Trisha O'Moore-Sullivan

Resveratrol Does Not Benefit Patients With Nonalcoholic Fatty Liver Disease

BACKGROUND & AIMS 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. METHODS 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 clamp), 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. RESULTS 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. CONCLUSIONS 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.

A randomized study of the beneficial effects of aldosterone antagonism on LV function, structure, and fibrosis markers in metabolic syndrome

OBJECTIVES The purpose of this study was to identify the effects of spironolactone on left ventricular (LV) structure and function, and serological fibrosis markers in patients with metabolic syndrome (MS) taking angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. BACKGROUND Myocardial fibrosis may be an important contributor to myocardial impairment in MS, and aldosterone antagonism may reduce fibrosis. METHODS Eighty patients (age 59 ± 11 years) with MS, already being treated with angiotensin II inhibition, were randomized to spironolactone 25 mg/day or placebo for 6 months. Each patient underwent baseline and follow-up conventional echocardiography and color tissue Doppler imaging. Raw data files were used to measure calibrated integrated backscatter and to calculate radial and longitudinal strain. Blood was obtained at baseline and follow-up to measure fibrosis markers (procollagen type III amino-terminal propeptide and procollagen type I carboxy-terminal propeptide [PICP]). RESULTS The spironolactone group showed significant improvement of LV function, myocardial reflectivity, and LV hypertrophy, with a parallel decrease in levels of PICP and procollagen type III amino-terminal propeptide. No analogous changes were seen in the placebo group. Baseline strain (β = 0.47, p < 0.0001), spironolactone therapy (β = -0.38, p < 0.0001), and change in PICP level (β = -0.19, p < 0.03) were independently associated with LV systolic function improvement (increase in strain). Correlates of LV diastolic function improvement (increase in early diastolic mitral annular velocity) were baseline early diastolic mitral annular velocity (β = 0.47, p < 0.0001), spironolactone therapy (β = -0.21, p < 0.03), change in PICP level (β = -0.23, p < 0.02), and age (β = 0.22, p < 0.04). Favorable effects of spironolactone on cardiac function were not demonstrated in patients with less fibrosis (the lower baseline PICP tertile) or preserved function (the upper baseline strain tertile). CONCLUSIONS Addition of spironolactone to standard angiotensin II inhibition improved myocardial abnormalities and decreased fibrotic markers in MS. The magnitude of benefit on cardiac performance is determined mainly by baseline LV dysfunction and collagen turnover as well its response to intervention.

Living Well with Diabetes: a randomized controlled trial of a telephone-delivered intervention for maintenance of weight loss, physical activity and glycaemic control in adults with type 2 diabetes

BackgroundBy 2025, it is estimated that approximately 1.8 million Australian adults (approximately 8.4% of the adult population) will have diabetes, with the majority having type 2 diabetes. Weight management via improved physical activity and diet is the cornerstone of type 2 diabetes management. However, the majority of weight loss trials in diabetes have evaluated short-term, intensive clinic-based interventions that, while producing short-term outcomes, have failed to address issues of maintenance and broad population reach. Telephone-delivered interventions have the potential to address these gaps.Methods/DesignUsing a two-arm randomised controlled design, this study will evaluate an 18-month, telephone-delivered, behavioural weight loss intervention focussing on physical activity, diet and behavioural therapy, versus usual care, with follow-up at 24 months. Three-hundred adult participants, aged 20-75 years, with type 2 diabetes, will be recruited from 10 general practices via electronic medical records search. The Social-Cognitive Theory driven intervention involves a six-month intensive phase (4 weekly calls and 11 fortnightly calls) and a 12-month maintenance phase (one call per month). Primary outcomes, assessed at 6, 18 and 24 months, are: weight loss, physical activity, and glycaemic control (HbA1c), with weight loss and physical activity also measured at 12 months. Incremental cost-effectiveness will also be examined. Study recruitment began in February 2009, with final data collection expected by February 2013.DiscussionThis is the first study to evaluate the telephone as the primary method of delivering a behavioural weight loss intervention in type 2 diabetes. The evaluation of maintenance outcomes (6 months following the end of intervention), the use of accelerometers to objectively measure physical activity, and the inclusion of a cost-effectiveness analysis will advance the science of broad reach approaches to weight control and health behaviour change, and will build the evidence base needed to advocate for the translation of this work into population health practice.Trial RegistrationACTRN12608000203358

Variability in adherence to an unsupervised exercise prescription in obese women.

