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IntroductionThe newer glucose-lowering therapies for type 2 diabetes (T2D), the glucagon-like peptide-1 receptor agonists (GLP1-RAs) and the sodium-glucose co-transporter 2 inhibitors (SGLT2i), have additional clinical benefits beyond improving glycaemic control; promoting weight loss, addressing associated cardiovascular risk factors and reducing macrovascular and microvascular complications. Considering their independent mechanisms of actions, there is a potential for significant synergy with combination therapy, yet limited data exist. This 32-week randomised, double-blind, placebo-controlled trial will gain mechanistic insight into the effects of coadministration of exenatide QW, a weekly subcutaneous GLP1-RA, with dapagliflozin, a once daily oral SGLT2i, on the dynamic, adaptive changes in energy balance, total, regional and organ-specific fat mass and multiorgan insulin sensitivity.Methods and analysis110 obese patients with diagnosed T2D (glycated haemoglobin, HbA1c ≥48 mmol/mol) will be treated for 32 weeks with dapagliflozin (10 mg once daily either alone or in combination with exenatide QW (2 mg once weekly); active treatments will be compared with a control group (placebo tablet and sham injection). The primary objective of the study is to compare the adjusted mean reduction in total body fat mass (determined by dual-energy X-ray absorptiometry, DEXA) from baseline following 32 weeks of treatment with exenatide QW and dapagliflozin versus dapagliflozin alone compared with control (placebo). Secondary outcome measures include changes in (1) energy balance (energy intake and energy expenditure measured by indirect calorimetry); (2) appetite (between and within meals) and satiety quotient; (3) body composition including visceral adipose tissue, subcutaneous adipose tissue, liver and pancreatic fat. Exploratory outcome measures include metabolic changes in hepatic and peripheral insulin sensitivity (using a two-stage hyperinsulinaemic, euglycaemic clamp), central nervous system responses to food images using blood oxygen level-dependent (BOLD) functional MRI (fMRI) and changes in cardiovascular function (using transthoracic echocardiography, cardiac MR and duplex ultrasonography).Ethics and disseminationThis study has been approved by the North West Liverpool Central Research Ethics Committee (14/NW/1147) and is conducted in accordance with the Declaration of Helsinki and the Good Clinical Practice. Results from the study will be published in peer-reviewed scientific and open access journals and/or presented at scientific conferences and summarised for distribution to the participants.Trial sponsorUniversity of Liverpool.Trial registration numberISRCTN 52028580; EUDRACT number 2015-005242-60.

Background Bariatric surgery promotes weight loss and improves co-morbid conditions, with patients who are more physically active having better outcomes. However, levels of physical activity and sedentary behaviour often remain unchanged following surgery. Objectives To identify interventions and components thereof that are able to facilitate changes in physical activity and sedentary behaviour. Eligibility Physical activity and/or sedentary behaviour must have been measured, pre and post intervention, in patients who have undergone bariatric surgery. Study appraisal and synthesis methods : Four databases were searched with key-words. Two researchers conducted paper screening, data extraction and risk-of-bias assessment. Results Twelve studies were included; eleven were randomised. Two were delivered pre-surgery and ten post-surgery; five found positive effect. Moderate to vigorous physical activity increased in three studies, two of which also found a significant increase in step count. The fourth found a significant increase in strenuous activity and the fifth a significant increase in metabolic equivalent of task/day and reduced time spent watching television. Funding Jennifer James is funded by a NIHR ICA Clinical Doctoral Research Fellowship. Limitations Meta-analysis could not be conducted due to heterogeneity of outcomes and the tools used. Conclusion and implications of key findings This review has identified interventions and components thereof that were able to provoke positive effect. However, intervention and control conditions were not always well described particularly in terms of behaviour change techniques and the rationale for their use. Systematic review registration number PROSPERO (CRD42019121372)

IntroductionObstructive sleep apnoea (OSA) and type 2 diabetes mellitus (T2DM) often occur concurrently, and untreated OSA may potentially amplify the high risk of cardiovascular disease in T2DM. Compliance with continuous positive airway pressure (CPAP), the conventional treatment for OSA, can be poor and considering weight loss is the most effective treatment for OSA. This trial examines whether the glucagon-like peptide-1 receptor agonist liraglutide, a glucose-lowering therapy associated with significant weight loss used in T2DM, can improve the severity and symptoms of OSA.Methods and analysisThis is an outpatient, single-centred, open-labelled, prospective, phase IV randomised controlled trial in a two-by-two factorial design. One hundred and thirty-two patients with newly diagnosed OSA (apnoea–hypopnoea index (AHI) ≥15 events/hour), and existing obesity and T2DM (glycated haemoglobin (HbA1c) ≥47 mmol/mol), will be recruited from diabetes and sleep medicine outpatient clinics in primary and secondary care settings across Liverpool. Patients will be allocated equally, using computer-generated random, permuted blocks of unequal sizes, to each of the four treatment arms for 26 weeks: (i) liraglutide (1.8 mg once per day) alone, (ii) liraglutide 1.8 mg once per day with CPAP, (iii) CPAP alone (conventional care) or (iv) no treatment (control). The primary outcome measure is change in OSA severity, determined by AHI. Secondary outcome measures include effects on glycaemic control (glycated haemoglobin (HbA1c)), body weight and quality of life measures. Exploratory measures include measures of physical activity, MRI-derived measures of regional body composition including fat mass (abdominal subcutaneous, visceral, neck and liver fat) and skeletal muscle mass (cross-sectional analysis of thigh), indices of cardiac function (using transthoracic echocardiography) and endothelial function.Ethical approvalThe study has been approved by the North West Liverpool Central Research Ethics Committee (14/NW/1019) and it is being conducted in accordance with the Declaration of Helsinki and Good Clinical Practice.Trial registration numbersISRCTN16250774. EUDRACT No. 2014-000988-41. UTN U1111-1139-0677.

