A safety and pharmacodynamics study of temelimab, an antipathogenic human endogenous retrovirus type W envelope monoclonal antibody, in patients with type 1 diabetes.

AIM: To report the first study of temelimab, a monoclonal antibody neutralizing the pathogenic human endogenous retrovirus type W envelope, in patients with type 1 diabetes (T1D). MATERIALS AND METHODS: This double-blind, placebo-controlled, randomized clinical trial recruited adult patients with T1D within 4 years postdiagnosis and remaining C-peptide secretion. Sixty-four patients were randomized (2:1) to monthly temelimab 6 mg/kg or placebo during 24 weeks followed by a 24-week, open-label extension, during which all patients received temelimab. The primary objective was the safety and tolerability of temelimab. The secondary objective was to assess the pharmacodynamics response such as C-peptide levels, insulin use, HbA1c, hypoglycaemia and autoantibodies. RESULTS: Temelimab was well tolerated without any group difference in the frequency or severity of adverse events. Concerning exploratory endpoints, there was no difference in the levels of C-peptide, insulin use or HbA1c between treatment groups at weeks 24 and 48. The frequency of hypoglycaemia events was reduced with temelimab (P = 0.0004) at week 24 and the level of anti-insulin antibodies was lower with temelimab (P < 0.01); the other autoantibodies did not differ between groups. CONCLUSIONS: Temelimab appeared safe in patients with T1D. Pharmacodynamics signals (hypoglycaemia and anti-insulin antibodies) under temelimab were observed. Markers of ß-cell functions were not modified by treatment. These results need to be further explored in younger patients with T1D with earlier disease onset.

Diabetes care: addressing psychosocial well-being in young adults with a newly developed assessment tool.

BACKGROUND: Psychosocial assessment should be part of clinic visits for people with diabetes mellitus (DM). AIMS: To assess the usage and acceptance of a diabetes psychosocial assessment tool (DPAT) and to profile the clinical and psychosocial characteristics of young people with diabetes. METHODS: Over a 12-month period, young adults (18-25 years) attending diabetes clinic were offered DPAT. The tool embeds validated screening tools including the Problem Areas in Diabetes 20 (PAID-20) questionnaire, the Patient Health Questionnaire-4 (PHQ-4) and the World Health Organization Well-Being Index-5 (WHO-5). Baseline clinical data were collected and questions regarding social support, body image, eating concerns, hypoglycaemia and finances were included. RESULTS: Over the 12 month, the form was offered to 155 participants (64.6% of eligible attendees). The majority (96.1%) had type 1 DM with a mean duration of 10.5 (±5.3 SD) years. Average glycated haemoglobin (HbA1c) was 8.7% (±1.5 SD) (or 71.2 mmol/mol ±16.5 SD). Severe diabetes-related distress (PAID-20 ≥ 40) was found in 19.4%. Low WHO-5 scores (28-50 points) were seen in 14.8%. PHQ-4 identified 25.8% with anxiety and 16.1% with depression. Significant weight, shape and eating concerns were identified in 27.1, 26.6 and 28.4%, respectively. Serious hypoglycaemia concerns were raised by 4.5%. CONCLUSION: DPAT revealed a high prevalence of psychosocial stress among young adults with DM. The tool was easy to use and accepted by patients and may aid streamlining referrals to relevant members of a multidisciplinary team.

Psychosocial screening and management of young people aged 18-25 years with diabetes.

