Secretory products from epicardial adipose tissue from patients with type 2 diabetes impair mitochondrial ß-oxidation in cardiomyocytes via activation of the cardiac renin-angiotensin system and induction of miR-208a.

Secretory products from epicardial adipose tissue (EAT) from patients with type 2 diabetes (T2D) impair cardiomyocyte function. These changes associate with alterations in miRNA expression, including the induction of miR-208a. Recent studies suggest that activation of the cardiac-specific renin-angiotensin system (RAS) may affect cardiac energy metabolism via induction of miR-208a. This study investigated whether cardiomyocyte dysfunction induced by conditioned media (CM) from EAT-T2D involves activation of the RAS/miR-208a pathway. Therefore, primary adult rat cardiomyocytes were incubated with CM generated from EAT biopsies from patients with T2D and without T2D (ND). Exposing cardiomyocytes to CM-EAT-T2D reduced sarcomere shortening and increased miR-208a expression versus cells exposed to CM-EAT-ND or control medium. The angiotensin II receptor type 1 (AGTR1) antagonist losartan reversed these effects. Accordingly, incubation with angiotensin II (Ang II) reduced sarcomere shortening, and lowered palmitate-induced mitochondrial respiration and carnitine palmitoyltransferase 1c (CPT1c) expression in cardiomyocytes. Locked-nucleic-acid-mediated inhibition of miR-208a function reversed the detrimental effects induced by Ang II. Interestingly, Ang II levels in CM-EAT-T2D were increased by 2.6-fold after culture with cardiomyocytes. The paracrine activation of the cardiac-specific RAS by CM-EAT-T2D was corroborated by increases in the expression of AGTR1 and renin, as well as a reduction in angiotensin-converting enzyme 2 levels. Collectively, these data show that secretory products from EAT-T2D impair cardiomyocyte contractile function and mitochondrial ß-oxidation via activation of the cardiac-specific RAS system and induction of miR-208a, and suggest that alterations in the secretory profile of EAT may contribute to the development of diabetes-related heart disease.

Secretory products from epicardial adipose tissue of patients with type 2 diabetes mellitus induce cardiomyocyte dysfunction.

BACKGROUND: Secreted factors from epicardial adipose tissue (EAT) have been implicated in the development of cardiomyocyte dysfunction. This study aimed to assess whether alterations in the secretory profile of EAT in patients with type 2 diabetes mellitus (DM2) affect contractile function and insulin action in cardiomyocytes. METHODS AND RESULTS: Contractile function and insulin action were analyzed in primary adult rat cardiomyocytes incubated with conditioned media (CM) generated from explants of EAT biopsies obtained from patients without and with DM2. CM from subcutaneous and pericardial adipose tissue biopsies from the same patients served as the control. Cardiomyocytes treated with CM (EAT) from DM2 patients showed reductions in sarcomere shortening, cytosolic Ca(2+) fluxes, expression of sarcoplasmic endoplasmic reticulum ATPase 2a, and decreased insulin-mediated Akt-Ser473-phosphorylation as compared with CM from the other groups. Profiling of the CM showed that activin A, angiopoietin-2, and CD14 selectively accumulated in CM-EAT-DM2 versus CM-EAT in patients without DM2 and CM from the other fat depots. Accordingly, EAT biopsies from DM2 patients were characterized by clusters of CD14-positive monocytes. Furthermore, SMAD2-phosphorylation, a downstream target of activin A signaling, was elevated in cardiomyocytes treated with CM (EAT) from DM2 patients, and the detrimental effects of CM (EAT) from DM2 patients were partially abolished in cardiomyocytes pretreated with a neutralizing antibody against activin A. Finally, both recombinant activin A and angiopoietin-2 reduced cardiomyocyte contractile function, but only activin A reduced the expression of sarcoplasmic endoplasmic reticulum ATPase 2a. CONCLUSIONS: Collectively, our data implicate DM2-related alterations in the secretory profile of EAT in the pathogenesis of diabetes mellitus-related heart disease.

Activin A is associated with impaired myocardial glucose metabolism and left ventricular remodeling in patients with uncomplicated type 2 diabetes.

