Book reviews

Teaching/Communication/Extension/Profession,

The acute effect of ‘breaking-up’ prolonged sitting on cardiovascular risk factors in overweight/obese adults

Session - Physical activity and cardiovascular disease in adults: paper no. 562This journal suppl. entitled: Be Avtive 2012INTRODUCTION: We have recently shown in a controlled laboratory setting that regularly ‘breaking up’ prolonged sitting with frequent short bouts of light-or moderate-intensity walking activity acutely lowers postprandial blood glucose and insulin concentrations. However, we are yet to report the effect of interrupting sitting time on secondary outcomes relating to cardiovascular disease. Consequently, we compared the effect of a single prolonged (7-hour) bout of sitting with a similar duration of sitting combined with intermittent bouts of light-intensity or moderate-intensity activity on blood pressure, blood lipids and CRP. METHODS: Overweight/obese adults (n=19; age range 45–65 yrs) were recruited for a randomized three-week, three-treatment acute cross-over trial: 1) uninterrupted sitting; 2) seated with 2-minute bouts of light-intensity walking at 3.2 km/hr every 20 minutes; and 3) seated with 2-minute bouts of moderate-intensity walking at between 5.8–6.4 km/hr every 20 minutes. Following the completion of baseline measurements and an initial 2 hour steady-state period, participants consumed a standard test meal (75 g glucose, 50 g fat). Serum triglycerides were assessed hourly to calculate the incremental area under the curve (iAUC) and high sensitivity C-reactive protein (hsCRP) was assessed at baseline and 7 hours. Seated brachial artery blood pressure was also measured every hour as a single measurement, 5 mins prior to each activity bout, with an automated oscillometric blood pressure monitor (Philips SureSigns VS3 Monitor). GEE models were adjusted for sex, age, BMI, fasting blood pressure and treatment order. RESULTS: Systolic blood pressure decreased similarly and significantly during the light and moderate-intensity activity conditions [light: 120±4mmHg (hourly mean±SEM), p=0.002; moderate: 120±3mmHg, p=0.02] compared to uninterrupted sitting (125±4mmHg). Diastolic blood pressure was also significantly reduced with both activity conditions (light: 78±3mmHg, p=0.006; moderate: 78±3mmHg, p=0.03) compared to uninterrupted sitting (79±3mmHg). No significant group differences were observed in triglyceride iAUC, hsCRP and the hourly measurement of heart rate. DISCUSSION: These findings indicate that breaking up prolonged sitting with frequent short breaks of either light or moderate-intensity physical activity may have favourable effects on seated blood pressure. Further studies are needed to evaluate the chronic effects of breaking up sedentary time on cardiovascular disease risk factors and the feasibility of such strategies in the general community

Hormone Therapy Reduces Bone Resorption but not Bone Formation in Postmenopausal Athletes

INTRODUCTION: Independently, hormone therapy and exercise have well-established protective effects on bone parameters. The combined effects of hormone therapy and exercise, however, are less clear. We, therefore, examined the effects of hormone therapy on bone turnover markers in postmenopausal women undergoing regular high intensity exercise. METHODS: In a randomised, double blind study, postmenopausal athletes competing at Masters level, received either hormone therapy (50 μg transdermal oestradiol, 5 mg MPA, n = 8) or placebo (n = 7) for 20 weeks. Women were tested before and after treatment for plasma concentrations of oestradiol, FSH, LH, and serum bone formation marker -osteocalcin (OC); and urine bone resorption markers-pyridinoline (PYD) and deoxypyridinoline (DPD). RESULTS: As a result of treatment with hormone therapy there were significant reductions in levels of FSH (73.3 ± 13.7 to 48.6 ± 10.5 mmol/L, p = 0.01) and bone resorption markers (PYD, 81.9 ± 7.7 to 57.8 ± 3.7 nmol/mmol Cr, p = 0.001, and DPD, 18.5 ± 3.1 to 11.8 ± 2.1 nmol/mmol Cr, p = 0.01). Oestradiol and bone formation markers were not significantly altered as a result of hormone therapy. There were no changes to any variables with placebo treatment. CONCLUSION: Hormone therapy reduced bone resorption, but not bone formation, in postmenopausal athletes. These favorable reductions in bone turnover; therefore, provide an effective treatment in combination with high intensity exercise to further reduce the subsequent risk of osteoporosis and associated fractures