Background Data suggest that metabolic health status, incorporating components of metabolic syndrome (MetS), predicts cardiovascular disease (CVD) risk better than BMI. This study explored the association of MetS and obesity with endothelial function, a prognostic risk factor for incident CVD. Methods Forty-four participants were phenotyped according to BMI as non-obese vs obese (30 kg/m2) and according to the International Diabetes Federation criteria of MetS: ≤2 criteria MetS (MetS−) vs ≥3 criteria MetS (MetS+); (1.)non-obese MetS− vs (2.) non-obese MetS+ and (3.) obese MetS− vs (4.) obese MetS+. Flow-mediated dilation (FMD), body composition including liver fat (MRI and spectroscopy), dietary intake, intensities of habitual physical activity and cardio-respiratory fitness were determined. Variables were analysed using a one-factor between-groups ANOVA and linear regression; mean (95% CI) are presented. Results Individuals with MetS+ displayed lower FMD than those with MetS−. For non-obese individuals mean difference between MetS+ and MetS− was 4.1% ((1.0, 7.3); P = 0.004) and obese individuals had a mean difference between MetS+ and MetS− of 6.2% ((3.1, 9.2); P P = 0.27), an increased number of MetS components was associated with a lower FMD (P = 0.005), and after adjustment for age and sex, 19.7% of the variance of FMD was explained by MetS, whereas only 1.1% was explained by BMI. Conclusions In this study cohort, components of MetS, rather than obesity per se, contribute to reduced FMD, which suggests a reduced bioavailability of nitric oxide and thus increased risk of CVD.

Background: Although the health benefits of regular physical activity and exercise are well established and have been incorporated into national public health recommendations, there is a relative lack of understanding pertaining to the harmful effects of physical inactivity. Experimental paradigms including complete immobilization and bed rest are not physiologically representative of sedentary living. A useful ‘real-world’ approach to contextualize the physiology of societal downward shifts in physical activity patterns is that of short-term daily step reduction. Results: Step-reduction studies have largely focused on musculoskeletal and metabolic health parameters, providing relevant disease models for metabolic syndrome, type 2 diabetes (T2D), nonalcoholic fatty liver disease (NAFLD), sarcopenia and osteopenia/osteoporosis. In untrained individuals, even a short-term reduction in physical activity has a significant impact on skeletal muscle protein and carbohydrate metabolism, causing anabolic resistance and peripheral insulin resistance, respectively. From a metabolic perspective, short-term inactivity-induced peripheral insulin resistance in skeletal muscle and adipose tissue, with consequent liver triglyceride accumulation, leads to hepatic insulin resistance and a characteristic dyslipidaemia. Concomitantly, various inactivity-related factors contribute to a decline in function; a reduction in cardiorespiratory fitness, muscle mass and muscle strength. Conclusions: Physical inactivity maybe particularly deleterious in certain patient populations, such as those at high risk of T2D or in the elderly, considering concomitant sarcopenia or osteoporosis. The effects of short-term physical inactivity (with step reduction) are reversible on resumption of habitual physical activity in younger people, but less so in older adults. Nutritional interventions and resistance training offer potential strategies to prevent these deleterious metabolic and musculoskeletal effects. Impact: Individuals at high risk of/with cardiometabolic disease and older adults may be more prone to these acute periods of inactivity due to acute illness or hospitalization. Understanding the risks is paramount to implementing countermeasures.

Background Premenopausal women have a lower incidence of cardiovascular disease, which may partly be due to a protective effect of estrogen on endothelial function. Animal studies suggest that estrogen may also improve the relationship between shear rate ( SR ) and endothelial function. We aimed to explore the relationship between endothelial function (ie, flow‐mediated dilation [ FMD ]) and SR (ie, SR area under the curve [ SRAUC ]) in women versus men, and between pre‐ versus postmenopausal women. Methods and Results Brachial artery FMD and SRAUC were measured in accordance with expert‐consensus guidelines in 932 healthy participants who were stratified into young adults (18‐40 years, 389 men, 144 women) and older adults (>40 years, 260 men, 139 women). Second, we compared premenopausal (n=173) and postmenopausal women (n=110). There was evidence of a weak correlation between SRAUC and FMD in all groups but older men, although there was variation in strength of outcomes. Further exploration using interaction terms (age‐sex× SRAUC ) in linear regression revealed differential relationships with FMD (young women versus young men [β=−5.8 −4 , P =0.017] and older women [β=−5.9 −4 , P =0.049]). The correlation between SRAUC and FMD in premenopausal women ( r 2 =0.097) was not statistically different from that in postmenopausal women ( r 2 =0.025; Fisher P =0.30). Subgroup analysis using stringent inclusion criteria for health markers (n=505) confirmed a stronger FMD ‐ SRAUC correlation in young women compared with young men and older women. Conclusions Evidence for a stronger relationship between endothelial function and the eliciting SR stimulus is present in young women compared with men. Estrogen may contribute to this finding, but larger healthy cohorts are required for conclusive outcomes.

Objectives: Post-menopausal hot flushes occur due to a reduction in oestrogen production causing thermoregulatory and vascular dysfunction. Exercise training enhances thermoregulatory control of sweating, skin and brain blood flow. We aimed to determine if improving thermoregulatory control and vascular function with exercise training alleviated hot flushes. Methods: Twenty one symptomatic females completed a 7-day hot flush questionnaire and underwent brachial artery flow-mediated dilation and a cardiorespiratory fitness test. Sweat rate and skin blood flow temperature thresholds and sensitivities, and middle cerebral artery velocity (MCAv) was measured during passive heating. Females performed 16-weeks of supervised exercise training or control, and measurements were repeated. Results: There was a greater improvement in cardiorespiratory fitness (4.45 ml•kg-1•min-1 (95% CI: 1.87, 8.16; P=0.04) and reduced hot flush frequency [48 hot flushes•week (39, 56) P

Exercise training has potential to positively impact cerebrovascular function in healthy and diseased individuals. Passive heat training using warm water immersion has recently been shown to enhance systemic vascular function including the cerebrovascular response to heating. We suggest that a passive heating intervention can be a useful adjunct or alternative to exercise training. Our aim was to directly compare the effects of exercise with warm water immersion training on cerebrovascular and thermoregulatory function. 18 females (25±5y) performed 8-weeks of moderate-intensity cycling (70% HRmax) or warm-water immersion (42°C) for 30 min three times per week. Brachial artery flow-mediated dilation (FMD) and cardiorespiratory fitness were measured prior to and following both interventions. A passive heat stress was employed to obtain temperature thresholds (Tb) and sensitivities for chest and forearm sweat rate (SR) and cutaneous vasodilation (CVC). Middle cerebral artery velocity (MCAv) was measured at rest and throughout heat stress. FMD (P=0.003) and VO2peak (P

