 53 delayed relaxation, n = 79 pseudonormal, n = 23). Arterial wave reflection parameters and central blood pressure were determined by radial tonometry. Arterial (brachial and carotid) structure and function were determined by standard ultrasound methods. There were no significant differences among the groups on central pressure or arterial function. LV filling pressure, determined by the ratio of early transmitral inflow velocity to diastolic early tissue velocity (E/E'), was significantly correlated with central pulse pressure (r = 0.21, p <0.05). Late diastolic inflow velocity (A) was significantly associated with central pulse pressure (r = 0.32, p <0.001), total arterial compliance (r = -0.35, p <0.001), and carotid artery stiffness (r = 0.34, p <0.001). Multiple regression analysis found central but not brachial pulse pressure independently predicted E/E' and A. In conclusion, increased central pulse pressure, possibly due to lified pressure wave reflections, is independently associated with abnormal LV diastolic function in patients with type 2 DM.
Publisher: American Society for Microbiology
Date: 06-2011
DOI: 10.1128/AAC.00416-10
Abstract: This work sought to define how pancreatitis affected antibiotic distribution in a perfused rat pancreas model. The distribution kinetics of four antibiotics were examined in control animals and animals with pancreatitis. Meropenem and piperacillin distributed into the extracellular space, and their distribution kinetics were unaffected by pancreatitis. In contrast, in pancreatic cells from animals with pancreatitis, ciprofloxacin showed a reduced uptake and clindamycin showed a reduced distribution.
Publisher: Wiley
Date: 04-2011
DOI: 10.1111/J.1445-5994.2011.02439.X
Abstract: Diabetes therapies based on manipulation of the incretin system are now widely available, with millions of people receiving treatment. The incretin hormones, glucose-dependent insulinotropic peptide and glucagon-like peptide-1 are released from endocrine cells in the small intestinal mucosa primarily in response to oral nutrient ingestion. They have various effects, but those most relevant to metabolic dysfunction include stimulation of insulin and suppression of glucagon secretion, with resultant reduction in fasting and postprandial glucose. Incretin secretion and/or action is impaired in type 2 diabetes, leading to development of strategies aimed at redressing this abnormality. These strategies include pharmacological inhibition of dipeptidyl peptidase-4, the enzyme responsible for the short half-life of endogenous incretins, and administration of long-acting dipeptidyl peptidase-4-resistant peptides that bind to and activate the glucagon-like peptide-1 receptor. In this review, we address aspects of incretin biology and pharmacotherapy with a view to highlighting potentially clinically relevant issues and areas of basic research that may impinge on these.
Publisher: American Diabetes Association
Date: 04-2005
Publisher: SAGE Publications
Date: 05-2006
Abstract: Tumour necrosis factor (TNF)α is implicated in the relationship between obesity and insulin resistance/type 2 diabetes. In an effort to understand this association better we (i) profiled gene expression patterns of TNF, TNFR1 and TNFR2 and (ii) investigated the effects of TNF on glucose uptake in isolated adipocytes and adipose tissue explants from omental and subcutaneous depots from lean, overweight and obese in iduals. TNF expression correlated with expression of TNFR2, but not TNFR1, and TNF and TNFR2 expression increased in obesity. TNFR1 expression was higher in omental than in subcutaneous adipocytes. Expression levels of TNF or either receptor did not differ between adipocytes from in iduals with central and peripheral obesity. TNF only suppressed glucose uptake in insulin-stimulated subcutaneous tissue and this suppression was only observed in tissue from lean subjects. These data support a relationship between the TNF system and body mass index (BMI), but not fat distribution, and suggest depot specificity of the TNF effect on glucose uptake. Furthermore, adipose tissue from obese subjects already appears insulin ‘resistant’ and this may be a result of the increased TNF levels.