Interleukin-6 Attenuates Insulin-Mediated Increases in Endothelial Cell Signaling but Augments Skeletal Muscle Insulin Action via Differential Effects on Tumor Necrosis Factor-α Expression

OBJECTIVE: The cytokine interleukin-6 (IL-6) stimulates AMP-activated protein kinase (AMPK) and insulin signaling in skeletal muscle, both of which result in the activation of endothelial nitric oxide synthase (eNOS). We hypothesized that IL-6 promotes endothelial cell signaling and capillary recruitment in vivo, contributing to increased glucose uptake. RESEARCH DESIGN AND METHODS: The effect of IL-6 with and without insulin on AMPK, insulin, and eNOS signaling in and nitric oxide (NO) release from human aortic endothelial cells (HAECs) was examined. The physiological significance of these in vitro signaling events was assessed by measuring capillary recruitment in rats during control and euglycemic-hyperinsulinemic clamps with or without IL-6 infusion. RESULTS: IL-6 blunted increases in insulin signaling, eNOS phosphorylation (Ser1177), and NO production and reduced phosphorylation of AMPK in HAEC in vitro and capillary recruitment in vivo. In contrast, IL-6 increased Akt phosphorylation (Ser473) in hindlimb skeletal muscle and enhanced whole-body glucose disappearance and glucose uptake during the clamp. The differences in endothelial cell and skeletal muscle signaling were mediated by the cell-specific, additive effects of IL-6 and insulin because this treatment markedly increased tumor necrosis factor (TNF)-alpha protein expression in HAECs without any effect on TNF-alpha in skeletal muscle. When HAECs were incubated with a TNF-alpha-neutralizing antibody, the negative effects of IL-6 on eNOS signaling were abolished. CONCLUSIONS: In the presence of insulin, IL-6 contributes to aberrant endothelial cell signaling because of increased TNF-alpha expression

Role of IL-6 in Exercise Training- and Cold-Induced UCP1 Expression in Subcutaneous White Adipose Tissue

Expression of brown adipose tissue (BAT) associated proteins like uncoupling protein 1 (UCP1) in inguinal WAT (iWAT) has been suggested to alter iWAT metabolism. The aim of this study was to investigate the role of interleukin-6 (IL-6) in exercise training and cold exposure-induced iWAT UCP1 expression. The effect of daily intraperitoneal injections of IL-6 (3 ng/g) in C57BL/6 mice for 7 days on iWAT UCP1 expression was examined. In addition, the expression of UCP1 in iWAT was determined in response to 3 days of cold exposure (4°C) and 5 weeks of exercise training in wild type (WT) and whole body IL-6 knockout (KO) mice. Repeated injections of IL-6 in C57BL/6 mice increased UCP1 mRNA but not UCP1 protein content in iWAT. Cold exposure increased iWAT UCP1 mRNA content similarly in IL-6 KO and WT mice, while exercise training increased iWAT UCP1 mRNA in WT mice but not in IL-6 KO mice. Additionally, a cold exposure-induced increase in iWAT UCP1 protein content was blunted in IL-6 KO mice, while UCP1 protein content in iWAT was lower in both untrained and exercise trained IL-6 KO mice than in WT mice. In conclusion, repeated daily increases in plasma IL-6 can increase iWAT UCP1 mRNA content and IL-6 is required for an exercise training-induced increase in iWAT UCP1 mRNA content. In addition IL-6 is required for a full induction of UCP1 protein expression in response to cold exposure and influences the UCP1 protein content iWAT of both untrained and exercise trained animals

TElmisartan in the management of abDominal aortic aneurYsm (TEDY): The study protocol for a randomized controlled trial

Background: 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. Methods/Design: 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. Discussion: 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. Trial registration: 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

Better Indigenous Risk stratification for Cardiac Health study (BIRCH) protocol: rationale and design of a cross-sectional and prospective cohort study to identify novel cardiovascular risk indicators in Aboriginal Australian and Torres Strait Islander adults