BACKGROUND: Activin A released from epicardial adipose tissue has been linked to contractile dysfunction and insulin resistance in cardiomyocytes. This study investigated the role of activin A in clinical diabetic cardiomyopathy by assessing whether circulating activin A levels associate with cardiometabolic parameters in men with uncomplicated type 2 diabetes (T2D), and the effects of treatment with pioglitazone versus metformin on these associations. METHODS: Seventy-eight men with uncomplicated T2D and fourteen healthy men with comparable age were included, in this randomized, double-blind, active comparator intervention study. All T2D men were on glimipiride monotherapy, and randomized to a 24-week intervention with either pioglitazone or metformin. Cardiac dimensions and -function were measured using magnetic resonance imaging, whilst myocardial glucose metabolism (MMRglu) was determined using [18F]-2-fluoro-2-deoxy-D-glucose positron emission tomography during a hyperinsulinemic-euglycemic clamp. RESULTS: Circulating activin A levels were comparable in T2D men and controls. Activin A levels were independently inversely associated with MMRglu, and positively with left ventricular mass/volume (LVMV)-ratio in T2D men. Intervention with metformin decreased activin A levels, whereas pioglitazone did not alter activin A levels. The changes in plasma activin A levels were not correlated with the changes in MMRglu following either pioglitazone or metformin treatment. A borderline significant correlation (p = 0.051) of changes in plasma activin A levels and changes in LVMV-ratio was observed after pioglitazone treatment. CONCLUSIONS: Circulating activin A levels are associated with impaired myocardial glucose metabolism and high LVMV-ratio in patients with uncomplicated T2D, reflecting a potential detrimental role in early human diabetic cardiomyopathy. TRIAL REGISTRATION NUMBER: Current Controlled Trials SRCTN53177482.

Opposite effects of insulin-like molecules and leptin in coronary heart disease of type 2 diabetes Preliminary data.

INTRODUCTION: Leptin and insulin have been reported to be risk factors for coronary heart disease (CHD) in the general population, but their role in type 2 diabetes still remains unclear. MATERIALS AND METHODS: The role of leptin and insulin upon CHD in type 2 diabetes was assessed in 154 patients, aged 31-77 years, who were treated with oral anti-diabetic agents. Multivariate logistic regression analyses were used with CHD (an established history of CHD or an abnormal treadmill test) as dependent, and leptin, insulin and potential confounders as independent variables. RESULTS: Endogenous insulin was significantly associated with CHD in a model controlling for gender, age, duration of diabetes, body mass index, smoking and leptin (Odds ratio 1.45 per decile, 95% confidence interval 1.11-1.90). Improving control for confounding by replacing body mass index by subcutaneous fat (CT-measured at the L4-L5 level) and height in this model, resulted in a significant negative association between leptin and CHD (OR 0.60, 95% CI 0.37-0.96). DISCUSSION: Leptin might have a beneficial effect on CHD in type 2 diabetes, probably by counteracting the effect of insulin-like molecules or insulin resistance. The effect was elucidated only after careful control for confounding by subcutaneous fat, the main source of leptin production.

Resting metabolic rate is an important predictor of serum adiponectin concentrations: potential implications for obesity-related disorders.

BACKGROUND: Little is known about the regulation of adiponectin. Animal studies suggest local regulation by adipocytokines or alterations in energy expenditure, and studies in humans suggest regulation by alcohol intake and ethnicity. OBJECTIVE: To identify regulators of adiponectin in humans, we measured resting metabolic rate (RMR), serum adiponectin, glucose, insulin, triacylglycerol, alcohol intake, and anthropometric indexes in 457 white patients with overweight or obesity. DESIGN: A cross-sectional design was used, and multivariate regression analysis was performed with adiponectin as the dependent variable and potential predictors as independent variables. RESULTS: Simple linear analyses showed significant associations between adiponectin and sex, with a standardized coefficient of -0.38 (women compared with men) and an explanation of variation of the model (R(2)) of 14%; age (0.21; 4%); RMR (-0.52; 27%); fat-free mass (-0.40; 16%); fat mass (-0.16; 2%); visceral fat (-0.24; 6%; computed tomography at L4-L5); fasting triacylglycerol (-0.28; 8%); and insulin resistance (-0.38; 14%; homeostasis model assessment). Adiponectin and alcohol were not associated (-0.04; 0%). Multivariate analyses, which allowed adjustment for confounding, showed that RMR is the most important predictor of adiponectin (-0.31; 29%), followed successively by insulin resistance (-0.16; 31%; model containing RMR and insulin resistance), fat mass (0.20; 34%), age (0.34; 35%), visceral fat (-0.34; 40%), and fasting triacylglycerol (-0.12, 41%). CONCLUSIONS: Low resting metabolism (RMR) is associated with high serum adiponectin. We speculate that subjects with low RMR, who are theoretically at greater risk of obesity-related disorders, are especially protected by adiponectin.