Publisher: Wiley
Date: 29-12-2008
DOI: 10.1111/J.1463-1326.2008.01016.X
Abstract: To evaluate the efficacy and safety of alogliptin, a potent and highly selective dipeptidyl peptidase-4 (DPP-4) inhibitor, in combination with glyburide in patients with type 2 diabetes inadequately controlled by sulphonylurea monotherapy. After a 2-week screening period, adult patients 18-80 years of age entered a 4-week run-in/stabilization period in which they were switched from their own sulphonylurea medication to an equivalent dose of glyburide (open label) plus placebo (single blind). After the run-in period, patients were randomly assigned to double-blind treatment with alogliptin 12.5 mg (n = 203), alogliptin 25 mg (n = 198), or placebo (n = 99) for 26 weeks. The primary end-point was change from baseline to week 26 in glycosylated haemoglobin (HbA1c). Secondary end-points included clinical response rates and changes in fasting plasma glucose, beta-cell function (fasting proinsulin, insulin, proinsulin/insulin ratio, and C-peptide, and homeostasis model assessment beta-cell function), body weight, and safety end-points [adverse events (AEs), clinical laboratory tests, vital signs and electrocardiographic readings]. The study population had a mean age of 57 years and a mean disease duration of 8 years it was well balanced for gender (52% women) and was mainly white (71%). The mean baseline HbA1c was approximately 8.1% in each group. Significantly greater least squares (LS) mean reductions in HbA1c were seen at week 26 with alogliptin 12.5 mg (-0.38%) and 25 mg (-0.52%) vs. placebo (+0.01% p < 0.001), and more patients in the alogliptin 25-mg group had HbA1c levels or =0.5% from baseline compared with patients in the placebo group (26.3% p < 0.001). Minor improvements in in idual markers of beta-cell function were seen with alogliptin, but no significant treatment group differences were noted relative to placebo. Minor LS mean changes in body weight were noted across groups (placebo, -0.20 kg alogliptin 12.5 mg, +0.60 kg alogliptin 25 mg, +0.68 kg). AEs were reported for 63-64% of patients receiving alogliptin and 54% of patients receiving placebo. Few AEs were treatment limiting (2.0-2.5% across groups), and serious AEs (2.0-5.6%) were infrequent, similar across groups, and generally considered not related to treatment. The incidences of hypoglycaemia for placebo, alogliptin 12.5 mg and alogliptin 25 mg groups were 11.1, 15.8 and 9.6% respectively. In patients with type 2 diabetes inadequately controlled by glyburide monotherapy, the addition of alogliptin resulted in clinically significant reductions in HbA1c without increased incidence of hypoglycaemia.
Publisher: American Diabetes Association
Date: 12-1997
Publisher: Portland Press Ltd.
Date: 12-1998
Abstract: Tumor necrosis factor (TNF) may cause apoptosis or necrosis and induces mitochondrial changes that have been proposed to be central to cytotoxicity. We report similar patterns of TNF-induced mitochondrial morphological alterations and autophagy in cell types with differing sensitivity to TNF-induced cytotoxicity. Specific ligation of TNFR-I or TNFR-II induces different rates of apoptosis and mitochondrial morphological change, but similar rates of autophagy. These changes do not invariably lead to cell death, and survival or progression to apoptosis or necrosis following TNF exposure may depend in part on the extent of mitochondrial damage and/or the autophagic capacity of the cell.
Publisher: BMJ
Date: 07-2002
DOI: 10.1136/GUT.51.1.89
Abstract: Steatosis occurs in more than 50% of patients with chronic hepatitis C and is associated with increased hepatic fibrosis. In many of these patients the pathogenesis of steatosis appears to be the same as for patients with non-alcoholic fatty liver disease-that is, related to visceral adiposity and obesity. The effect of a three month weight reduction programme on liver biochemistry and metabolic parameters was examined in 19 subjects with steatosis and chronic hepatitis C. Paired liver biopsies were performed in 10 subjects, prior to and 3-6 months following the intervention, to determine the effect of weight loss on liver histology. There was a mean weight loss of 5.9 (3.2) kg and a mean reduction in waist circumference of 9.0 (5.0) cm. In 16 of the 19 patients, serum alanine aminotransferase levels fell progressively with weight loss. Mean fasting insulin fell from 16 (7) to 11 (4) mmol/l (p<0.002). Nine of 10 patients with paired liver biopsies had a reduction in steatosis irrespective of viral genotype. In these subjects the median modified Knodell fibrosis score decreased from 3 to 1 (p=0.04) and activated stellate cells significantly decreased (p<0.004). Weight loss in patients with chronic hepatitis C may be associated with a reduction in steatosis and abnormal liver enzymes and an improvement in fibrosis, despite the persistence of the virus. Weight reduction may provide an important adjunct treatment strategy for patients with chronic hepatitis C.