Weight loss during SGLT2i therapy is less than predicted from urinary glucose loss. Modelling suggests a 10-15% compensatory increase in energy intake. We compared effects of 12 weeks’ dapagliflozin 10mg od vs. placebo on food intake in a double-blind, placebo-controlled study with short (1 week) and long-term (12 week) crossover periods. Food intake was measured during test meals at baseline, pre and post each crossover using the Sussex Ingestion Pattern Monitor, continuously recording intake during the meal; primary outcome was the difference after 12 weeks’ treatment. 52 patients with T2DM treated with diet or oral agents were recruited (45 completed;43% female). Median age 60y, weight 98.4 kg, BMI 34, HbA1c 59.5 mmol/mol. Analysis used a linear mixed model with the random effect as study subject and fixed effects of sex, visit, study arm and arm:visit interaction. Dapagliflozin use was associated with a reduction in HbA1c -9.73mmol/mol (95% CI 3.91, 16.27; p=0.004), and body weight (-2.84 vs. -0.87 kg) vs. placebo. There was no difference in test meal food intake between dapagliflozin and placebo at 12 weeks median difference, 2.63g (95% CI,-31.65,36.9); p=0.659 or at other time points. Dapagliflozin was not associated with a compensatory increase in food intake. Disclosure S. Rajeev: None. C.A. Roberts: None. D.J. Cuthbertson: None. V.S. Sprung: None. E. Brown: Research Support; Self; AstraZeneca. J.C. Halford: Advisory Panel; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S. J.A. Harrold: None. G.J. Kemp: None. A. Stancak: None. J.P. Wilding: Other Relationship; Self; Astellas, AstraZeneca, Boehringer Ingelheim GmbH, Janssen Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi, Eli Lilly and Company, Orexigen Therapeutics, Inc., Merck & Co., Inc..

Low physical activity levels and sedentary behaviour are associated with obesity, insulin resistance and type 2 diabetes. We investigated the effects of a short-term reduction in physical activity with increased sedentary behaviour on metabolic profiles and body composition, comparing the effects in individuals with first-degree relatives with type 2 diabetes (FDR+ve) vs those without (FDR−ve). Forty-five habitually active participants (16 FDR+ve [10 female, 6 male] and 29 FDR−ve [18 female, 11 male]; age 36 ± 14 years) were assessed at baseline, after 14 days of step reduction and 14 days after resuming normal activity. We determined physical activity (using a SenseWear armband), cardiorespiratory fitness ( $$ \dot{\mathrm{V}}{\mathrm{O}}_{2\mathrm{peak}} $$ ), body composition (dual-energy x-ray absorptiometry/magnetic resonance spectroscopy) and multi-organ insulin sensitivity (OGTT) at each time point. Statistical analysis was performed using a two-factor between-groups ANCOVA, with data presented as mean ± SD or (95% CI). There were no significant between-group differences in physical activity either at baseline or following step reduction. During the step-reduction phase, average daily step count decreased by 10,285 steps (95% CI 9389, 11,182; p

Commentary on : Zhang HJ, He J, Pan LL, et al . Effects of moderate and vigorous exercise on non-alcoholic fatty liver disease: a randomized clinical trial. JAMA Intern Med 2016;176:1074–82. Non-alcoholic fatty liver disease (NAFLD) is associated with an increased risk of liver morbidity and mortality, type 2 diabetes mellitus and cardiovascular disease (CVD). Lifestyle modification is the mainstay of treatment, with uncertainty regarding the effectiveness of drug therapy for patients with NAFLD.1 Exercise intervention studies demonstrate that exercise effectively reduces liver fat, even in the absence of significant weight loss. In free-living individuals, higher exercise frequency is associated with a lower risk NAFLD and higher rates of resolution of existing NAFLD over 5 years of follow-up.2 However, widespread implementation of exercise as a therapeutic modality …

Introduction Sodium glucose cotransporter 2 (SGLT2) inhibitors are effective blood-glucose-lowering medications with beneficial effects on body weight in patients with type 2 diabetes mellitus (T2DM). However, observed weight loss is less than that predicted from quantified glycosuria, suggesting a compensatory increase in energy intake or a decrease in energy expenditure. Studies using dual-energy X-ray absorptiometry (DEXA) have suggested most body weight change is due to loss of adipose tissue, but organ-specific changes in fat content (eg, liver, skeletal muscle) have not been determined. In this randomised, double-blind, placebo-controlled crossover study, we aim to study the compensatory changes in energy intake, eating behaviour and energy expenditure accompanying use of the SGLT2 inhibitor, dapagliflozin. Additionally, we aim to quantify changes in fat distribution using MRI, in liver fat using proton magnetic resonance spectroscopy (1H-MRS) and in central nervous system (CNS) responses to food images using blood oxygen level dependent (BOLD) functional MRI (fMRI). Methods and analysis This outpatient study will evaluate the effect of dapagliflozin (10 mg), compared with placebo, on food intake and energy expenditure at 7 days and 12 weeks. 52 patients with T2DM will be randomised to dapagliflozin or placebo for short-term and long-term trial interventions in a within participants, crossover design. The primary outcome is the difference in energy intake during a test meal between dapagliflozin and placebo. Intake data are collected automatically using a customised programme operating a universal eating monitor (UEM). Secondary outcomes include (1) measures of appetite regulation including rate of eating, satiety quotient, appetite ratings (between and within meals), changes in CNS responses to food images measured using BOLD-fMRI, (2) measures of energy expenditure and (3) changes in body composition including changes in liver fat and abdominal visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT). Ethical approval This study has been approved by the North West Liverpool Central Research Ethics Committee (14/NW/0340) and is conducted in accordance with the Declaration of Helsinki and the Good Clinical Practice (GCP). Trial registration number ISRCTN14818531. EUDRACT number 2013-004264-60.