Inverse relationship between plasminogen activator inhibitor-I activity and adiponectin in overweight and obese women. Interrelationship with visceral adipose tissue, insulin resistance, HDL-chol and inflammation.

Adipose tissue is an active endocrine organ secreting different adipokines such as plasminogen activator inhibitor-1 (PAI-1) and adiponectin, among many others. In this study, we investigated the association between PAI-1 activity and serum adiponectin levels in a group of 444 overweight and obese women and assessed the interrelationship with visceral adipose tissue (VAT; CT-scan L4-L5), insulin resistance (HOMA-IR), HDL cholesterol (HDL-chol) and inflammation (hs-CRP). PAI-1 was inversely related to adiponectin (r = -0.25, p < 0.001; adjusted for age and BMI). After adjustment for age, VAT, HOMA-IR and hs-CRP, the relationship remained significant (r = -0.15; p = 0.001), but disappeared after additional adjustment for HDL-chol (r = -0.09; p = 0.067). Subjects were divided in two groups according to the median levels of adiponectin or PAI-1 levels. PAI-1 activity (19.1 +/- 11.4 vs. 15.8 +/- 8.6 AU/ml; p = 0.003) and adiponectin levels (9.8 +/- 4.6 vs. 8.4 +/- 4.0 microg/ml; p < 0.001) were significantly higher in the low adiponectin/PAI-1 groups. The difference in PAI-1 remained significant after adjustment for age and BMI (p = 0.001), became borderline significant after adjustment for age and VAT (p = 0.052), and disappeared after adjustment for age and HOMA-IR (p = 0.116) or age and HDL-chol (p = 0.443). The difference in adiponectin levels remained significant after adjustment for age, VAT, HOMA-IR and hs-CRP (p = 0.006), but disappeared after additional adjustment for HDL-chol (p = 0.089). Further analyses suggest a contribution of HOMA-IR and/or HDL-chol in the relationship between PAI-1 and adiponectin. HDL-chol was found to be the only factor independently determining both factors. In conclusion, in overweight and obese women, PAI-1 activity was inversely related to serum adiponectin, independent of visceral adipose tissue.

Determinants of testosterone levels in human male obesity.

Testosterone (T) levels are decreased in obese men, but the underlying causes are incompletely understood. Our objective was to explore the relation between low (free) T levels and male obesity, by evaluating metabolic parameters, subcutaneous adipose tissue (SAT) aromatase expression, and parameters of the hypothalamic-pituitary-gonadal axis. We recruited 57 morbidly obese men [33 had type 2 diabetes (DM2)] and 25 normal-weight men undergoing abdominal surgery. Fourteen obese men also attended a follow-up, 2 years after gastric bypass surgery (GBS). Circulating T levels were quantified by LC-MS/MS, whereas free T levels were measured using serum equilibrium dialysis and sex hormone-binding globulin, luteinizing hormone, and follicle-stimulating hormone by immunoassay. SAT biopsies were used to determine adipocyte cell size and aromatase expression by real-time PCR. Total and free T levels were decreased in obese males versus controls, with a further decrease in obese men with DM2 versus obese men without DM2. There were no differences in aromatase expression among the study groups, and sex steroids did not correlate with aromatase expression. Pearson analysis revealed an inverse association between (free) T and SAT cell size, triglycerides, and HOMA-IR. Multivariate analysis confirmed the inverse association between (free) T and SAT cell size (ß = -0.321, P = 0.037 and ß = -0.441, P = 0.011, respectively), independent of age, triglycerides, HOMA-IR, obesity, or diabetes. T levels were normalized 2 years after GBS. These data suggest that SAT cell size rather than SAT aromatase expression or parameters of the hypothalamic-pituitary-gonadal axis is related to low T in male obesity, which points to adipose cell size-related metabolic changes as a major trigger in decreased T levels.

