Heart and Diabetes Institute

Melbourne, Australia

Heart and Diabetes Institute

Melbourne, Australia

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Heilbronn L.K.,University of Adelaide | Coster A.C.F.,Garvan Institute of Medical Research | Coster A.C.F.,University of New South Wales | Campbell L.V.,Garvan Institute of Medical Research | And 8 more authors.
Obesity | Year: 2013

Objectives While chronic obesity is associated with alterations in circulating glycerolipids, sphingolipids and plasmalogens, the effects of short-term overfeeding in humans are unclear. Design and Methods Healthy individuals (n = 40) were overfed by 1,250 kcal day-1 for 28 days. Insulin sensitivity (hyperinsulinemic-euglycemic clamp), abdominal fat distribution and serum lipidomics (mass spectrometry) were assessed. Results Overfeeding increased liver fat, insulin resistance, serum C-reactive protein and urinary F2-isoprostanes. HDL increased (11% ± 2%, P < 0.001) while LDL, triglycerides and nonesterified fatty acids were unchanged. Three hundred and thirty three serum lipids were detected, of which 13% increased and 20% decreased with overfeeding. Total diacylglycerol and lysoalkylphosphatidylcholine (LPC(O)) concentrations decreased (P < 0.01), while total ceramide, Cer22:0 and Cer24:0 increased (P ≤ 0.01). The most notable increases were observed in the HDL-associated phosphatidylethanolamine- based plasmalogens and their precursors alkylhosphatidylethanolamine (18 ± 5% and 38 ± 8% respectively, P ≤ 0.01). Conclusions Overfeeding led to weight gain and changes in the serum lipid profile. Increases in ceramides were noted, which left unchecked may promote systemic insulin resistance. Uniform increases were observed in plasmalogens and their precursors. Because plasmalogens are powerful antioxidants, this may be an appropriate response against increased oxidative stress generated by over-nutrition. The metabolic consequences of changes in concentrations of many circulating lipid species with overfeeding require further study. Copyright © 2013 The Obesity Society.


Dickinson K.M.,CSIRO | Dickinson K.M.,University of Adelaide | Dickinson K.M.,National Health and Medical Research Council of Australia | Clifton P.M.,CSIRO | And 6 more authors.
American Journal of Clinical Nutrition | Year: 2011

Background: Dietary salt is related to blood pressure (BP), and cardiovascular disease and increased sodium intakes have been shown to impair vascular function. The effect of salt on endothelial function postprandially is unknown. Objective: The aim was to investigate the postprandial effect of dietary salt on endothelial function as measured by flow-mediated dilatation (FMD) and peripheral arterial tonometry in healthy subjects. Design: Sixteen healthy, normotensive subjects received a meal with added salt (HSM; 65 mmol Na) and a control low-salt meal (LSM; 5 mmol Na) on 2 separate occasions in a randomized order. Endothelial function was measured while fasting and postprandially at 30, 60, 90, and 120 min by using FMD and reactive hyperemia peripheral arterial tonometry. BP was also measured. Results: Baseline FMD, reactive hyperemia index (RHI), and BP values were similar across interventions. Overall FMD was reduced 2 h postprandially. FMD was significantly more impaired after the HSM than after the LSM at 30 min [HSM (mean ± SD): 3.39 ± 2.44%; LSM: 6.05 ± 3.21%; P < 0.01] and at 60 min (HSM: 2.20 ± 2.77%; LSM: 4.64 ± 2.48%; P < 0.01). No significant differences in BP or RHI were observed between meals. Conclusions: An HSM, which reflects the typical amount of salt consumed in a commonly eaten meal, can significantly suppress brachial artery FMD within 30 min. These results suggest that high salt intakes have acute adverse effects on vascular dilatation in the postprandial state. This trial was registered at www.anzctr.org.au/trial-view. aspx?ID=335115 as ACTRN12610000124033. © 2011 American Society for Nutrition.