Publisher: Wiley
Date: 12-2004
Publisher: American Diabetes Association
Date: 02-2003
Abstract: OBJECTIVE—To assess the effect of age on glucose metabolism by examining 1) glucose metabolism in young and middle-aged subjects when total or regional adiposity is taken into account and 2) in vitro glucose transport in adipose tissue explants from young and middle-aged women paired for total and abdominal adiposity. RESEARCH DESIGN AND METHODS—Study 1: body composition, subcutaneous abdominal and visceral adipose tissue areas, and fasting and oral glucose–stimulated glucose and insulin were measured in 84 young and 81 middle-aged men and in 110 young and 91 middle-aged women. Study 2: glucose uptake in subcutaneous abdominal and visceral adipose tissue explants were measured in eight young and eight middle-aged women. RESULTS—Study 1: young and middle-aged men showed similar subcutaneous abdominal tissue area, whereas fat mass and visceral adipose tissue were greater in middle-aged than in young men (P & 0.01). Fat mass and subcutaneous and visceral adipose tissue areas were greater in middle-aged as compared with young women (P & 0.01). Fasting plasma glucose and the glucose response to an oral glucose tolerance test were significantly higher in middle-aged than in young men and women (P & 0.001). Statistical control for visceral adipose tissue area eliminated the difference seen in glucose response in men and women. Study 2: glucose transport in subcutaneous and omental adipose tissue did not differ between young and middle-aged women. CONCLUSIONS—1) Visceral obesity, more than age per se, correlates with glucose intolerance in middle-aged subjects 2) aging does not influence in vitro adipose tissue glucose uptake.
Publisher: Elsevier BV
Date: 05-2011
DOI: 10.1016/J.JSAMS.2010.11.003
Abstract: It is unclear whether the glucose lowering effects of an exercise session are augmented by training. Therefore, we sought to assess the effects of a four-week exercise training program on the acute response of blood glucose to a single exercise session in patients with T2DM. A Quasi experimental design was used. Thirty-four patients with T2DM (18 males) completed a four-week exercise regime consisting of two 1-h supervised sessions and one 30 min unsupervised home session per week. The sessions contained cardiorespiratory and resistance exercises. Blood glucose was measured prior to and after each training session. Resting heart rate (HR), blood pressure (BP), body composition, lipid profile and cardiorespiratory fitness (VO2max) were determined before and after the four week training program. Decreases in blood glucose (pre to post exercise session) over the four weeks were (mean±SD) week 1: 13.3±18.6%, week 2: 19.7±18.5%, week 3: 18.1±20.8%, week 4: 22.8±17.9%. General linear modelling with repeated measures ANCOVA showed that there was a significant (p<0.01) time effect over this period. Additionally, there were small, but significant decreases in resting heart rate (-6.6±10.3 bpm, p=0.001), systolic blood pressure (-5.6±14.9 mmHg, p=0.043) and fat mass (-1.6±3.2%, p=0.024) and an increase in VO(2max) (1.6±3.7 ml/kg/min, p=0.025) over the four weeks. Four weeks of exercise training augments the exercise-induced decrease in blood glucose that occurs in a single exercise session.