Beneficial and adverse effects of testosterone on the cardiovascular system in men.

CONTEXT: The widespread use of T therapy, particularly in aging males, necessitates knowledge of the relationship between T and the cardiovascular system. EVIDENCE ACQUISITION: The review is based on a 1970 to 2013 PubMed search with terms related to androgens in combination with cardiovascular disease, including T, dihydrotestosterone, trial, mortality, cardiovascular disease, myocardial infarction, blood pressure, endothelial function, dyslipidemia, thrombosis, ventricular function, and arrhythmia. Original articles, systematic reviews and meta-analyses, and relevant citations were screened. EVIDENCE SYNTHESIS: Low T has been linked to increased blood pressure, dyslipidemia, atherosclerosis, arrhythmia, thrombosis, endothelial dysfunction, as well as to impaired left ventricular function. On the one hand, a modest association is suggested between low endogenous T and incident cardiovascular disease or cardiovascular mortality, implying unrecognized beneficial T effects, residual confounding, or a relationship with health status. On the other hand, treatments with T to restore "normal concentrations" have so far not been proven to be beneficial with respect to cardiovascular disease; neither have they definitely shown specific adverse cardiovascular effects. The cardiovascular risk-benefit profile of T therapy remains largely evasive in view of a lack of well-designed and adequately powered randomized clinical trials. CONCLUSIONS: The important knowledge gap as to the exact relationship between T and cardiovascular disease would support a cautious, restrained approach to T therapy in aging men, pending clarification of benefits and risks by adequately powered clinical trials of sufficient duration.

Activin A impairs insulin action in cardiomyocytes via up-regulation of miR-143.

AIMS: Enhanced activin A release from epicardial adipose tissue (EAT) has been linked to the development of cardiac dysfunction in type 2 diabetes (T2D). This study examined whether the inhibition of insulin action induced by epicardial adipokines in cardiomyocytes can be ascribed to alterations in miRNA expression. METHODS AND RESULTS: Expression levels of miRNAs were assessed by real-time PCR in primary adult rat cardiomyocytes (ARC) exposed to conditioned media generated from EAT biopsies (CM-EAT) from patients with and without T2D. CM-EAT-T2D altered the expression of eight miRNAs in ARC vs. CM-EAT from patients without T2D. Of these, only expression of the miR-143/145 cluster was affected by activin A in the same direction as CM-EAT-T2D. Accordingly, activin A neutralizing antibodies prevented the induction of the miR-143/145 cluster by CM-EAT-T2D. Subsequently, the impact of the miR-143/145 cluster on insulin action was investigated. Transfection of HL-1 cells with precursor-miR-143 (pre-miR-143), but not pre-miR-145, blunted the insulin-mediated phosphorylation of Akt and its substrate proline-rich Akt substrate of 40 kDa (PRAS40), and reduced insulin-stimulated glucose uptake. Also lentivirus-mediated expression of pre-miR-143 in ARC reduced insulin-induced Akt phosphorylation. These effects were ascribed to down-regulation of the miR-143 target and regulator of insulin action, the oxysterol-binding protein-related protein 8 (ORP8) in both ARC and HL-1 cells. Finally, LNA-anti-miR-143 protected against the detrimental effects of CM-EAT-T2D on insulin action in ARC. CONCLUSION: Activin A released from EAT-T2D inhibits insulin action via the induction of miR-143 in cardiomyocytes. This miRNA inhibits the Akt pathway through down-regulation of the novel regulator of insulin action, ORP8.

Endogenous oestradiol and cardiovascular disease in healthy men: a systematic review and meta-analysis of prospective studies.

