[Show abstract][Hide abstract] ABSTRACT: High-density lipoprotein (HDL) and its principal apolipoprotein A-I (ApoA-I) have now been convincingly shown to influence glucose metabolism through multiple mechanisms. The key clinically relevant observations are that both acute HDL elevation via short-term reconstituted HDL (rHDL) infusion and chronically raising HDL via a cholesteryl ester transfer protein (CETP) inhibitor reduce blood glucose in individuals with type 2 diabetes mellitus (T2DM). HDL may mediate effects on glucose metabolism through actions in multiple organs (e.g., pancreas, skeletal muscle, heart, adipose, liver, brain) by three distinct mechanisms: (i) Insulin secretion from pancreatic beta cells, (ii) Insulin-independent glucose uptake, (iii) Insulin sensitivity. The molecular mechanisms appear to involve both direct HDL signaling actions as well as effects secondary to lipid removal from cells. The implications of glucoregulatory mechanisms linked to HDL extend from glycemic control to potential anti-ischemic actions via increased tissue glucose uptake and utilization. Such effects not only have implications for the prevention and management of diabetes, but also for ischemic vascular diseases including angina pectoris, intermittent claudication, cerebral ischemia and even some forms of dementia. This review will discuss the growing evidence for a role of HDL in glucose metabolism and outline related potential for HDL therapies.
Preview · Article · Oct 2015 · Frontiers in Pharmacology
[Show abstract][Hide abstract] ABSTRACT: The impact of statin treatment on the abnormal plasma lipidome of mixed dyslipidemic patients with Metabolic syndrome (MetS), a group at increased risk of developing diabetes, was evaluated. Insulin-resistant, hypertriglyceridemic, hypertensive, obese males (n=12) displaying MetS were treated with pitavastatin (4 mg/day) for 180 days; healthy, normolipidemic, age-matched non-obese males (n=12) acted as controls. Statin treatment substantially normalised triglyceride (-41%), remnant cholesterol (-55%) and LDL-cholesterol (-39%), with minor effect on HDL-cholesterol (+4%). Lipidomic analysis, normalized to non-HDL-cholesterol in order to probe statin-induced differences in molecular composition independently of reduction in plasma cholesterol, revealed increment in 132 of 138 lipid species which were subnormal at baseline and significantly shifted towards the control group on statin treatment. Increment in alkyl- and alkenylphospholipids (plasmalogens) was prominent, and consistent with significant statin-induced increase in plasma polyunsaturated fatty acid levels. Comparison of the statin-mediated lipidomic changes in MetS with the abnormal plasma lipidomic profile characteristic of prediabetes and type 2 diabetes in the AusDiab and SAFHS cohorts by hypergeometric analysis revealed a significant shift toward the lipid profile of controls, indicative of a marked trend toward a normolipidemic phenotype. Pitavastatin attenuated the abnormal plasma lipidome of MetS patients typical of prediabetes and type 2 diabetes.
No preview · Article · Oct 2015 · The Journal of Lipid Research
[Show abstract][Hide abstract] ABSTRACT: Liver steatosis is associated with the development of insulin resistance and the pathogenesis of type 2 diabetes. We tested the hypothesis that protein signals originating from steatotic hepatocytes communicate with other cells to modulate metabolic phenotypes. We show that the secreted factors from steatotic hepatocytes induce pro-inflammatory signaling and insulin resistance in cultured cells. Next, we identified 168 hepatokines, of which 32 were differentially secreted in steatotic versus non-steatotic hepatocytes. Targeted analysis showed that fetuin B was increased in humans with liver steatosis and patients with type 2 diabetes. Fetuin B impaired insulin action in myotubes and hepatocytes and caused glucose intolerance in mice. Silencing of fetuin B in obese mice improved glucose tolerance. We conclude that the protein secretory profile of hepatocytes is altered with steatosis and is linked to inflammation and insulin resistance. Therefore, preventing steatosis may limit the development of dysregulated glucose metabolism in settings of overnutrition.
[Show abstract][Hide abstract] ABSTRACT: Experimental studies suggest that angiotensin II plays a central role in the pathogenesis of abdominal aortic aneurysm. This trial aims to evaluate the efficacy of the angiotensin receptor blocker telmisartan in limiting the progression of abdominal aortic aneurysm.