Publisher: The Endocrine Society
Date: 02-2003
Abstract: We report a novel activating mutation (E604K) of the calcium-sensing receptor in a family with autosomal dominant hypocalcemia. Whereas all affected in iduals exhibited marked hypocalcemia, some cases with untreated hypocalcemia exhibited seizures in infancy, whereas others were largely asymptomatic from birth into adulthood. The missense mutation E604K (G2182A GenBank accession no. U20759), which affects an amino acid residue in the C terminus of the cysteine-rich domain of the extracellular head, cosegregated with hypocalcemia in all seven in iduals for whom DNA was available. Two unaffected, normocalcemic members of the family did not exhibit the mutation. The molecular impact of the mutation on two key components of the signaling response was assessed in HEK-293 cells transiently transfected with cDNA corresponding to either the wild-type calcium-sensing receptor or the E604K mutation derived by site-directed mutagenesis. There was a significant leftward shift in the concentration response curves for the effects of extracellular Ca(2+) on both intracellular Ca(2+) mobilization (determined by aequorin luminescence) and MAPK activity (determined by luciferase expression). The C terminus of the cysteine-rich domain of the extracellular head may normally act to suppress receptor activity in the presence of low extracellular Ca(2+) concentrations.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2011
DOI: 10.1161/CIRCHEARTFAILURE.110.959312
Abstract: Diastolic dysfunction (DD) is associated with adverse cardiovascular outcomes. We studied the impact of an exercise-based lifestyle intervention on the evolution of DD in patients with type 2 diabetes mellitus (T2DM) and prospectively investigated the clinical correlates of DD progression. A total of 223 outpatients with T2DM were randomized to supervised exercise-based lifestyle intervention (initial gym-based program and lifestyle and diet advice followed by telephone-guided supervision) or usual care. Patients underwent echocardiographic assessment of diastolic function and metabolic and clinical evaluation at baseline and 3 years. Changes in prevalence and evolution of DD were assessed and correlations sought with clinical and metabolic variables. DD was present in 50% of patients at baseline and 54% at 3 years, with no difference between the usual care and intervention groups (60% versus 48%, P =0.10). Abnormal DD at the final visit was independently associated with older age and a decrease in peak oxygen consumption over time ( P .05). There was no impact on glycemic control or exercise capacity. In a subanalysis restricted to patients who finished the full 3-year follow-up, control subjects were independently associated with DD at 3 years (β=0.90 odds ratio, 2.46 P =0.034), with the only other independent correlate being older age (β=0.05 odds ratio, 1.06 P =0.019). Despite being efficacious in the subgroup who completed 3 years of exercise-based lifestyle intervention, randomization to this program was not effective in reducing progression of subclinical DD in patients with T2DM, which may reflect the recognized difficulty of adherence to prolonged exercise intervention. URL: www.anzctr.org.au . Unique identifier: ACTRN12607000060448.
Publisher: Bioscientifica
Date: 10-1999
Abstract: Tumour necrosis factor-alpha (TNF-alpha), secreted by cells of the macrophage-monocyte lineage, has a well established role in inflammation and host-defence. The more recent discovery that adipocytes also secrete TNF-alpha has led to a substantial body of research implicating this molecule in the insulin resistance of obesity. However, little is known about the normal regulation of TNF-alpha release from human adipose tissue. In particular, it is not known whether adipocyte production of TNF-alpha is responsive to similar or different molecular regulators than those relevant to macrophages. TNF-alpha release from cultured human adipose tissue and isolated adipocytes was examined using an ELISA. Insulin, cortisol or the thiazolidinedione, BRL 49653, did not have a significant effect on TNF-alpha release from adipose tissue or isolated adipocytes. In contrast, lipopolysaccharide (LPS), a major stimulus of TNF-alpha protein production in monocytes and macrophages, resulted in a fivefold stimulation of TNF-alpha release from human adipose tissue. Significant stimulation of TNF-alpha release was also seen from isolated adipocytes, indicating that the increase in TNF-alpha release from adipose tissue in the presence of LPS is unlikely to be entirely attributable to contaminating monocytes or macrophages. Consistent with this observation was the finding that mRNA for CD14, a known cellular receptor for LPS, is expressed in human adipocytes. The increase in TNF-alpha protein release in response to LPS was blocked by an inhibitor of the matrix metalloproteinase responsible for the cleavage of the membrane-bound proform of TNF-alpha, indicating that this release represented regulated secretion and was not due to cell lysis. In conclusion, the regulation of TNF-alpha protein release from human adipose tissue and isolated adipocytes appears to be similar to its regulation in cell types more traditionally implicated in host defence. The production by the adipocyte of a range of molecules involved in host defence-TNF-alpha, factors D, B and C3, interleukin-6, and macrophage colony-stimulating factor--suggest that this cell type may make a significant contribution to innate immunity.