Nonalcoholic fatty liver disease (NAFLD) is an independent risk factor for cardiovascular disease (CVD). Endothelial dysfunction is an early manifestation of atherosclerosis and an important prognostic marker for future cardiovascular events. The aim of this study was twofold: to examine 1) the association between liver fat, visceral adipose tissue (VAT), and endothelial dysfunction in obese NAFLD patients and 2) the impact of supervised exercise training on this vascular defect. Brachial artery endothelial function was assessed by flow-mediated dilatation (FMD) in 34 obese NAFLD patients and 20 obese controls of similar age and cardiorespiratory fitness [peak oxygen uptake (V̇o2 peak)] (48 ± 2 vs. 47 ± 2 yr; 27 ± 1 vs. 26 ± 2 ml·kg−1·min−1−1). Magnetic resonance imaging and spectroscopy quantified abdominal and liver fat, respectively. Twenty-one NAFLD patients completed either 16 wk of supervised moderate-intensity exercise training ( n = 13) or conventional care ( n = 8). Differences between NAFLD and controls were compared using independent t-tests and effects of interventions by analysis of covariance. NAFLD patients had higher liver fat [11.6% (95% CI = 7.4, 18.1), P < 0.0005] and VAT [1.6 liters (95% CI = 1.2, 2.0), P < 0.0001] than controls and exhibited impaired FMD compared with controls [−3.6% (95% CI = −4.9, −2.2), P < 0.0001]. FMD was inversely correlated with VAT ( r = −0.54, P = 0.001) in NAFLD, although the impairment in FMD remained following covariate adjustment for VAT [3.1% (95% CI = 1.8, 4.5), P < 0.001]. Exercise training, but not conventional care, significantly improved V̇o2 peak [9.1 ml·kg−1·min−1 (95% CI = 4.1, 14.1); P = 0.001] and FMD [3.6% (95% CI = 1.6, 5.7), P = 0.002]. Endothelial dysfunction in NAFLD cannot be fully explained by excess VAT but can be reversed with exercise training; this has potential implications for the primary prevention of CVD in NAFLD.

The aim of this study was to examine the contribution of arterial shear to changes in flow-mediated dilation (FMD) during sympathetic nervous system (SNS) activation in healthy humans. Ten healthy men reported to our laboratory four times. Bilateral FMD, shear rate (SR), and catecholamines were examined before/after 10-min of −35-mmHg lower body negative pressure (LBNP10). On day 1, localized forearm heating (LBNP10+heat) was applied in one limb to abolish the increase in retrograde SR associated with LBNP. Day 2 involved unilateral cuff inflation to 75 mmHg around one limb to exaggerate the LBNP-induced increase retrograde SR (LBNP10+cuff). Tests were repeated on days 3 and 4, using 30-min interventions (i.e., LBNP30+heat and LBNP30+cuff). LBNP10 significantly increased epinephrine levels and retrograde SR and decreased FMD (all P < 0.05). LBNP10+heat prevented the increase in retrograde SR, whereas LBNP10+cuff further increased retrograde SR ( P < 0.05). Heating prevented the decrease in percent FMD (FMD%) after LBNP10 (interaction effect, P < 0.05), whereas cuffing did not significantly exaggerate the decrease in FMD% (interaction effect, P > 0.05). Prolongation of the LBNP stimulus for 30-min normalized retrograde SR, catecholamine levels, and FMD (all P > 0.05). Attenuation of retrograde SR during 30 min (LBNP30+heat) was associated with increased FMD% (interaction effects, P < 0.05), whereas increased retrograde SR (LBNP30+cuff) diminished FMD% (interaction effects, P < 0.05). These data suggest that LBNP-induced SNS stimulation decreases FMD, at least in part due to the impact of LBNP on arterial shear stress. Prolonged LBNP stimulation was not associated with changes in SR or FMD%. Our data support a role for changes in SR to the impact of SNS stimulation on FMD.

SPRUNG, V. S., D. J. CUTHBERTSON, C. J. A. PUGH, N. AZIZ, G. J. KEMP, C. DAOUSI, D. J. GREEN, N. T. CABLE, and H. JONES. Exercise Training in Polycystic Ovarian Syndrome Enhances Flow-Mediated Dilation in the Absence of Changes in Fatness. Med. Sci. Sports Exerc., Vol. 45, No. 12, pp. 2234–2242, 2013. Introduction: Polycystic ovarian syndrome (PCOS) is associated with an adverse cardiovascular disease (CVD) profile. A surrogate marker for CVD risk is endothelial dysfunction. Limited studies exist examining the cardiovascular and metabolic effects of exercise in PCOS and specifically its impact on endothelial function. Therefore, the aim of the current study was to investigate the impact of exercise on endothelial function, in parallel with body composition, insulin resistance, and cardiopulmonary fitness in PCOS. Methods: Ten women with PCOS (27 yr, 95% confidence interval [CI] = 23–32; 31 kgIm j2 , 95% CI = 28–34) completed a 16-wk exercise (EX) program, and seven women with PCOS (29 yr, 95% CI = 24–35; 35 kgIm j2 , 95% CI = 31–40) undertook conventional care (CC) following lifestyle advice. Brachial artery endothelial function was assessed pre- and postintervention using flow-mediated dilation adjusted for variability in baseline diameter. Visceral and abdominal subcutaneous adipose tissue was assessed using whole-body magnetic resonance imaging and 1 H magnetic resonance spectroscopy quantified liver fat. Cardiorespiratory fitness, glycemic control, hormone, and lipid profiles were also assessed. Data were analyzed using covariate-controlled generalized estimating equations. Results: At follow-up, EX improved flow-mediated dilation by 3.6% (95% CI = 0.5–6.7, P = 0.03) more than CC. There was a parallel improvement in cardiorespiratory fitness of 4.7 mLIkg j1 Imin j1 (95% CI = 1.4–7.9, P G 0.001) with EX versus CC. These changes were not explained by changes in visceral adipose tissue, subcutaneous adipose tissue, liver fat or insulin resistance. Conclusions: Supervised exercise in women with PCOS improves endothelial function, an adaptation associated with reduced CVD risk. This change occurs independent of changes in body weight or composition. The success of public health interventions in this