BACKGROUND: Routine psychosocial screening and management of people with diabetes is recommended. AIMS: To profile demographic, medical and psychosocial characteristics of young people with diabetes, and to develop a screening tool and care pathway for routine use. METHODS: Indices of diabetes control and recorded diabetes complications were complimented by psychosocial screening tools assessing psychological, diabetes specific and perceived stress (Kessler 10, Problem Area in Diabetes, Perceived Stress Scale), well-being (World Health Organization Well Being Index-5), disordered eating (Eating Disorder Risk Inventory-3 Risk Composite), compensatory behaviour questionnaire, social support (Multidimensional Scale of Perceived Social Support), resilience (Connor Davidson Resilience Scale - 2 item) and financial concerns. Service provision and demographic data were also collected. Diabetes and mental health clinicians then identified a subset of measures to use for routine screening along with care pathways. RESULTS: Psychosocial screening was well accepted. Participants (151) had suboptimal glycaemic control (glycated haemoglobin 8.0 interquartile range 1.8%/64 interquartile range 22 mmol/mol). Severe diabetes-related distress (Problem Area in Diabetes ≥40) was found in 19.4% and 26.0% reported difficulties managing healthcare costs. A mental health disorder was likely in 9.7%, whilst 23.4% had high Kessler 10 scores. Low World Health Organization Well Being Index-5 scores (≤13) were seen in 29.0%. Risk for an eating disorder (Eating Disorder Risk Inventory-3 Risk Composite) was 12.7%, whereas approximately 36.0% had disturbed eating behaviours. CONCLUSION: Psychosocial screening of young adults with diabetes identified complex needs. A brief psychosocial screening tool and associated care pathways were developed for routine use in a young adult tertiary referral diabetes clinic. The tool assesses constructs, such as diabetes distress, depression, anxiety, well-being, hypoglycaemia-unawareness, fear of hypoglycaemia, social support, weight, shape and eating concerns and financial concerns. This will provide a longitudinal data source for further research to inform clinical practice.

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.

Whole-body substrate metabolism is associated with disease severity in patients with non-alcoholic fatty liver disease.

OBJECTIVES: In non-alcoholic fatty liver disease (NAFLD), hepatic steatosis is intricately linked with a number of metabolic alterations. We studied substrate utilisation in NAFLD during basal, insulin-stimulated and exercise conditions, and correlated these outcomes with disease severity. METHODS: 20 patients with NAFLD (mean ± SD body mass index (BMI) 34.1 ± 6.7 kg/m(2)) and 15 healthy controls (BMI 23.4 ± 2.7 kg/m(2)) were assessed. Respiratory quotient (RQ), whole-body fat (Fat ox) and carbohydrate (CHO ox) oxidation rates were determined by indirect calorimetry in three conditions: basal (resting and fasted), insulin-stimulated (hyperinsulinaemic-euglycaemic clamp) and exercise (cycling at an intensity to elicit maximal Fat ox). Severity of disease and steatosis were determined by liver histology, hepatic Fat ox from plasma ß-hydroxybutyrate concentrations, aerobic fitness expressed as VO2 peak, and visceral adipose tissue (VAT) measured by computed tomography. RESULTS: Within the overweight/obese NAFLD cohort, basal RQ correlated positively with steatosis (r=0.57, p=0.01) and was higher (indicating smaller contribution of Fat ox to energy expenditure) in patients with NAFLD activity score (NAS) ≥ 5 vs <5 (p=0.008). Both results were independent of VAT, % body fat and BMI. Compared with the lean control group, patients with NAFLD had lower basal whole-body Fat ox (1.2 ± 0.3 vs 1.5 ± 0.4 mg/kg FFM/min, p=0.024) and lower basal hepatic Fat ox (ie, ß-hydroxybutyrate, p=0.004). During exercise, they achieved lower maximal Fat ox (2.5 ± 1.4 vs. 5.8 ± 3.7 mg/kg FFM/min, p=0.002) and lower VO2 peak (p<0.001) than controls. Fat ox during exercise was not associated with disease severity (p=0.79). CONCLUSIONS: Overweight/obese patients with NAFLD had reduced hepatic Fat ox and reduced whole-body Fat ox under basal and exercise conditions. There was an inverse relationship between ability to oxidise fat in basal conditions and histological features of NAFLD including severity of steatosis and NAS.

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 ß = 0.446; p < 0.001), waist circumference (standardised ß = -0.216; p < 0.05), BMI (standardised ß = -0.212; p < 0.05), and age (standardised ß = -0.298; p < 0.001) were independently associated with insulin sensitivity. Serum 25(OH)D (standardised ß = 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.

Health outcomes of patients with type 2 diabetes following bariatric surgery: Results from a publicly funded initiative.