Telmisartan in the management of abdominal aortic aneurysm (TEDY) is a multicentre, parallel-design, randomised, double-blind, placebo-controlled trial with an intention-to-treat analysis. We aim to randomly assign 300 participants with small abdominal aortic aneurysm to either 40 mg of telmisartan or identical placebo and follow patients over 2 years. The primary endpoint will be abdominal aortic aneurysm growth as measured by 1) maximum infra-renal aortic volume on computed tomographic angiography, 2) maximum orthogonal diameter on computed tomographic angiography, and 3) maximum diameter on ultrasound. Secondary endpoints include change in resting brachial blood pressure, abdominal aortic aneurysm biomarker profile and health-related quality of life. TEDY is an international collaboration conducted from major vascular centres in Australia, the United States and the Netherlands.
Currently, no medication has been convincingly demonstrated to limit abdominal aortic aneurysm progression. TEDY will examine the potential of a promising treatment strategy for patients with small abdominal aortic aneurysms.
Australian and Leiden study centres: Australian New Zealand Clinical Trials Registry ACTRN12611000931976 , registered on 30 August 2011; Stanford study centre: clinicaltrials.gov NCT01683084 , registered on 5 September 2012.
[Show abstract][Hide abstract] ABSTRACT: To determine whether alternating bouts of sitting and standing at work influences daily workplace energy expenditure (EE).
23 overweight/obese office workers (mean ± SD; age: 48.2 ± 7.9 yrs, BMI: 29.6 ± 4.0 kg/m2) undertook two, 5-day experimental conditions in an equal, randomised order. Participants wore a 'metabolic armband' (SenseWear Armband Mini) to estimate daily workplace EE (KJ/8 hours) while working in a: 1) seated work posture (SIT condition); or, 2) alternating between a standing and seated work posture every 30-min using a sit-stand workstation (STAND-SIT condition). To assess the validity of the metabolic armband, a criterion measure of acute EE (KJ/min; indirect calorimetry) was performed on day 4 of each condition.
Standing to work acutely increased EE by 0.7 [0.3, 1.0] KJ/min (13%), relative to sitting (p=0.002). Compared to indirect calorimetry, the metabolic armband provided a valid estimate of EE while standing to work (mean bias: 0.1 [-0.3, 0.4] KJ/min) but modestly overestimated EE while sitting (p=0.005). Daily workplace EE was greatest during the STAND-SIT condition (mean condition difference [95% CI]: 76 [8, 144] KJ/8-hour workday, p=0.03).
Intermittent standing at work can modestly increase daily workplace EE compared to seated work in overweight/obese office workers.
No preview · Article · Apr 2015 · Journal of Physical Activity and Health
[Show abstract][Hide abstract] ABSTRACT: Aim: To compare the cumulative (three-day) effect of prolonged sitting on metabolic responses during a mixed meal tolerance test (MTT), with sitting that is regularly interrupted with brief bouts of light-intensity walking. Research design and methods: Overweight/obese adults (n=19) were recruited for a randomized, three-day, outpatient, crossover trial involving: 1) 7-hour days of uninterrupted sitting (SIT); and, 2) 7-hour days of sitting with light-intensity activity breaks [BREAKS; 2-minutes of treadmill walking (3.2 km/hour) every 20 minutes (total: 17 breaks/day)]. On days 1 and 3, participants underwent a MTT (75g carbohydrate, 50g fat), and the incremental area under the curve (iAUC) was calculated from hourly blood samples. GEE models were adjusted for gender, BMI, energy intake, treatment order and pre-prandial values to determine effects of time, condition and time x condition. Results: The glucose iAUC was 1.3 ± 0.5 and 1.5 ± 0.5 mmol.hr.L-1 (mean difference ± SEM) higher in SIT compared with BREAKS on days 1 and 3 respectively (condition effect: P=0.001), with no effect of time (P=0.48) or time x condition (P=0.8). The insulin iAUC was also higher on both days in SIT (Day 1: ∆151 ± 73, Day 3: ∆91 ± 73 pmol.hr.L-1, P=0.01), with no effect of time (P=0.52) or time x condition (P=0.71). There was no between-treatment difference in triglycerides iAUC. Conclusion: There were significant between-condition effects but no temporal change in metabolic responses to MTT, indicating that breaking up sitting over three days sustains, but does not enhance, the lowering of postprandial glucose and insulin.