PCOS (polycystic ovary syndrome) is associated with IR (insulin resistance), increased visceral fat and NAFLD (non-alcoholic fatty liver disease) all of which may contribute to endothelial dysfunction, an early marker of CVD (cardiovascular disease) risk. Our objective was to examine the relationships between endothelial dysfunction in PCOS, the volume of AT (adipose tissue) compartments and the size of intracellular TAG (triacylglycerol) pools in liver and skeletal muscle. A total of 19 women with PCOS (means±S.D.; 26±6 years, 36±5 kg/m2) and 16 control women (31±8 years, 30±6 kg/m2) were recruited. Endothelial function was assessed in the brachial artery using FMD (flow-mediated dilation). VAT (visceral AT) and abdominal SAT (subcutaneous AT) volume were determined by whole body MRI, and liver and skeletal muscle TAG by 1H-MRS (proton magnetic resonance spectroscopy). Cardiorespiratory fitness and HOMA-IR (homoeostasis model assessment of IR) were also determined. Differences between groups were analysed using independent Student's t tests and ANCOVA (analysis of co-variance). FMD was impaired in PCOS by 4.6% [95% CI (confidence interval), 3.0–7.7; P

Polycystic ovary syndrome (PCOS) is associated with cardiovascular disease. The contribution of the nitric oxide (NO) dilator system to cutaneous endothelial dysfunction is currently unknown in PCOS. Our aim was to examine whether women with PCOS demonstrate impaired cutaneous microvascular NO function and whether exercise training can ameliorate any impairment. Eleven women with PCOS (age, 29 ± 7 years; body mass index, 34 ± 6 kg m(-2)) were compared with six healthy obese control women (age, 29 ± 7 years; body mass index, 34 ± 5 kg m(-2)). Six women with PCOS (30 ± 7 years; 31 ± 6 kg m(-2)) then completed 16 weeks of exercise training. Laser Doppler flowmetry, combined with intradermal microdialysis of l-N(G)-monomethyl-l-arginine, a nitric oxide antagonist, in response to incremental local heating of the forearm was assessed in women with PCOS and control women, and again in women with PCOS following exercise training. Cardiorespiratory fitness, homeostasis model assessment for insulin resistance, hormone and lipid profiles were also assessed. Differences between women with PCOS and control women and changes with exercise were analysed using Student's unpaired t tests. Differences in the contribution of NO to cutaneous blood flow [expressed as a percentage of maximal cutaneous vasodilatation (CVCmax)] were analysed using general linear models. At 42°C heating, cutaneous NO-mediated vasodilatation was attenuated by 17.5%CVCmax (95% confidence interval, 33.3, 1.7; P = 0.03) in women with PCOS vs. control women. Exercise training improved cardiorespiratory fitness by 5.0 ml kg(-1) min(-1) (95% confidence interval, 0.9, 9.2; P = 0.03) and NO-mediated cutaneous vasodilatation at 42°C heating by 19.6% CVCmax (95% confidence interval, 4.3, 34.9; P = 0.02). Cutaneous microvascular NO function is impaired in women with PCOS compared with obese matched control women but can be improved with exercise training.

AIMS: Supervised exercise reduces liver fat and improves endothelial function, a surrogate of cardiovascular disease risk, in non-alcoholic fatty liver disease (NAFLD). We hypothesised that after a 16-week supervised exercise program, patients would maintain longer-term improvements in cardiorespiratory fitness, liver fat and endothelial function. MATHERIALS AND METHODS: Ten NAFLD patients [5/5 males/females, age 51±13years, BMI 31±3 kg.m(2) (mean±s.d.)] underwent a 16-week supervised moderate-intensity exercise intervention. Biochemical markers, cardiorespiratory fitness (VO2peak), subcutaneous, visceral and liver fat (measured by magnetic resonance imaging and spectroscopy respectively) and brachial artery flow-mediated dilation (FMD) were assessed at baseline, after 16 weeks supervised training and 12-months after ending supervision. RESULTS: Despite no significant change in body weight, there were significant improvements in VO2peak [6.5 ml.kg(-1).min(-1) (95% CI 2.8, 10.1); P=0.003], FMD [2.9% (1.5, 4.2); P=0.001], liver transaminases (P0.05) and liver fat [1.4% (-13.0, 15.9); P=0.83] were not significantly different from baseline. CONCLUSIONS: Twelve months following cessation of supervision, exercise-mediated improvements in liver fat and other cardiometabolic variables had reversed with cardiorespiratory fitness at baseline levels. Maintenance of high cardiorespiratory fitness and stability of body weight are critical public health considerations for the treatment of NAFLD.International Journal of Obesity accepted article preview online, 21 July 2016. doi:10.1038/ijo.2016.123.

Non-alcoholic fatty liver disease (NAFLD) is associated with multi-organ (hepatic, skeletal muscle, adipose tissue) insulin resistance (IR). Exercise is an effective treatment for lowering liver fat but its effect on IR in NAFLD is unknown. We aimed to determine whether supervised exercise in NAFLD would reduce liver fat and improve hepatic and peripheral (skeletal muscle and adipose tissue) insulin sensitivity. Sixty nine NAFLD patients were randomized to 16 weeks exercise supervision (n=38) or counselling (n=31) without dietary modification. All participants underwent MRI/spectroscopy to assess changes in body fat and in liver and skeletal muscle triglyceride, before and following exercise/counselling. To quantify changes in hepatic and peripheral insulin sensitivity, a pre-determined subset (n=12 per group) underwent a two-stage hyperinsulinaemic euglycaemic clamp pre- and post-intervention. Results are shown as mean [95% confidence interval (CI)]. Fifty participants (30 exercise, 20 counselling), 51 years (IQR 40, 56), body mass index (BMI) 31 kg/m2 (IQR 29, 35) with baseline liver fat/water % of 18.8% (IQR 10.7, 34.6) completed the study (12/12 exercise and 7/12 counselling completed the clamp studies). Supervised exercise mediated a greater reduction in liver fat/water percentage than counselling [Δ mean change 4.7% (0.01, 9.4); P

