Dynapenic obesity and the risk of incident Type 2 diabetes: the English Longitudinal Study of Ageing

Aim Obesity is a well‐established risk factor for developing Type 2 diabetes. Evidence suggests that sarcopenia, the age‐related decline in muscle mass and strength, may exacerbate diabetes risk in obese individuals. The aim of this study was to determine the combined effect of obesity and low muscle strength, dynapenia, on the risk of incident Type 2 diabetes in older adults. Methods Participants were 5953 (1670 obese) men and women from the English Longitudinal Study of Ageing without known Type 2 diabetes at baseline and for whom handgrip strength, biochemical and other clinical data were collected. A diagnosis of Type 2 diabetes was recorded from self‐reported physician diagnosis over 6 years. Results For each unit increase in grip strength, there was a reduction in diabetes risk (age‐, sex‐ and BMI adjusted HR; 0.98; 95% CI 0.96–0.99). The risk of Type 2 diabetes was elevated in all obese participants, but was greatest in those with low handgrip strength (HR = 4.93, 95% CI 2.85, 8.53) compared with non‐obese individuals with high handgrip strength. Eleven per cent of the sample met the threshold for weakness (handgrip strength: men < 26 kg; women < 16 kg) that was associated with elevated Type 2 diabetes risk in obese (HR = 3.57, 95% CI 2.04, 6.24) but not in non‐obese (HR = 0.86, 95% CI, 0.44, 1.68) compared with normal/non‐obese participants. Conclusion Dynapenic obesity, determined by high BMI and low handgrip strength, is associated with increased risk of incident Type 2 diabetes in older people

EffectS of non-nutritive sWeetened beverages on appetITe during aCtive weigHt loss (SWITCH): Protocol for a randomized, controlled trial assessing the effects of non-nutritive sweetened beverages compared to water during a 12-week weight loss period and a follow up weight maintenance period

Background Acute and medium-term intervention studies suggest that non-nutritive sweeteners (NNS) are beneficial for weight loss, however there is limited human data on the long-term effects of consuming NNS on weight loss, maintenance, and appetite. Further research is therefore required to elucidate the prolonged impact of NNS consumption on these outcome measures. Methods/design A randomized parallel groups design will be used to assess whether regular NNS beverage intake is equivalent to a water control in promoting weight loss over 12-weeks (weekly weight loss sessions; Phase I), then supporting weight maintenance over 40-weeks (monthly sessions; Phase II) and subsequently independent weight maintenance over 52-weeks (Phase III) in 432 participants. A subset of these participants (n = 116) will complete laboratory-based appetite probe days (15 sessions; 3 sessions each at baseline, at the start of phase I and the end of each phase). A separate subset (n = 50) will complete body composition scans (DXA) at baseline and at the end of each phase. All participants will regularly be weighed and will complete questionnaires and cognitive tasks to assess changes in body weight and appetitive behaviours. Measures of physical activity and biochemical markers will also be taken. Discussion The trial will assess the efficacy of NNS beverages compared to water during a behavioural weight loss and maintenance programme. We aim to understand whether the impact of NNS on weight, dietary adherence and well-being are beneficial or transient and effects on prolonged successful weight loss and weight maintenance through sustained changes in appetite and eating behaviour. Trial registration: Clinical Trials: NCT02591134; registered: 23.10.201

Compensatory changes in energy balance during dapagliflozin treatment in type 2 diabetes mellitus: a randomised double-blind, placebo-controlled, cross-over trial (ENERGIZE)-study protocol.

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 ((1)H-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

Metabolically healthy and unhealthy obesity: differential effects on myocardial function according to metabolic syndrome, rather than obesity.

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

Exercise-induced improvements in liver fat and endothelial function are not sustained 12 months following cessation of exercise supervision in non-alcoholic fatty liver disease (NAFLD).

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

11C-metomidate PET-CT scanning can identify aldosterone-producing adenomas after unsuccessful lateralisation with CT/MRI and adrenal venous sampling.