Colagiuri S.,University of Sydney | Lee C.M.Y.,University of Sydney | Wong T.Y.,University of Melbourne | Wong T.Y.,Singapore Eye Research Institute | And 5 more authors.
Diabetes Care | Year: 2011

OBJECTIVE - To re-evaluate the relationship between glycemia and diabetic retinopathy. RESEARCH DESIGN AND METHODS - We conducted a data-pooling analysis of nine studies from five countries with 44,623 participants aged 20-79 years with gradable retinal photographs. The relationship between diabetes-specific retinopathy (defined as moderate or more severe retinopathy) and three glycemic measures (fasting plasma glucose [FPG; n = 41,411], 2-h post oral glucose load plasma glucose [2-h PG; n=21,334], and A1C [n=28,010]) was examined. RESULTS - When diabetes-specific retinopathy was plotted against continuous glycemic measures, a curvilinear relationship was observed for FPG and A1C. Diabetes-specific retinopathy prevalence was low for FPG <6.0 mmol/l and A1C <6.0% but increased above these levels. Based on vigintile (20 groups with equal numbers) distributions, glycemic thresholds for diabetes-specific retinopathy were observed over the range of 6.4-6.8 mmol/l for FPG, 9.8 -10.6 mmol/l for 2-h PG, and 6.3-6.7% for A1C. Thresholds for diabetes-specific retinopathy from receiver-operating characteristic curve analyses were 6.6 mmol/l for FPG, 13.0 mmol/l for 2-h PG, and 6.4% for A1C. CONCLUSIONS - This study broadens the evidence based on diabetes diagnostic criteria. A narrow threshold range for diabetes-specific retinopathy was identified for FPG and A1C but not for 2-h PG. The combined analyses suggest that the current diabetes diagnostic level for FPG could be lowered to 6.5 mmol/l and that an A1C of 6.5% is a suitable alternative diagnostic criterion. © 2011 by the American Diabetes Association.


Huet O.,Heart and Diabetes Institute | Huet O.,University Paris - Sud | Dupic L.,University Paris - Sud | Harrois A.,University Paris - Sud | Duranteau J.,University Paris - Sud
Frontiers in Bioscience | Year: 2011

Endothelial activation and dysfunction play a key role in the pathogenesis of sepsis. During septic shock, endothelial dysfunction is involved in microcirculation impairment and organ dysfunction. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) have several potentially important effects on endothelial function and are implicated in physiological regulation and disease pathophysiology. The imbalance between the production of ROS and their effective removal by non-enzymatic and enzymatic antioxidants systems could induce endothelial dysfunction with alterations of vascular tone, increases in cell adhesion properties (leukocytes and platelet adhesion), increase in vascular wall permeability and a pro-coagulant state. Increasing evidence supports the idea that the principal cause of EC dysfunction during sepsis is cell injury. ROS and RNS contribute to mitochondrial dysfunction by a range of mechanisms and induce both necrotic and apoptotic cell death. Understanding the mechanisms underlying the generation of ROS and RNS in endothelial cells and the causes of endothelial dysfunction in sepsis may help provide therapeutic strategies to tackle endothelial dysfunction and microcirculatory failure in sepsis.


Koulis C.,Heart and Diabetes Institute | Chen Y.-C.,Heart and Diabetes Institute | Hausding C.,Heart and Diabetes Institute | Ahrens I.,Heart and Diabetes Institute | And 13 more authors.
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2014

OBJECTIVE - : Atherosclerosis is driven by inflammatory reactions that are shared with the innate immune system. Toll-like receptor-9 (TLR9) is an intracellular pattern recognition receptor of the innate immune system that is currently under clinical investigation as a therapeutic target in inflammatory diseases. Here, we investigated whether TLR9-/- has a role in the development of atherosclerosis in apolipoprotein E-deficient (ApoE -/-) mice. APPROACH AND RESULTS - : Newly generated double-knockout ApoE-/-:TLR9-/- mice and control ApoE-/- mice were fed a high-fat diet from 8 weeks and effects on lesion size, cellular composition, inflammatory status, and plasma lipids were assessed after 8, 12, 15, and 20 weeks. All 4 time points demonstrated exacerbated atherosclerotic lesion severity in ApoE-/-:TLR9-/- mice, with a corresponding increase in lipid deposition and accumulation of macrophages, dendritic cells, and CD4 T cells. Although ApoE-/-:TLR9-/- mice exhibited an increase in plasma very low-density lipoprotein/low-density- lipoprotein cholesterol, the very low-density lipoprotein/low-density lipoprotein:high-density lipoprotein ratio was unaltered because of a parallel increase in plasma high-density lipoprotein cholesterol. As a potential mechanism accounting for plaque progression in ApoE-/-:TLR9 -/- mice, CD4 T-cell accumulation was further investigated and depletion of these cells in ApoE-/-:TLR9-/- mice significantly reduced lesion severity. As a final translational approach, administration of a TLR9-/- agonist (type B CpG oligodeoxynucleotide 1668) to ApoE-/- mice resulted in a reduction of lesion severity. CONCLUSIONS - : Genetic deletion of the innate immune receptor TLR9 -/- exacerbated atherosclerosis in ApoE-/- mice fed a high-fat diet. CD4 T cells were identified as potential mediators of this effect. A type B CpG oligodeoxynucleotide TLR9-/- agonist reduced lesion severity, thus identifying a novel therapeutic approach in atherosclerosis. © 2013 American Heart Association, Inc.