BACKGROUND: The term 'metabolically healthy obese (MHO)' is distinguished using body mass index (BMI), yet BMI is a poor index of adiposity. Some epidemiological data suggest that MHO carries a lower risk of cardiovascular disease (CVD) or mortality than being normal weight yet metabolically unhealthy. OBJECTIVES: We aimed to undertake a detailed phenotyping of individuals with MHO by using imaging techniques to examine ectopic fat (visceral and liver fat deposition) and myocardial function. We hypothesised that metabolically unhealthy individuals (irrespective of BMI) would have adverse levels of ectopic fat and myocardial dysfunction compared with MHO individuals. SUBJECTS: Individuals were categorised as non-obese or obese (BMI ⩾30 kg m(-2)) and as metabolically healthy or unhealthy according to the presence or absence of metabolic syndrome. METHODS: Sixty-seven individuals (mean±s.d.: age 49±11 years) underwent measurement of (i) visceral, subcutaneous and liver fat using magnetic resonance imaging and proton magnetic resonance spectroscopy, (ii) components of metabolic syndrome, (iii) cardiorespiratory fitness and (iv) indices of systolic and diastolic function using tissue Doppler echocardiography. RESULTS: Cardiorespiratory fitness was similar between all groups; abdominal and visceral fat was highest in the obese groups. Compared with age- and BMI-matched metabolically healthy counterparts, the unhealthy (lean or obese) individuals had higher liver fat and decreased early diastolic strain rate, early diastolic tissue velocity and systolic strain indicative of subclinical systolic and diastolic dysfunction. The magnitude of dysfunction correlated with the number of components of metabolic syndrome but not with BMI or with the degree of ectopic (visceral or liver) fat deposition. CONCLUSIONS: Myocardial dysfunction appears to be related to poor metabolic health rather than simply BMI or fat mass. These data may partly explain the epidemiological evidence on CVD risk relating to the different obesity phenotypes.

Item does not contain fulltext BACKGROUND: Ischaemic preconditioning has well-established cardiac and vascular protective effects. Short interventions (one week) of daily ischaemic preconditioning episodes improve conduit and microcirculatory function. This study examined whether a longer (eight weeks) and less frequent (three per week) protocol of repeated ischaemic preconditioning improves vascular function. METHODS: Eighteen males were randomly allocated to either ischaemic preconditioning (22.4 +/- 2.3 years, 23.7 +/- 3.1 kg/m(2)) or a control intervention (26.0 +/- 4.8 years, 26.4 +/- 1.9 kg/m(2)). Brachial artery endothelial-dependent (FMD), forearm cutaneous microvascular function and cardiorespiratory fitness were assessed at zero, two and eight weeks. RESULTS: A greater improvement in FMD was evident following ischaemic preconditioning training compared with control at weeks 2 (2.24% (0.40, 4.08); p=0.02) and 8 (1.11% (0.13, 2.10); p=0.03). Repeated ischaemic preconditioning did not change cutaneous microcirculatory function or fitness. CONCLUSIONS: These data indicate that a feasible and practical protocol of regular ischaemic preconditioning episodes improves endothelial function in healthy individuals within two weeks, and these effects persist following repeated ischaemic preconditioning for eight weeks. 01 augustus 2015

Item does not contain fulltext INTRODUCTION: Regular exercise induces recurrent increases in cerebrovascular perfusion. In peripheral arteries, such episodic increases in perfusion are responsible for improvement in arterial function and health. We examined the hypothesis that exercise during immersion augments cerebral blood flow velocity compared with intensity-matched land-based exercise. METHODS: Fifteen normotensive participants were recruited (26 +/- 4 yr, 24.3 +/- 1.9 kg.m). We continuously assessed mean arterial blood pressure, HR, stroke volume, oxygen consumption, and blood flow velocities through the middle and posterior cerebral arteries before, during, and after 20-min bouts of water- and land-based stepping exercise of matched intensity. The order in which the exercise conditions were performed was randomized between subjects. Water-based exercise was performed in 30 degrees C water to the level of the right atrium. RESULTS: The water- and land-based exercise bouts were closely matched for oxygen consumption (13.3 mL.kg.min (95% confidence interval (CI), 12.2-14.6) vs 13.5 mL.kg.min (95% CI, 12.1-14.8), P = 0.89) and HR (95 bpm (95% CI, 90-101) vs 96 bpm (95% CI, 91-102), P = 0.65). Compared with land-based exercise, water-based exercise induced an increase in middle cerebral artery blood flow velocity (74 cm.s (95% CI, 66-81) vs 67 cm.s (95% CI, 60-74) P < 0.001), posterior cerebral artery blood flow velocity (47 cm.s (95% CI, 40-53) vs 43 cm.s (95% CI, 37-49), P < 0.001), mean arterial blood pressure (106 mm Hg (95% CI, 100-111) vs 101 mm Hg (95% CI, 95-106), P < 0.001), and partial pressure of expired CO2 (P

Contains fulltext : 137986.pdf (Publisher’s version ) (Closed access) The objectives of our study were to examine 1) the proportion of responders and nonresponders to exercise training in terms of vascular function; 2) a priori factors related to exercise training-induced changes in conduit artery function, and 3) the contribution of traditional cardiovascular risk factors to exercise-induced changes in artery function. We pooled data from our laboratories involving 182 subjects who underwent supervised, large-muscle group, endurance-type exercise training interventions with pre-/posttraining measures of flow-mediated dilation (FMD%) to assess artery function. All studies adopted an identical FMD protocol (5-min ischemia, distal cuff inflation), contemporary echo-Doppler methodology, and observer-independent automated analysis. Linear regression analysis was used to identify factors contributing to changes in FMD%. We found that cardiopulmonary fitness improved, and weight, body mass index (BMI), cholesterol, and mean arterial pressure (MAP) decreased after training, while FMD% increased in 76% of subjects (P < 0.001). Training-induced increase in FMD% was predicted by lower body weight (beta = -0.212), lower baseline FMD% (beta = -0.469), lower training frequency (beta = -0.256), and longer training duration (beta = 0.367) (combined: P < 0.001, r = 0.63). With the exception of a modest correlation with total cholesterol (r = -0.243, P < 0.01), changes in traditional cardiovascular risk factors were not significantly related to changes in FMD% (P > 0.05). In conclusion, we found that, while some subjects do not demonstrate increases following exercise training, improvement in FMD% is present in those with lower pretraining body weight and endothelial function. Moreover, exercise training-induced change in FMD% did not correlate with changes in traditional cardiovascular risk factors, indicating that some cardioprotective effects of exercise training are independent of improvement in risk factors.