Publisher: Springer Science and Business Media LLC
Date: 31-01-2015
DOI: 10.1007/S12020-015-0536-7
Abstract: The prevalence of osteoporosis in men with prostate cancer (PCa) on androgen deprivation therapy (ADT) is well documented, with up to 53% affected by this bone condition. However, there has been less emphasis on the burden of severe bone loss in men with PCa but not undergoing ADT. Therefore, the purpose of this meta-analysis is to compile evidence from the literature on the bone health of hormone-naïve PCa patients and to compare it to the bone health of men with PCa on ADT. Three databases were searched for the relevant literature published from 1990 until January 2014. The pooled prevalence of osteoporosis, low bone mass, and normal bone mass were estimated for this patient group and compared with similar subgroups from a previously published meta-analysis. The prevalence of osteoporosis varies from 4 to 38% in hormone-naïve PCa patients, and men with more advanced disease have a higher prevalence of osteoporosis. Men with PCa on ADT have poorer bone health than their hormone-naïve counterparts, but the trend toward poorer bone health with metastatic disease remains. In conclusion, it was found that men with PCa experience poor bone health prior to treatment with ADT. These results suggest that all men with PCa should have regular bone health monitoring, whether they commence ADT or not, in order to prevent or indeed minimize the morbidity that accompanies osteoporosis.
Publisher: Elsevier BV
Date: 11-2005
DOI: 10.1016/J.AHJ.2005.01.029
Abstract: Screening for coronary artery disease is constrained by its low prevalence in unselected patients. We compared the ability of clinical scores to identify a high-risk group with diabetes mellitus and investigated a Bayesian strategy by combination with exercise echocardiography (ExE). The Framingham risk score (FRS), a score based on the American Diabetes Association (ADA) screening guidelines, the United Kingdom Prospective Diabetes Study (UKPDS) risk engine, and a disease-specific diabetic cardiac risk score (DCRS) were calculated in 199 asymptomatic patients with type 2 diabetes mellitus undergoing ExE. The frequency of abnormal ExE and the proportion of these with coronary stenoses were sought in groups designated as high risk on the basis of optimal cutoffs for each score. All patients were followed up for 1 year. High risk was identified in fewer patients with the DCRS (27%) than FRS (38%, P = .02), ADA (41%, P = .004), and UKPDS (43%, P = .001). Exercise echocardiography was positive in 27 (14%) 11 of 23 proceeding to angiography showed significant stenoses. Areas under the receiver operator characteristic curves for prediction of a positive ExE were similar for DCRS, UKPDS, and FRS but less for ADA (P = .04). Positive ExE was uncommon in low-risk patients (8%-11%) and most were false positives (58%-80%). Cardiovascular events (n = 9) were more likely in the high-risk compared with the low-risk UKPDS (9% vs 2%, P = .03) and DCRS (12% vs 2%, P = .01). Combination of the UKPDS or DCRS with ExE may optimize detection of coronary artery disease and cardiac events in asymptomatic patients, while minimizing the numbers of ExE and false-positive rate.
Publisher: Wiley
Date: 28-12-2011
DOI: 10.1111/J.1440-1797.2011.01520.X
Abstract: Uraemia is associated with hyperprolactinaemia, low total (TT) and free (FT) serum testosterone, high luteinizing hormone (LH) and follicle-stimulating hormone (FSH) and, in women, anovulatory cycles and premature menopause. We hypothesize that extended hours haemodialysis may improve these derangements. This is an observational cohort study of 30 men (age 54±13 years, body mass index (BMI) 28.1±5.8 kg/m2) and seven women (age 41±11 years, BMI 32.2±11.2 kg/m2) established on chronic home haemodialysis (3-5 h, 3.5-5 sessions weekly) who were converted to nocturnal home haemodialysis (6-9 h, 3.5-5 sessions weekly). Serum was collected at baseline and 6 months for measurement of TT, sex hormone binding globulin (SHBG), LH, FSH, prolactin, thyroid-stimulating hormone and thyroxine. In the male patients (n=25), serum prolactin significantly fell (281 (209.5-520) vs 243 (187-359) mU/L, P=0.001) and TT (12.6±5.8 vs 15.2±8.1 nmol/L, P=0.06) and FT (281±118 vs 359±221 pmol/L, P=0.01) increased. SHBG, LH and FSH were unchanged. At 6 months, two of the three women under 40 years of age had return of regular menses after being amenorrhoeic or having prolonged and irregular menses at baseline. There were insufficient women in this study to further analyse changes in sex hormone levels. Thyroid function tests remained stable. Alternate nightly nocturnal haemodialysis significantly improves hyperprolactinaemia and hypotestosteronaemia in men. Menstrual cycling may be re-established in young women. The effect of these changes on fertility has not been established. Patients should be counselled about the possibility of increased fertility before conversion to extended hours haemodialysis regimens.