Objective:To measure adherence to a specific exercise prescription (1500 kcal week−1) by objectively quantifying unsupervised exercise energy expenditure (ExEE) in obese women.Design: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).Participants: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.Measurements: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.Results: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<0.001). Exercise ‘adherers’ (>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).Discussion: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.

Subclinical impairment of left ventricular function in young obese women: contributions of polycystic ovary disease and insulin resistance.

CONTEXT Obesity and insulin resistance (IR) may produce disturbances of left ventricular (LV) function. Obese women with polycystic ovary syndrome (PCO), characterized by hormonal and metabolic abnormalities, are thought to be at particularly increased cardiovascular risk. OBJECTIVES We sought to determine the influence of IR on LV function in obese young women with and without PCO and without other comorbidities. DESIGN This was a cross-sectional study. SETTING The study was performed at a university hospital. PATIENTS A total of 150 women aged younger than 40 yr with a body mass index (BMI) of 30 kg/m(2) or more was classified into three groups: with both PCO and IR, without PCO and with IR, and without either PCO or IR. MAIN OUTCOME MEASURES Tissue Doppler-derived myocardial velocities, strain-rate and strain, and metabolic and hormonal measurements were calculated. RESULTS Subclinical impairment of LV systolic and diastolic function as indicated by lower peak strain (P < 0.001), peak systolic strain rate (P < 0.001), peak early diastolic strain rate (P < 0.001), and peak early diastolic velocity (P < 0.01) was demonstrated in both groups with IR. IR subjects with and without PCO did not differ in any LV function indices. Strain was independently associated with fasting insulin (beta = -0.39; P < 0.001), urinary albumin excretion (UAE) (beta = -0.36; P < 0.001), and BMI (beta = -0.22; P < 0.03), and peak early diastolic strain rate was associated with UAE (beta = -0.35; P < 0.001), fasting insulin (beta = -0.24; P < 0.02), BMI (beta = -0.23; P < 0.02), and SHBG (beta = 0.20; P < 0.04). CONCLUSIONS In obese young women, fasting insulin, BMI, SHBG, and UAE are independent correlates of impaired LV performance. The contribution of PCO to LV function abnormalities is linked to IR, but not to other hormonal aberrations associated with this condition.

Arterial stiffness, central blood pressure and body size in health and disease

Background:Body size is associated with increased brachial systolic blood pressure (SBP) and aortic stiffness. The aims of this study were to determine the relationships between central SBP and body size (determined by body mass index (BMI), waist circumference and waist/hip ratio) in health and disease. We also sought to determine if aortic stiffness was correlated with body size, independent of BP.Methods:BMI, brachial BP and estimated central SBP (by SphygmoCor and radial P2) were recorded in controls (n=228), patients with diabetes (n=211), coronary artery disease (n=184) and end-stage kidney disease (n=68). Additional measures of waist circumference and arterial stiffness (aortic and brachial pulse wave velocity (PWV)) were recorded in a subgroup of 75 controls (aged 51±12 years) who were carefully screened for factors affecting vascular function.Results.BMI was associated with brachial (r=0.30; P<0.001) and central SBP (r=0.29; P<0.001) in the 228 controls, but not the patient populations (r<0.13; P>0.15 for all comparisons). In the control subgroup, waist circumference was also significantly correlated with brachial SBP (r=0.29; P=0.01), but not central SBP (r=0.22; P=0.07). Independent predictors of aortic PWV in the control subgroup were brachial SBP (β=0.43; P<0.001), age (β=0.37; P<0.001), waist circumference (β=0.39; P=0.02) and female sex (β=−0.24; P=0.03), but not BMI.Conclusion.In health, there are parallel increases in central and brachial SBP as BMI increases, but these relationships are not observed in the presence of chronic disease. Moreover, BP is a stronger correlate of arterial stiffness than body size.