Anuradha S.,University of Queensland | Dunstan D.W.,University of Queensland | Dunstan D.W.,Heart and Diabetes Institute | Dunstan D.W.,Edith Cowan University | And 7 more authors.
Medicine and Science in Sports and Exercise | Year: 2011

Purpose: To examine the associations of physical activity and television (TV) viewing time with retinal vascular caliber in Australian adults. Methods: A total of 2024 adults aged 25 yr or older without known diabetes in the Australian Diabetes, Obesity, and Lifestyle Study (AusDiab, 1999-2000), a population-based cross-sectional study, were evaluated. Retinal vascular calibers (both arteriolar and venular calibers) were measured from digital retinal photographs using a computer-assisted method and were summarized into central retinal artery and vein equivalents. Self-reported physical activity time and TV viewing time were obtained using interviewer-administered questionnaires. Results: For physical activity, no statistically significant multivariate relationships emerged for men or for women. After adjusting for confounders (age, sex, education, cigarette smoking, diet quality, waist circumference, systolic blood pressure, plasma glucose levels, serum fibrinogen, serum triglyceride, and physical activity time), men who watched TV for at least 2 h•d had a venular caliber that was 4.71 μm (95% confidence interval = 1.37-8.04 μm, P = 0.006) wider compared with those watching <2 h•d of TV. No significant association with venular caliber was noted in women. Conclusions: These findings provide the first evidence of an association between TV viewing time (a common, leisure time sedentary behavior) and retinal microcirculation. Further research is needed to examine these associations in different populations and by using more comprehensive physical activity and sedentary behavior measures. © 2011 by the American College of Sports Medicine.


Holman R.R.,University of Oxford | Zinman B.,Samuel Lunenfeld Research Institute | Yusuf S.,Hamilton Health Sciences | Sheridan P.M.,McMaster University | And 9 more authors.
Diabetes Care | Year: 2011

OBJECTIVE - To examine the impact of withdrawing rosiglitazone and ramipril medication on diabetes incidence after closeout of the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) trial. RESEARCH DESIGN AND METHODS - The 3,366 DREAM subjects at trial end who had not developed diabetes while taking double-blind study medication were transferred to single-blind placebo for 2 to 3months before undergoing an oral glucose tolerance test. Glycemic status was analyzed for the trial plus washout period and for the washout period alone. RESULTS - Following median (interquartile range) 71 (63-86) days drug withdrawal, overall glycemic status remained modestly improved in those allocated ramipril during the trial with an 11% increase in regression to normoglycemia, compared with placebo. In those previously allocated rosiglitazone, glycemic status remained substantially improved with a 49% reduction of new-onset diabetes or death and a 22% increase in regression to normoglycemia, compared with placebo. However, during the washout phase alone the incidence of diabetes or death was identical for those allocated previously to ramipril or placebo, or to rosiglitazone or placebo. CONCLUSIONS - In people allocated to ramipril comparedwith those not allocated ramipril during the trial, the postwashout normoglycemia incidence was higher. In people allocated to rosiglitazone compared with those not allocated rosiglitazone during the trial, the postwashout incidence of diabetes was significantly lower and the incidence of normoglycemia was higher. During the washout period, diabetes incidence was the same for ramipril versus placebo and for rosiglitazone versus placebo. Rosiglitazone delays disease progression during treatment but the process resumes at the placebo rate when the drug is stopped. © 2011 by the American Diabetes Association.