OBJECTIVE: Bariatric surgery is an effective treatment for type 2 diabetes and morbid obesity. This paper analyses the clinical and patient-reported outcomes of patients treated through the Bariatric Surgery Initiative, a health system collaboration providing bariatric surgery as a state-wide public service in Queensland, Australia. RESEARCH DESIGN AND METHODS: A longitudinal prospective cohort study was undertaken. Eligible patients had type 2 diabetes and morbid obesity (BMI ≥ 35 kg/m2). Following referral by specialist outpatient clinics, 212 patients underwent Roux-en-Y gastric bypass or sleeve gastrectomy. Outcomes were tracked for a follow-up of 12-months and included body weight, BMI, HbA1c, comorbidities, health-related quality of life, eating behaviour, and patient satisfaction. RESULTS: Following surgery, patients' average body weight decreased by 23.6%. Average HbA1c improved by 24.4% and 48.8% of patients were able to discontinue diabetes-related treatment. The incidence of hypertension, non-alcoholic steatohepatitis, and renal impairment decreased by 37.1%, 66.4%, and 62.3%, respectively. Patients' emotional eating scores, uncontrolled eating and cognitive restraint improved by 32.5%, 20.7%, and 6.9%, respectively. Quality of life increased by 18.8% and patients' overall satisfaction with the treatment remained above 97.5% throughout the recovery period. CONCLUSIONS: This study confirmed previous work demonstrating the efficacy of publicly funded bariatric surgery in treating obesity, type 2 diabetes and related comorbidities, and improving patients' quality of life and eating behaviour. Despite the short follow-up period, the results bode well for future weight maintenance in this cohort.

Advanced glycation end products as predictors of renal function in youth with type 1 diabetes.

To examine if skin autofluorescence (sAF) differed in early adulthood between individuals with type 1 diabetes and age-matched controls and to ascertain if sAF aligned with risk for kidney disease. Young adults with type 1 diabetes (N = 100; 20.0 ± 2.8 years; M:F 54:46; FBG-11.6 ± 4.9 mmol/mol; diabetes duration 10.7 ± 5.2 years; BMI 24.5(5.3) kg/m2) and healthy controls (N = 299; 20.3 ± 1.8 years; M:F-83:116; FBG 5.2 ± 0.8 mmol/L; BMI 22.5(3.3) kg/m2) were recruited. Skin autofluorescence (sAF) and circulating AGEs were measured. In a subset of both groups, kidney function was estimated by GFRCKD-EPI CysC and uACR, and DKD risk defined by uACR tertiles. Youth with type 1 diabetes had higher sAF and BMI, and were taller than controls. For sAF, 13.6% of variance was explained by diabetes duration, height and BMI (Pmodel = 1.5 × 10-12). In the sub-set examining kidney function, eGFR and sAF were higher in type 1 diabetes versus controls. eGFR and sAF predicted 24.5% of variance in DKD risk (Pmodel = 2.2 × 10-9), which increased with diabetes duration (51%; Pmodel < 2.2 × 10-16) and random blood glucose concentrations (56%; Pmodel < 2.2 × 10-16). HbA1C and circulating fructosamine albumin were higher in individuals with type 1 diabetes at high versus low DKD risk. eGFR was independently associated with DKD risk in all models. Higher eGFR and longer diabetes duration are associated with DKD risk in youth with type 1 diabetes. sAF, circulating AGEs, and urinary AGEs were not independent predictors of DKD risk. Changes in eGFR should be monitored early, in addition to uACR, for determining DKD risk in type 1 diabetes.

T-Cell Expression and Release of Kidney Injury Molecule-1 in Response to Glucose Variations Initiates Kidney Injury in Early Diabetes.