A Pilot Randomised Study of the Metabolic and Histological Effects of Exercise in Non-alcoholic Steatohepatitis

Aims: Type 2 diabetes is a risk factor for the development and progression of non-alcoholic fatty liver disease (NAFLD). Lifestyle intervention is the principal treatment for NAFLD however the effects of exercise alone on the histological and metabolic severity of NAFLD are unclear. This study assessed the effects of 6 months exercise training and diet-induced weight loss on insulin resistance and liver histologyin overweight patients with NAFLD. Methods: 21 patients were randomised to circuit exercise (EX) training (60 min×3/week) or dietary induced weight loss (DIWL) (-500 kcal/d). Insulin sensitivity (euglycaemic-hyperinsulinemic clamp with tracer), adiposity (CT scan) and histology (liver biopsy) were assessed at 0 and 6 months. Results: Weight decreased by 9.7 ± 4.6% (-6.7 ± 6.3 kg p=0.02) with DIWL but was unchanged after EX. Both groups equivalently reduced visceral fat (DIWL -22 ± 24% p=0.06 and EX -18 ± 18% p<0.05) while only EX increased lean mass (+3% p<0.01). DIWL markedly reduced steatosis (73 ± 36% to 23 ± 32%, p<0.05) and NAFLD activity score NAS (median (range) 5 (1-7) to 1 (0-5), p<0.05). After EX, there was no change in steatosis or NAS. A decrease in steatosis was associated with weight loss (r s =0.82, p<0.0001). An improvement in fibrosis was associated with a decrease in steatosis (r s =0.64, p=0.02). Small improvements in fasting hepatic insulin resistance were similar in both groups while changes in muscle insulin resistance were not significant. Conclusions: Circuit exercise is safe and efficacious for improving cardiometabolic risk factors in patients with NAFLD, however this dose of circuit training, without concomitant weight loss, was insufficient for histological improvements in NAFLD. The pilot study outcomes should stimulate further development of different exercise protocols (type, frequency and intensity) to address disease-specific conditions in those with severe insulin resistance.

Effect of 1-h moderate-intensity aerobic exercise on intramyocellular lipids in obese men before and after a lifestyle intervention

Intramyocellular lipids (IMCL) are depleted in response to an acute bout of exercise in lean endurance-trained individuals; however, it is unclear whether changes in IMCL content are also seen in response to acute and chronic exercise in obese individuals. 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 participants maximal whole-body rate of fat oxidation (Fatmax). Fatmax 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 Fatmax 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 Fatmax 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.

The effect of 25-hydroxyvitamin D on insulin sensitivity in obesity: is it mediated via adiponectin?

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.

Insulin Analogues: Reviewing the Pros and Cons in Managing Diabetes Mellitus

The issue of planning the timing and dosing of insulin in relation to food is one of the most difficult issues confronting people with diabetes. Recent focus on improving quality of life in this area has focused on developing different modes of administration of insulin thereby avoiding subcutaneous injections and developing new analogues of insulin. Both inhalational and buccal administration technologies have been developed, and have essentially overcome some of the difficult pharmacokinetic issues regarding large peptide molecules, however there remain some clinical problems. Advances in the practicalities of treating insulin have occurred, such as more accurate and less expensive glucometers, new administration alternatives such as implantable pumps, with further developments in the pipeline including islet and gene replacement for Type I disease. However all of these newer options have limitations and currently subcutaneous administration is the only real option for most people. Insulin analogues have so far been relatively disappointing in terms of improvement in mortality and morbidity although for some patients the ability to alter the dosage of insulin depending on the planned meal size or reduction of between meal snacks has been helpful. Furthermore there is a yet unknown question around long term safety. This review will discuss the major clinical issues surrounding the new insulin analogues as they relate to efficacy and side effects.