The leading causes of mortality in nonalcoholic fatty liver disease (NAFLD) relate to cardiovascular disease (CVD). The contribution of nitric oxide (NO) to endothelial function, a surrogate of CVD risk, is currently unknown in NAFLD. We hypothesize that NO-mediated cutaneous microvessel function would be impaired in NAFLD compared with controls and that exercise would enhance microvessel function compared with conventional care. Thirteen NAFLD patients (aged 50 ± 3 yr, BMI 31 ± 1 kg/m2) and seven controls (48 ± 4 yr, 30 ± 2 kg/m2) were studied. NAFLD patients were randomized to either 16 wk of exercise or conventional care. Cutaneous microvessel function was examined using laser Doppler flowmetry combined with intradermal microdialysis of NG-monomethyl-l-arginine to assay the NO dilator response to local forearm heating. Magnetic resonance imaging and spectroscopy quantified abdominal and liver fat, respectively, and cardiorespiratory fitness was assessed. Differences in NO contribution to cutaneous blood flow between NAFLD and control individuals and between interventions were analyzed using general linear modeling. NO contribution to cutaneous blood flow was similar between NAFLD and controls ( P = 0.47). Cardiorespiratory fitness was greater following exercise training compared with conventional care. NO contribution to cutaneous blood flow in response to heating at 42°C was 20.4% CVCmax (95% CI = 4.4, 36.4) greater following exercise training compared with conventional care ( P = 0.02). Exercise training improves cutaneous microvascular NO function in NAFLD patients. The benefit of exercise training compared with conventional care strongly supports a role for exercise in the prevention of CVD in NAFLD.

Nonalcoholic fatty liver disease may be evident in women with polycystic ovary syndrome (PCOS), both conditions being associated with obesity and insulin resistance. However, few studies have accounted for the high prevalence of obesity in PCOS.The aim of this study was to determine whether PCOS is independently associated with hepatic steatosis, compared with healthy controls of similar age and body mass index (BMI), and whether steatosis is associated with hyperandrogenemia.We conducted a cross-sectional, case-control study at two tertiary referral centers.Twenty-nine women with PCOS diagnosed by the Rotterdam criteria [aged 28 yr; 95% confidence interval (CI), 26-31; BMI, 33 kg/m2; 95% CI, 31-36] and 22 healthy controls (aged 29 yr; 95% CI, 28-31; BMI, 30 kg/m2; 95% CI, 28-33) were studied.Proton-magnetic resonance spectroscopy quantified hepatic and skeletal muscle fat; whole body magnetic resonance imaging quantified internal, visceral, and sc adipose tissue volumes. Differences were assessed between PCOS and controls using t tests, and between hyperandrogenic (HA) PCOS, PCOS with normal androgens (NA), and controls using analysis of covariance.After statistical adjustment for BMI, HA-PCOS had significantly higher liver fat vs. NA-PCOS (3.7%; 95% CI, 0.6-13.1) and vs. controls (2.1%; 95% CI, 0.3-6.6). Similarly, after adjustment for homeostasis model assessment for insulin resistance, internal and visceral adipose tissue volumes, liver fat remained significantly greater in HA-PCOS compared to NA-PCOS and controls.These data suggest that HA-PCOS is associated with hepatic steatosis, independent of obesity and insulin resistance.

Objective Women with polycystic ovary syndrome (PCOS) demonstrate an increased prevalence of cardiovascular disease (CVD) risk factors. Previous researchers have compared flow-mediated dilation (FMD), an early marker of CVD, in women with and without PCOS. Evidence for a PCOS-mediated reduction in FMD remains equivocal, potentially because of study differences in cohort-matching and measurement approaches. The aims of this systematic review and meta-analysis were to examine to what extent FMD is impaired in PCOS and to explore the influence of potential moderators of FMD reduction, such as age and BMI. Design A systematic review and meta-analysis of published observational studies comparing FMD in PCOS with control women. Patients Twenty-one published studies were included (PCOS, n = 908; controls, n = 566). A subanalysis, using tighter inclusion criteria, involved seven studies (PCOS, n = 402; control, n = 251). Measurements Mean differences in FMD between PCOS and controls were synthesized. The subanalysis was delimited to the inclusion of age and BMI-matched controls. These factors were then explored as moderators using meta-regression. Results The pooled mean FMD was 3·4% (95% CI=1·9, 4·9) lower in PCOS compared with control women, with substantial heterogeneity between studies. In the subanalysis, the PCOS-mediated reduction in FMD was 4·1% (95% CI=2·7, 5·5). Heterogeneity remained substantial (I2=81%). Subsequent meta-regression indicated that the magnitude of FMD difference was not influenced by BMI (P = 0·17) nor age (P = 0·38). Conclusions This systematic research synthesis indicates that endothelial function is compromised in PCOS women, even if they are young and nonobese.

ObjectivesTo summarize existing evidence and quantify the effects of physical activity on vascular function and structure in autoimmune rheumatic diseases (ARDs).MethodsDatabases were searched (through March 2020) for clinical trials evaluating the effects of physical activity interventions on markers of micro- and macrovascular function and macrovascular structure in ARDs. Studies were combined using random effects meta-analysis, which was conducted using Hedges’ g. Meta-analyses were performed on each of the following outcomes: microvascular function [i.e. skin blood flow or vascular conductance responses to acetylcholine (ACh) or sodium nitropusside (SNP) administration]; macrovascular function [i.e. brachial flow-mediated dilation (FMD%) or brachial responses to glyceryl trinitrate (GTN%); and macrovascular structure [i.e. aortic pulse wave velocity (PWV)].ResultsTen studies (11 trials) with a total of 355 participants were included in this review. Physical activity promoted significant improvements in microvascular [skin blood flow responses to ACh, g = 0.92 (95% CI 0.42, 1.42)] and macrovascular function [FMD%, g = 0.94 (95% CI 0.56, 1.02); GTN%, g = 0.53 (95% CI 0.09, 0.98)]. Conversely, there was no evidence for beneficial effects of physical activity on macrovascular structure [PWV, g = −0.41 (95% CI −1.13, 0.32)].ConclusionsOverall, the available clinical trials demonstrated a beneficial effect of physical activity on markers of micro- and macrovascular function but not on macrovascular structure in patients with ARDs. The broad beneficial impact of physical activity across the vasculature identified in this review support its role as an effective non-pharmacological management strategy for patients with ARDs.