Half of the mortality in diabetes is seen in individuals <50 years of age and commonly predicted by the early onset of diabetic kidney disease (DKD). In type 1 diabetes, increased urinary albumin-to-creatinine ratio (uACR) during adolescence defines this risk, but the pathological factors responsible remain unknown. We postulated that early in diabetes, glucose variations contribute to kidney injury molecule-1 (KIM-1) release from circulating T cells, elevating uACR and DKD risk. DKD risk was assigned in youth with type 1 diabetes (n = 100; 20.0 ± 2.8 years; males/females, 54:46; HbA1c 66.1 [12.3] mmol/mol; diabetes duration 10.7 ± 5.2 years; and BMI 24.5 [5.3] kg/m2) and 10-year historical uACR, HbA1c, and random blood glucose concentrations collected retrospectively. Glucose fluctuations in the absence of diabetes were also compared with streptozotocin diabetes in apolipoprotein E -/- mice. Kidney biopsies were used to examine infiltration of KIM-1-expressing T cells in DKD and compared with other chronic kidney disease. Individuals at high risk for DKD had persistent elevations in uACR defined by area under the curve (AUC; uACRAUC0-10yrs, 29.7 ± 8.8 vs. 4.5 ± 0.5; P < 0.01 vs. low risk) and early kidney dysfunction, including ∼8.3 mL/min/1.73 m2 higher estimated glomerular filtration rates (modified Schwartz equation; Padj < 0.031 vs. low risk) and plasma KIM-1 concentrations (∼15% higher vs. low risk; P < 0.034). High-risk individuals had greater glycemic variability and increased peripheral blood T-cell KIM-1 expression, particularly on CD8+ T cells. These findings were confirmed in a murine model of glycemic variability both in the presence and absence of diabetes. KIM-1+ T cells were also infiltrating kidney biopsies from individuals with DKD. Healthy primary human proximal tubule epithelial cells exposed to plasma from high-risk youth with diabetes showed elevated collagen IV and sodium-glucose cotransporter 2 expression, alleviated with KIM-1 blockade. Taken together, these studies suggest that glycemic variations confer risk for DKD in diabetes via increased CD8+ T-cell production of KIM-1.

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.

BACKGROUND: By 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/DESIGN: Using 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. DISCUSSION: This 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 REGISTRATION: ACTRN12608000203358.

Altered clot kinetics in patients with non-alcoholic fatty liver disease.

BACKGROUND: Emerging evidence has linked the presence of non-alcoholic fatty liver disease (NAFLD) with an increased risk for cardiovascular events. We hypothesised that altered clot kinetics and platelet function may contribute to this increased risk. This study compared whole blood clotting kinetics in patients with 1) non-cirrhotic NAFLD (n = 28) and 2) healthy control subjects (n = 22). METHODS: Clotting kinetics were assessed in whole blood using thromboelastography (TEG) and assessed for correlations with cardiovascular risk factors. RESULTS: Clot kinetics in patients with NAFLD showed significantly stronger clot development (maximum amplitude (MA); 58.3 +/- 6.3 mm vs. 52.0 +/- 10.1 mm, p = 0.01) and reduced clot lysis in the presence of thrombin (35 +/- 30% vs. 51 +/- 26% clot lysis 30 minutes after MA, p = 0.03) compared to control subjects. Clot strength was independently positively associated with body mass index in NAFLD, but not in control subjects. There was a greater platelet contribution to clot strength in patients with NAFLD compared to controls despite similar platelet counts. There was no association between clot kinetics and features of the metabolic syndrome or presence of type 2 diabetes. CONCLUSION: Patients with NAFLD have disturbances in ex-vivo clot kinetics including increased clot strength and clots that are more resistant to thrombin-stimulated lysis.

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.

Effect of weight loss due to lifestyle intervention on subclinical cardiovascular dysfunction in obesity (body mass index >30 kg/m2).