Publisher: Elsevier BV
Date: 02-2005
DOI: 10.1016/J.AHJ.2004.06.021
Abstract: The prevalence of left ventricular hypertrophy (LVH), coronary artery disease, and subclinical cardiomyopathy in diabetic patients without known cardiac disease is unclear. We sought the frequency of these findings to determine whether plasma brain natriuretic peptide (BNP) could be used as an alternative screening tool to identify subclinical LV dysfunction. Asymptomatic patients with diabetes mellitus without known cardiac disease (n = 101) underwent clinical evaluation, measurement of BNP, exercise stress testing, and detailed echocardiographic assessment. After exclusion of overt dysfunction or ischemia, subclinical myocardial function was sought on the basis of myocardial systolic (Sm) and diastolic velocity (Em). Association was sought between subclinical dysfunction and clinical, biochemical, exercise, and echocardiographic variables. RESULTS Of 101 patients, 22 had LVH and 16 had ischemia evidenced by exercise-induced wall motion abnormalities. Only 4 patients had abnormal BNP levels BNP was significantly increased in patients with LVH. After exclusion of LVH and coronary artery disease, subclinical cardiomyopathy was identified in 24 of 66 patients. Subclinical disease could not be predicted by BNP. Even after exclusion of asymptomatic ischemia and hypertrophy, subclinical systolic and diastolic dysfunction occurs in a significant number of patients with type 2 diabetes. However, screening approaches, including BNP, do not appear to be sufficiently sensitive to identify subclinical dysfunction, which requires sophisticated echocardiographic analysis.
Publisher: Elsevier BV
Date: 03-2001
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2005
DOI: 10.1097/01.TP.0000173792.53561.B6
Abstract: Insulin resistance (IR) may be implicated in the pathogenesis of atherosclerosis in renal transplant recipients (RTRs) and be contributed to, in part, by free fatty acids (FFAs), produced in excess in centrally obese in iduals. The aim of this study was to determine the prevalence of IR and the relationships between FFAs, central obesity, and atherosclerosis in a cohort of prevalent RTRs. Observational data were collected on 85 RTRs (mean age 54 years 49% male, 87% Caucasian). Fasting serum was analyzed for FFAs, glucose, and insulin IR was calculated using the homeostasis model assessment (HOMA-IR) score. Vascular structure was assessed by carotid intima-media thickness (IMT) measurement. Linear regression analyses were performed to determine the factors associated with IR and atherosclerosis. IR occurred in 75% of RTRs, and FFA levels were independently associated with its occurrence (beta: -0.55, 95% CI: -1.02 to -0.07, P = 0.02). Other variables independently associated with IR were male sex, body mass index, central obesity, diabetes, systolic blood pressure and corticosteroid use. There was a significant correlation between FFA levels and IMT (r = 0.3, P=0.01). On multivariate analysis, IMT correlated with elevated FFA (beta: 0.07, 95% CI: 0.02-0.12, P = 0.007), diabetes mellitus (P = 0.05), older age (P 25 kg/m (P = 0.002). FFAs are associated with the development of IR and may be involved in the pathogenesis of atherosclerosis in RTRs. Additional studies are required to explore these associations further before considering whether an interventional trial aimed at lowering FFA would be a worthwhile undertaking.
No related grants have been discovered for Johannes Prins.