Background and Aims. Simple clinical algorithms including the Fatty Liver Index (FLI) and Lipid Accumulation Product (LAP) have been developed as a surrogate marker for Non-Alcoholic Fatty Liver Disease (NAFLD). These algorithms have been constructed using ultrasonography, a semi-quantitative method. This study aimed to validate FLI and LAP as measures of hepatic steatosis, as measured quantitatively by proton magnetic resonance spectroscopy (1H-MRS). \ud Methods. Data were collected from 168 patients with NAFLD and 168 controls who had undergone clinical, biochemical and anthropometric assessment in the course of research studies. Values of FLI and LAP were determined, and assessed both as predictors of the presence of hepatic steatosis (liver fat >5.5 %) and of actual liver fat content, as measured by 1H MRS. The discriminative ability of FLI and LAP was estimated using the area under the Receiver Operator Characteristic curve (AUROC). Since FLI can also be interpreted as a predictive probability of hepatic steatosis, we assessed how well calibrated it was in our cohort. Linear regression with prediction intervals was used to assess the ability of FLI and LAP to predict liver fat content. \ud Results. FLI and LAP discriminated between patients with and without hepatic steatosis with an AUROC of 0.79 (IQR= 0.74, 0.84) and 0.78 (IQR= 0.72, 0.83), although quantitative prediction of liver fat content was unsuccessful. Additionally, the algorithms accurately matched the observed percentages of patients with hepatic steatosis in our cohort. \ud Conclusions. FLI and LAP may be used clinically, and for metabolic and epidemiological research, to identify patients with hepatic steatosis, but not as surrogates for liver fat content.

Background and aimsSimple clinical algorithms including the fatty liver index (FLI) and lipid accumulation product (LAP) have been developed as surrogate markers for non-alcoholic fatty liver disease (NAFLD), constructed using (semi-quantitative) ultrasonography. This study aimed to validate FLI and LAP as measures of hepatic steatosis, as determined quantitatively by proton magnetic resonance spectroscopy (1H-MRS).MethodsData were collected from 168 patients with NAFLD and 168 controls who had undergone clinical, biochemical and anthropometric assessment. Values of FLI and LAP were determined and assessed both as predictors of the presence of hepatic steatosis (liver fat >5.5%) and of actual liver fat content, as measured by 1H-MRS. The discriminative ability of FLI and LAP was estimated using the area under the receiver operator characteristic curve (AUROC). As FLI can also be interpreted as a predictive probability of hepatic steatosis, we assessed how well calibrated it was in our cohort. Linear regression with prediction intervals was used to assess the ability of FLI and LAP to predict liver fat content. Further validation was provided in 54 patients with type 2 diabetes mellitus.ResultsFLI, LAP and alanine transferase discriminated between patients with and without steatosis with an AUROC of 0.79 (IQR=0.74, 0.84), 0.78 (IQR=0.72, 0.83) and 0.83 (IQR=0.79, 0.88) respectively although could not quantitatively predict liver fat. Additionally, the algorithms accurately matched the observed percentages of patients with hepatic steatosis in our cohort.ConclusionsFLI and LAP may be used to identify patients with hepatic steatosis clinically or for research purposes but could not predict liver fat content.

Background Remote ischaemic preconditioning (rIPC) may improve cardiac/cerebrovascular outcomes of ischaemic events. Ischaemic damage caused by cardiovascular/cerebrovascular disease are primary causes of mortality in type 2 diabetes mellitus (T2DM). Due to the positive effects from a bout of rIPC within the vasculature, we explored if daily rIPC could improve endothelial and cerebrovascular function. The aim of this pilot study was to obtain estimates for the change in conduit artery and cerebrovascular function following a 7-day rIPC intervention. Methods Twenty-one patients with T2DM were randomly allocated to either 7-day daily upper-arm rIPC (4 × 5 min 220 mmHg, interspaced by 5-min reperfusion) or control. We examined peripheral endothelial function using flow mediated dilation (FMD) before and after ischemia-reperfusion injury (IRI, 20 min forearm ischaemic-20 min reperfusion) and cerebrovascular function, assessed by dynamic cerebral autoregulation (dCA) at three time points; pre, post and 8 days post intervention. Results For exploratory purposes, we performed statistical analysis on our primary comparison (pre-to-post) to provide an estimate of the change in the primary and secondary outcome variables. Using pre-intervention data as a covariate, the change from pre-post in FMD was 1.3% (95% CI: 0.69 to 3.80; P = 0.09) and 0.23 %cm/s %/mmHg mmHg/% (−0.12, 0.59; P = 0.18) in dCA normalised gain with rIPC versus control. Based upon this, a sample size of 20 and 50 for FMD and normalised gain, respectively, in each group would provide 90% power to detect statistically significant (P Conclusion We provide estimates of sample size for a randomised control trial exploring the impact of daily rIPC for 7 days on peripheral endothelial and cerebrovascular function. The directional changes outline from our pilot study suggest peripheral endothelial function can be enhanced by daily rIPC in patients with T2DM.

ObjectiveThis study examined the effects of a short-term reduction in physical activity, and subsequent resumption, on metabolic profiles, body composition and cardiovascular (endothelial) function.DesignTwenty-eight habitually active (≥10,000 steps/day) participants (18 female, 10 male; age 32 ± 11 years; BMI 24.3 ± 2.5 kg/m2) were assessed at baseline, following 14 days of step-reduction and 14 days after resuming habitual activity.MethodsPhysical activity was monitored throughout (SenseWear Armband). Endothelial function (flow mediated dilation; FMD), cardiorespiratory fitness (V.⁢O2 peak) and body composition including liver fat (dual-energy x-ray absorptiometry and magnetic resonance spectroscopy) were determined at each assessment. Statistical analysis was performed using one-way within subject’s ANOVA; data presented as mean (95% CI).ResultsParticipants decreased their step count from baseline by 10,111 steps/day (8949, 11,274; P < 0.001), increasing sedentary time by 103 min/day (29, 177; P < 0.001). Following 14 days of step-reduction, endothelial function was reduced by a 1.8% (0.4, 3.3; P = 0.01) decrease in FMD. Following resumption of habitual activity, FMD increased by 1.4%, comparable to the baseline level 0.4% (–1.8, 2.6; P = 1.00). Total body fat, waist circumference, liver fat, whole body insulin sensitivity and cardiorespiratory fitness were all adversely affected by 14 days step-reduction (P < 0.05) but returned to baseline levels following resumption of activity.ConclusionThis data shows for the first time that whilst a decline in endothelial function is observed following short-term physical inactivity, this is reversed on resumption of habitual activity. The findings highlight the need for public health interventions that focus on minimizing time spent in sedentary behavior.