Subclinical myocardial and vascular dysfunctions occur in subjects with obesity. We investigated whether these changes were reversible with weight loss due to lifestyle intervention. Quantitative assessment of myocardial and vascular functions was performed at baseline and after a minimum of 8 weeks of a lifestyle intervention program in 106 subjects with significant risk factors but no history of cardiovascular disease and normal ejection fractions. Myocardial function was assessed using strain rate, strain, regional myocardial systolic velocity, and diastolic velocity (e(m)). Myocardial reflectivity was assessed by calibrated integrated backscatter. Vascular function was assessed using brachial arterial reactivity and arterial compliance. Exercise capacity was measured by peak oxygen consumption per unit time (VO(2)). Weight loss (-4.5 +/- 2.0%) was achieved by 48 subjects, and 58 maintained or increased weight (+1 +/- 1.5%, p <0.001). Compared with the stable weight group, the weight loss group showed significant improvement in brachial arterial reactivity (8.6 +/- 4.9% vs 6.7 +/- 4.9%, p <0.05), e(m) (6.4 +/- 1.9 vs 5.5 +/- 1.9 cm/s, p <0.01), and reflectivity (calibrated integrated backscatter, 18.3 +/- 4.9 vs 16.2 +/- 5.2 dB, p <0.01). The magnitude of weight change correlated with changes in e(m) (r = 0.36) and calibrated integrated backscatter (r = 0.33). The change in e(m) correlated with peak VO(2) (r = 0.38, p <0.001) and was an independent predictor for peak VO(2) even after adjustment for age and body mass index in a multivariate model (R(2) = 0.45, p <0.001). Weight loss was not associated with a significant change in systolic parameters (regional myocardial systolic velocity, global strain, and strain rate) or arterial compliance.

Independent effects of diet and exercise training on fat oxidation in non-alcoholic fatty liver disease.

AIM: To investigate the independent effects of 6-mo of dietary energy restriction or exercise training on whole-body and hepatic fat oxidation of patients with non-alcoholic fatty liver disease (NAFLD). METHODS: Participants were randomised into either circuit exercise training (EX; n = 13; 3 h/wk without changes in dietary habits), or dietary energy restriction (ER) without changes in structured physical activity (ER; n = 8). Respiratory quotient (RQ) and whole-body fat oxidation rates (Fatox) were determined by indirect calorimetry under basal, insulin-stimulated and exercise conditions. Severity of disease and steatosis was determined by liver histology; hepatic Fatox was estimated from plasma ß-hydroxybutyrate concentrations; cardiorespiratory fitness was expressed as VO2peak. Complete-case analysis was performed (EX: n = 10; ER: n = 6). RESULTS: Hepatic steatosis and NAFLD activity score decreased with ER but not with EX. ß-hydroxybutyrate concentrations increased significantly in response to ER (0.08 ± 0.02 mmol/L vs 0.12 ± 0.04 mmol/L, P = 0.03) but remained unchanged in response to EX (0.10 ± 0.03 mmol/L vs 0.11 ± 0.07 mmol/L, P = 0.39). Basal RQ decreased (P = 0.05) in response to EX, while this change was not significant after ER (P = 0.38). VO2peak (P < 0.001) and maximal Fatox during aerobic exercise (P = 0.03) improved with EX but not with ER (P > 0.05). The increase in ß-hydroxybutyrate concentrations was correlated with the reduction in hepatic steatosis (r = -0.56, P = 0.04). CONCLUSION: ER and EX lead to specific benefits on fat metabolism of patients with NAFLD. Increased hepatic Fatox in response to ER could be one mechanism through which the ER group achieved reduction in steatosis.

Alterations of left ventricular myocardial characteristics associated with obesity.

BACKGROUND: Obesity is associated with heart failure, but an effect of weight, independent of comorbidities, on cardiac structure and function is not well established. We sought whether body mass index (BMI) and insulin levels were associated with subclinical myocardial disturbances. METHODS AND RESULTS: Transthoracic echocardiography, myocardial Doppler-derived systolic (sm) and early diastolic velocity (em), strain and strain rate imaging and tissue characterization with cyclic variation (CVIB), and calibrated integrated backscatter (cIB) were obtained in 109 overweight or obese subjects and 33 referents (BMI <25 kg/m2). BMI correlated with left ventricular (LV) mass and wall thickness (P<0.001). Severely obese subjects (BMI >35) had reduced LV systolic and diastolic function and increased myocardial reflectivity compared with referents, evidenced by lower average long-axis strain, sm, cIB, lower CVIB, and reduced em, whereas LV ejection fraction remained normal. Differences in regional or global strain, sm, and em were identified between the severely obese (BMI >35) and the referent patients (P<0.001). Similar but lesser degrees of reduced function by sm, em, and basal septal strain and increased reflectivity by cIB were present in overweight (BMI, 25 to 29.9) and mildly obese (BMI, 30 to 35) groups (P<0.05). Although tissue Doppler measures were not associated with duration of obesity, they did correlate with fasting insulin levels and reduced exercise capacity. BMI was independently related to average LV strain (beta=0.40, P=0.02), sm (beta=-0.36, P=0.002), and em (beta=-0.41, P<0.001). CONCLUSIONS: Overweight subjects without overt heart disease have subclinical changes of LV structure and function even after adjustment for mean arterial pressure, age, gender, and LV mass.