Background: Of the estimated 10-11 year life expectancy gap between Indigenous (Aboriginal and Torres Strait Islander people) and non-Indigenous Australians, approximately one quarter is attributable to cardiovascular disease (CVD). Risk prediction of CVD is imperfect, but particularly limited for Indigenous Australians. The BIRCH (Better Indigenous Risk stratification for Cardiac Health) project aims to identify and assess existing and novel markers of early disease and risk in Indigenous Australians to optimise health outcomes in this disadvantaged population. It further aims to determine whether these markers are relevant in non-Indigenous Australians. Methods/design: BIRCH is a cross-sectional and prospective cohort study of Indigenous and non-Indigenous Australian adults (≥ 18 years) living in remote, regional and urban locations. Participants will be assessed for CVD risk factors, left ventricular mass and strain via echocardiography, sleep disordered breathing and quality via home-based polysomnography or actigraphy respectively, and plasma lipidomic profiles via mass spectrometry. Outcome data will comprise CVD events and death over a period of five years. Discussion: Results of BIRCH may increase understanding regarding the factors underlying the increased burden of CVD in Indigenous Australians in this setting. Further, it may identify novel markers of early disease and risk to inform the development of more accurate prediction equations. Better identification of at-risk individuals will promote more effective primary and secondary preventive initiatives to reduce Indigenous Australian health disadvantage.Marc G. W. Rémond, Simon Stewart, Melinda J. Carrington, Thomas H. Marwick, Bronwyn A. Kingwell, Peter Meikle, Darren O’Brien, Nathaniel S. Marshall and Graeme P. Maguir

Glucose-6-phosphate dehydrogenase contributes to the regulation of glucose uptake in skeletal muscle

The development of skeletal muscle insulin resistance is an early physiological defect, yet the intracellular mechanisms accounting for this metabolic defect remained unresolved. Here, we have examined the role of glucose-6-phosphate dehydrogenase (G6PDH) activity in the pathogenesis of insulin resistance in skeletal muscle. Methods Multiple mouse disease states exhibiting insulin resistance and glucose intolerance, as well as obese humans defined as insulin-sensitive, insulin-resistant, or pre-diabetic, were examined. Results We identified increased glucose-6-phosphate dehydrogenase (G6PDH) activity as a common intracellular adaptation that occurs in parallel with the induction of insulin resistance in skeletal muscle and is present across animal and human disease states with an underlying pathology of insulin resistance and glucose intolerance. We observed an inverse association between G6PDH activity and nitric oxide synthase (NOS) activity and show that increasing NOS activity via the skeletal muscle specific neuronal (n)NOS&mu; partially suppresses G6PDH activity in skeletal muscle cells. Furthermore, attenuation of G6PDH activity in skeletal muscle cells via (a) increased nNOS&mu;/NOS activity, (b) pharmacological G6PDH inhibition, or (c) genetic G6PDH inhibition increases insulin-independent glucose uptake. Conclusions We have identified a novel, previously unrecognized role for G6PDH in the regulation of skeletal muscle glucose metabolism. <br /

c-Jun NH2-Terminal Kinase Activity in Subcutaneous Adipose Tissue but Not Nuclear Factor-κB Activity in Peripheral Blood Mononuclear Cells Is an Independent Determinant of Insulin Resistance in Healthy Individuals

OBJECTIVE Chronic low-grade activation of the immune system (CLAIS) predicts type 2 diabetes via a decrease in insulin sensitivity. Our study investigated potential relationships between nuclear factor-κB (NF-κB) and c-Jun NH2-terminal kinase (JNK) pathways—two pathways proposed as the link between CLAIS and insulin resistance. RESEARCH DESIGN AND METHODS Adiposity (dual-energy X-ray absorptiometry), waist-to-hip ratio (WHR), and insulin sensitivity (M, hyperinsulinemic-euglycemic clamp) were measured in 22 healthy nondiabetic volunteers (aged 29 ± 11 years, body fat 28 ± 11%). NF-κB activity (DNA-binding assay) and JNK1/2 activity (phosphorylated JNK) were assessed in biopsies of the vastus lateralis muscle and subcutaneous adipose tissue and in peripheral blood mononuclear cell (PBMC) lysates. RESULTS NF-κB activities in PBMCs and muscle were positively associated with WHR after adjustment for age, sex, and percent body fat (both P 0.1), although it was inversely related to M (r = −0.54, P < 0.05) and explained 29% of its variance. When both NF-κB and JNK1/2 were examined statistically, only JNK1/2 activity in adipose tissue was a significant determinant of insulin resistance (P = 0.02). CONCLUSIONS JNK1/2 activity in adipose tissue but not NF-κB activity in PBMCs is an independent determinant of insulin resistance in healthy individual