PubMed | King Abdulaziz University, Heart and Diabetes Institute and Norwegian University of Science and Technology
Type: Journal Article | Journal: BMJ open diabetes research & care | Year: 2016

The Finnish Diabetes Risk Score (FINDRISC) is recommended as a screening tool for diabetes risk. However, there is a lack of well-powered studies examining the performance of FINDRISC by sex and age. We aim to estimate, by sex and age, the prevalence of elevated FINDRISC and positive predictive value (PPV) of FINDRISC for identifying impaired glucose metabolism (IGM) in a general Norwegian population.We estimated the prevalence of elevated FINDRISC (15) among 47694 adults in the third survey of the Nord-Trndelag Health Study (HUNT3, 2006-08). Among 2559 participants who participated in oral glucose tolerance testing, we estimated the PPV of elevated FINDRISC for identifying unknown prevalent diabetes and other forms of IGM.The prevalence of elevated FINDRISC was 12.1% in women, 9.6% in men, and increased from 1.5% at age 20-39 to 25.1% at age 70-79years. The PPVs of elevated FINDRISC were 9.8% for diabetes, 16.9% for impaired glucose tolerance, 8.2% for impaired fasting glucose, and 34.9% for any form of IGM. The PPV for IGM was lower in women (31.2%) than in men (40.4%), and increased from 19.1% at age 20-39 to 55.5% at age 80years.FINDRISC identified more women than men as high-risk individuals for diabetes. FINDRISC had a high PPV for detecting prevalent IGM, and the PPV was higher in men than in women and in the older individuals. Our data indicate that the impact of sex and age on diabetes risk is not fully captured by FINDRISC, and that refinements to it might improve diabetes prediction.


Grubb D.R.,Heart and Diabetes Institute | Iliades P.,Heart and Diabetes Institute | Cooley N.,Heart and Diabetes Institute | Yu Y.L.,Heart and Diabetes Institute | And 3 more authors.
FASEB Journal | Year: 2011

Activation of the heterotrimeric G protein Gq causes cardiomyocyte hypertrophy in vivo and in cell models. Our previous studies have shown that responses to activated Gq in cardiomyocytes are mediated exclusively by phospholipase Cβ1b (PLCβ1b), because only this PLCβ subtype localizes at the cardiac sarcolemma. In the current study, we investigated the proteins involved in targeting PLCβ1b to the sarcolemma in neonatal rat cardiomyocytes. PLCβ1b, but not PLCβ1a, coimmunoprecipitated with the high-MW scaffolding protein SH3 and ankyrin repeat protein 3 (Shank3), as well as the known Shank3-interacting protein α-fodrin. The 32-aa splice-variant-specific C-terminal tail of PLCβ1b also associated with Shank3 and α-fodrin, indicating that PLCβ1b binds via the C-terminal sequence. Shank3 colocalized with PLCβ1b at the sarcolemma, and both proteins were enriched in the light membrane fractions. Knockdown of Shank3 using siRNA reduced PLC activation and downstream hypertrophic responses, demonstrating the importance of sarcolemmal localization for PLC signaling. These data indicate that PLCβ1b associates with a Shank3 complex at the cardiac sarcolemma via its splice-variant-specific C-terminal tail. Sarcolemmmal localization is central to PLC activation and subsequent downstream signaling following Gq-coupled receptor activation. © FASEB.


Villani A.M.,CSIRO | Villani A.M.,Flinders University | Clifton P.M.,CSIRO | Clifton P.M.,Heart and Diabetes Institute | And 2 more authors.
Journal of Human Nutrition and Dietetics | Year: 2012

Background: Hypertension is common in individuals with type 2 diabetes mellitus (T2DM). Dietary sodium plays an important regulatory role in blood pressure management. However, dietary sodium intakes and the major food sources of dietary sodium have yet to be thoroughly investigated in individuals with T2DM. Methods: In a cross-sectional study sample of 88 overweight and obese men (n=52) and women (n=36) with T2DM in Adelaide, Australia, sodium intake and excretion was investigated using two different methodologies, including a 4-day weighed food record and 24-h urinary sodium excretion. The major dietary contributors to sodium intake in this population were also explored. Results: Mean (SD) 24-h urinary sodium excretion was greater (P<0.001) in males [195.1(74.6)mmol] compared to females [144.3(41.8)mmol]. Breads and cereals (B&Cs) were the largest contributors to dietary sodium intake (23% of intake). There was an association between sodium intake from B&Cs and 24-h urinary sodium excretion (r=0.235; P=0.02); however, when controlled for gender, B&Cs were not associated with urinary sodium excretion (males, r=0.134; P=0.343; females, r=0.102; P=0.554). Conclusions: The findings of the present study show that sodium intake and excretion in individuals with T2DM is more than two-fold greater than the current recommendations for chronic disease prevention. B&Cs were the major dietary contributors of sodium intake, suggesting that they are primary targets for a reduction in their sodium content. © 2012 The Authors. Journal of Human Nutrition and Dietetics © 2012 The British Dietetic Association Ltd.

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