Primary hyperaldosteronism, characterised by hypertension and hypokalaemia, is a syndrome caused by aldosterone excess most commonly from either a unilateral aldosterone-producing adenoma or bilateral adrenal hyperplasia. Subtype classification can be challenging with cross-sectional imaging and even with interventional radiological techniques such as adrenal venous sampling. Imaging with 11C-metomidate positron emission tomography-computed tomography (PET-CT) is an emerging tool that facilitates functional characterisation and potentially successful surgical intervention of aldosterone-producing adenomas. This technique has highlighted that, although unilateral adenomas and bilateral hyperplasia represent opposite ends of the disease spectrum, a relatively common intermediate phenotype exists of unilateral/bilateral multinodular disease

Improved Glycaemia correlates with liver fat reduction in obese, type 2 diabetes, patients given glucagon-like peptide-1 (GLP-1) receptor agonists

Glucagon-like peptide-1 receptor agonists (GLP-1 RA) are effective for obese patients with type 2 diabetes mellitus (T2DM) because they concomitantly target obesity and dysglycaemia. Considering the high prevalence of non-alcoholic fatty liver disease (NAFLD) in patients with T2DM, we determined the impact of 6 months' GLP-1 RA therapy on intrahepatic lipid (IHL) in obese, T2DM patients with hepatic steatosis, and evaluated the inter-relationship between changes in IHL with those in glycosylated haemoglobin (HbA(1)c), body weight, and volume of abdominal visceral and subcutaneous adipose tissue (VAT and SAT). We prospectively studied 25 (12 male) patients, age 50±10 years, BMI 38.4±5.6 kg/m(2) (mean ± SD) with baseline IHL of 28.2% (16.5 to 43.1%) and HbA(1)c of 9.6% (7.9 to 10.7%) (median and interquartile range). Patients treated with metformin and sulphonylureas/DPP-IV inhibitors were given 6 months GLP-1 RA (exenatide, n = 19; liraglutide, n = 6). IHL was quantified by liver proton magnetic resonance spectroscopy ((1)H MRS) and VAT and SAT by whole body magnetic resonance imaging (MRI). Treatment was associated with mean weight loss of 5.0 kg (95% CI 3.5,6.5 kg), mean HbA(1c) reduction of 1·6% (17 mmol/mol) (0·8,2·4%) and a 42% relative reduction in IHL (-59.3, -16.5%). The relative reduction in IHL correlated with that in HbA(1)c (ρ = 0.49; p = 0.01) but was not significantly correlated with that in total body weight, VAT or SAT. The greatest IHL reduction occurred in individuals with highest pre-treatment levels. Mechanistic studies are needed to determine potential direct effects of GLP-1 RA on human liver lipid metabolism

Peptidergic control in a fruit crop pest: The spotted-wing drosophila, Drosophila suzukii

Neuropeptides play an important role in the regulation of feeding in insects and offer potential targets for the development of new chemicals to control insect pests. A pest that has attracted much recent attention is the highly invasive Drosophila suzukii, a polyphagous pest that can cause serious economic damage to soft fruits. Previously we showed by mass spectrometry the presence of the neuropeptide myosuppressin (TDVDHVFLRFamide) in the nerve bundle suggesting that this peptide is involved in regulating the function of the crop, which in adult dipteran insects has important roles in the processing of food, the storage of carbohydrates and the movement of food into the midgut for digestion. In the present study antibodies that recognise the C-terminal RFamide epitope of myosuppressin stain axons in the crop nerve bundle and reveal peptidergic fibres covering the surface of the crop. We also show using an in vitro bioassay that the neuropeptide is a potent inhibitor (EC50 of 2.3 nM) of crop contractions and that this inhibition is mimicked by the non-peptide myosuppressin agonist, benzethonium chloride (Bztc). Myosuppressin also inhibited the peristaltic contractions of the adult midgut, but was a much weaker agonist (EC50 = 5.7 μM). The oral administration of Bztc (5 mM) in a sucrose diet to adult female D. suzukii over 4 hours resulted in less feeding and longer exposure to dietary Bztc led to early mortality. We therefore suggest that myosuppressin and its cognate receptors are potential targets for disrupting feeding behaviour of adult D. suzukii

Physical Activity and Sedentary Time: Association with Metabolic Health and Liver Fat.