Myocardial and vascular dysfunction and exercise capacity in the metabolic syndrome.

The metabolic syndrome (MS) is associated with cardiovascular risk exceeding that expected from atherosclerotic risk factors, but the mechanism of this association is unclear. We sought to determine the effects of the MS on myocardial and vascular function and cardiorespiratory fitness in 393 subjects with significant risk factors but no cardiovascular disease and negative stress echocardiographic findings. Myocardial function was assessed by global strain rate, strain, and regional systolic velocity (s(m)) and diastolic velocity (e(m)) using tissue Doppler imaging. Arterial compliance was assessed using the pulse pressure method, involving simultaneous radial applanation tonometry and echocardiographic measurement of stroke volume. Exercise capacity was measured by expired gas analysis. Significant and incremental variations in left ventricular systolic (s(m), global strain, and strain rate) and diastolic (e(m)) function were found according to the number of components of MS (p <0.001). MS contributed to reduced systolic and diastolic function even in those without left ventricular hypertrophy (p <0.01). A similar dose-response association was present between the number of components of the MS and exercise capacity (p <0.001) and arterial compliance. The global strain rate and e(m) were independent predictors of exercise capacity. In conclusion, subclinical left ventricular dysfunction corresponded to the degree of metabolic burden, and these myocardial changes were associated with reduced cardiorespiratory fitness. Subjects with MS who also have subclinical myocardial abnormalities and reduced cardiorespiratory fitness may have a higher risk of cardiovascular disease events and heart failure.

Aging per se does not influence glucose homeostasis: in vivo and in vitro evidence.

OBJECTIVE: To assess the effect of age on glucose metabolism by examining 1) glucose metabolism in young and middle-aged subjects when total or regional adiposity is taken into account and 2) in vitro glucose transport in adipose tissue explants from young and middle-aged women paired for total and abdominal adiposity. RESEARCH DESIGN AND METHODS: Study 1: body composition, subcutaneous abdominal and visceral adipose tissue areas, and fasting and oral glucose-stimulated glucose and insulin were measured in 84 young and 81 middle-aged men and in 110 young and 91 middle-aged women. Study 2: glucose uptake in subcutaneous abdominal and visceral adipose tissue explants were measured in eight young and eight middle-aged women. RESULTS: Study 1: young and middle-aged men showed similar subcutaneous abdominal tissue area, whereas fat mass and visceral adipose tissue were greater in middle-aged than in young men (P < 0.01). Fat mass and subcutaneous and visceral adipose tissue areas were greater in middle-aged as compared with young women (P < 0.01). Fasting plasma glucose and the glucose response to an oral glucose tolerance test were significantly higher in middle-aged than in young men and women (P < 0.001). Statistical control for visceral adipose tissue area eliminated the difference seen in glucose response in men and women. Study 2: glucose transport in subcutaneous and omental adipose tissue did not differ between young and middle-aged women. CONCLUSIONS: 1) Visceral obesity, more than age per se, correlates with glucose intolerance in middle-aged subjects; 2) aging does not influence in vitro adipose tissue glucose uptake.

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 participant's 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.

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 (ß = 0.47, p < 0.0001), spironolactone therapy (ß = -0.38, p < 0.0001), and change in PICP level (ß = -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 (ß = 0.47, p < 0.0001), spironolactone therapy (ß = -0.21, p < 0.03), change in PICP level (ß = -0.23, p < 0.02), and age (ß = 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.