[Show abstract][Hide abstract] ABSTRACT: Clinically significant modulating effects of lifestyle factors on both age- and disease-related arterial stiffening – particularly those relating to habitual physical activity – are widely recognised. Consequently, exercise training may represent an important strategy in the non-pharmacological treatment of arterial stiffening and related complications – often apparent even at an early stage of the cardiometabolic disease continuum. Observational and interventional data relevant to this context are reviewed in the current chapter.
Arterial de-stiffening certainly appears achievable with aerobic exercise in young adults, and may even begin at a lower volume threshold than current exercise guidelines. However, the response in older individuals and those with cardiovascular risk factors appears highly variable. Where short-term training adaptations are evident (weeks to months), these probably reflect functional mechanisms related to blood pressure-lowering. Intrinsic changes in arterial wall structure are difficult to assess in humans, but may be possible when exercise is commenced in young adulthood and performed continually throughout the life course. Resistance training promotes arterial stiffening at high intensities, but may otherwise have a neutral or beneficial effect – particularly in combination with aerobic exercise.
[Show abstract][Hide abstract] ABSTRACT: Brown adipose tissue (BAT) activation increases energy expenditure and may have therapeutic potential to combat obesity. The primary activating and adaptive signal for BAT is via β-adrenergic signalling. We previously demonstrated that human BAT is acutely responsive to oral administration of the sympathomimetic, ephedrine. Here we aimed to determine whether adaptive thermogenesis can be induced via chronic treatment with ephedrine.
Twenty-three healthy young men, recruited from the general public in Melbourne, Australia, who were non-smokers, physically inactive and non-medicated with no prior history of cardiovascular disease or diabetes were recruited for this study. They were assigned to receive either 1.5 mg kg(-1) day(-1) ephedrine ('active' group; n = 12, age 23 ± 1 years, BMI 24 ± 1 kg/m(2)) or placebo (n = 11; 22 ± 2 years, 23 ± 2 kg/m(2)) for 28 days in a randomised (computer-generated random order sequence), placebo-controlled, parallel-group trial. Participants and all investigators were blinded to treatments. Body composition was measured before and after the intervention by dual energy X-ray absorptiometry. BAT activity, measured via (18)F-fluorodeoxyglucose positron emission tomography-computed tomography, in response to a single dose of 2.5 mg/kg ephedrine, was the primary outcome measure to be determined before and after the 28 day treatment period.
Twenty-eight individuals were randomised and consented to the study. Twenty-three completed the trial and only these participants were included in the final analyses. After 28 days of treatment, the active group lost a significant amount of total body fat (placebo 1.1 ± 0.3 kg, ephedrine -0.9 ± 0.5 kg; p < 0.01) and visceral fat (placebo 6.4 ± 19.1 g, ephedrine -134 ± 43 g; p < 0.01), with no change in lean mass or bone mineral content compared with the placebo group. In response to acute ephedrine, BAT activity (change in mean standardised uptake value: placebo -3 ± 7%, ephedrine -22 ± 6%) and the increase in systolic blood pressure were significantly reduced (p < 0.05) in the active group compared with placebo.
Chronic ephedrine treatment reduced body fat content, but this was not associated with an increase in BAT activity. Rather, chronic ephedrine suppressed BAT glucose disposal, suggesting that chronic ephedrine treatment decreased, rather than increased, BAT activity. Trial registration: ClinicalTrials.gov NCT02236962 Funding: This study was funded by the National Health and Medical Research Council of Australia Program Grant (1036352) and the OIS scheme from the Victorian State Government.
[Show abstract][Hide abstract] ABSTRACT: Obesity is a major risk factor for chronic disease. A new molecule serotonin outside of the brain reduces obesity energy expenditure. study in mice reveals that lowering levels of the signaling and its complications by increasing brown adipose tissue (BAT)