INTRODUCTION/PURPOSE: To investigate whether a) lower levels of daily physical activity (PA) and greater sedentary time accounted for contrasting metabolic phenotypes (higher liver fat/presence of metabolic syndrome [MetS+] vs lower liver fat/absence of metabolic syndrome [MetS-]) in individuals of similar BMI and b) the association of sedentary time on metabolic health and liver fat. METHODS: Ninety-eight habitually active participants (53 female, 45 male; age 39±13 years; BMI 26.9±5.1 kg/m), underwent assessments of PA (SenseWear armband; wear time ~98%), cardio-respiratory fitness (V[Combining Dot Above]O2 peak), body composition (MRI and MRS) and multi-organ insulin sensitivity (OGTT). We undertook a) cross-sectional analysis comparing four groups: non-obese or obese, with and without metabolic syndrome (MetS+ vs MetS-) and b) univariate and multivariate regression for sedentary time and other levels of PA in relation to liver fat. RESULTS: Light, moderate and vigorous PA did not account for differences in metabolic health between individuals, whether non-obese or obese, although MetS+ individuals were more sedentary, with a higher number, and prolonged bouts (~1-2 hours). Overall, sedentary time, average daily METS and V[Combining Dot Above]O2 peak were each independently associated with liver fat percentage. Each additional hour of daily sedentary time was associated with a 1.15% (95% CI, 1.14-1.50%) higher liver fat content. CONCLUSIONS: Greater sedentary time, independent of other levels of PA, is associated with being metabolically unhealthy; even in habitually active people, lesser sedentary time, and higher cardio-respiratory fitness and average daily METS is associated with lower liver fat.This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

A free-living, walking-based, exercise programme, with exercise timed relative to breakfast, to improve metabolic health in people living with overweight and obesity: A feasibility study

Optimising the timing of food intake relative to exercise may maximise the effectiveness of free-living exercise programmes on improvements in glycaemic control and cardio-metabolic health. This study aimed to assess the feasibility of a free-living, walking-based exercise programme and determine whether undertaking each exercise session before or after breakfast would most benefit longer-term metabolic health. Thirty-four people living with obesity (43±12 y, BMI 35.1±5.1 kg.m-2) undertook a 12-week walking-based programme, consisting of two continuous (30-60 min at 50% HRmax) and two interval exercise sessions per week (30-60 min, alternating 3 min at 85% HRmax and 3 min at 50% HRmax). Participants were allocated to exercise before (FASTED) or after (FED) breakfast (n = 17 per group). Feasibility (acceptability, adherence and compliance) to the exercise intervention were assessed, as well as changes in anthropometric variables, 24-hour continuous glucose monitoring, serum biochemistry including HbA1c, lipid profile and liver transaminases. Exercise adherence (FASTED: 93±4%, FED: 95±5%) and compliance (FASTED: 85±10%, FED: 88±10%) was high in both groups, and participants described exercise monitoring, programme structure and support as facilitators to this. Body mass, BMI, waist-to-hip ratio and HbA1c decreased similarly between groups (all P<0.01). However, serum ALT concentrations decreased after FASTED (-16± -14%; P = 0.001), but not FED training (-2 ± -4%; P = 0.720). We demonstrate that a free-living walking-based exercise programme, with exercise timed relative to breakfast can achieve high adherence and compliance and improve some anthropometric variables and HbA1c. Whether FASTED exercise can elicit greater improvements in liver health requires further investigation