CONTEXT: The literature provides no clear answer as to whether total oestradiol (E2) concentrations increase the risk of incident cardiovascular disease (CVD) in healthy men. OBJECTIVE: The authors conducted a systematic review and meta-analysis to estimate the predictive value of E2 for CVD, and to identify study features explaining conflicting results. DATA SOURCES: Articles were identified by a Medline and Embase search and citation tracking. STUDY SELECTION: Eligible articles were prospective population-based cohorts and nested case-control studies on E2 and incident cardiovascular disease (CVD), including myocardial infarction, stroke or death from coronary heart disease. DATA-EXTRACTION: Independent researchers re-expressed associations of E2 and incident CVD in a uniform manner to be used in meta-regression analyses for identification of study features explaining conflicting results, and to estimate the predictive value of E2 for CVD. RESULTS AND CONCLUSIONS: 14 studies out of 128 electronically identified articles were eligible. Data to be used for meta-analysis could be calculated in seven cases, and in the remaining seven cases, data of three more became available by contacting those authors. Overall, a non-significant association was found with an estimated summary RR of 0.98 for a change of >75th versus <25th percentile in E2 (95% CI 0.74 to 1.31). Mean body mass index (BMI) of the study population (ßs -0.8, p<0.004), and quality of E2 assay (ßs -0.6, p<0.08) may have modified the relationship between E2 and incident CVD. The present systematic review does not provide evidence for a pronounced harmful or beneficial effect of E2 on risk for incident CVD in healthy men. If present, an effect of E2 on risk for CVD might be modulated by BMI.

Glucose intolerance and the amount of visceral adipose tissue contribute to an increase in circulating triglyceride concentrations in Caucasian obese females.

CONTEXT: Lipotoxicity is a risk factor for developing obesity-related metabolic complications, including non-alcoholic fatty liver disease, type 2 diabetes (DM2), cardiovascular disease and stroke. Yet, the mechanisms underlying the development of lipotoxicity itself remain poorly understood. Here, we investigated whether glucose intolerance aggravates lipotoxicity by evaluating the association between triglyceride (TG) concentrations and glucose tolerance status in a cross-sectional study on obese Caucasian women at risk for DM2. METHODS: 913 obese females unknown to have diabetes were recruited (mean age: 41.2 ± SD 12.3; median BMI: 36.2, IQR 32.9-40.2). Visceral (VAT) and subcutaneous abdominal adipose tissue volumes were quantified with computed tomography. Glucose, insulin, and triglyceride concentrations were determined in fasting state and following a 75 gram oral glucose tolerance test. RESULTS: Based on fasting and 2 h post-load glucose levels, 27% of the women had impaired glucose tolerance (IGT), and 8% had newly diagnosed DM2. Fasting TG concentrations were similar between the IGT- and DM2-groups, and increased as compared to women with normal glucose tolerance (NGT). Even when adjusting for age, hip circumference and VAT, fasting TG concentrations remained elevated as compared to NGT. Mixed modelling analysis of post-load responses showed that TG concentrations declined more slowly in the DM2-group as compared to IGT and NGT. However, when adjusting for VAT the difference in decline between the glucose tolerance groups disappeared. CONCLUSIONS: Glucose intolerance associates with elevated fasting TG concentrations in obese Caucasian women. We propose that glucose intolerance and increased VAT reduce lipid disposal mechanisms and may accelerate lipotoxicity.

Chemerin as biomarker for insulin sensitivity in males without typical characteristics of metabolic syndrome.

To allow early detection and prevention of metabolic disorders, circulating levels of adipokines involved in insulin sensitivity were compared with the hyperinsulinemic-euglycemic clamp. Twenty non-obese normo-glycaemic men (age 32.1 ± 6 years) underwent a clamp procedure. Levels of leptin, adiponectin, resistin, visfatin, omentin and chemerin levels were determined in fasting blood samples. Pearson correlation coefficients between the M-value for insulin sensitivity and fasting levels of chemerin (r = -0.63, P = 0.003) and leptin (r = -0.54, P = 0.013) performed better than conventional surrogate measures of insulin sensitivity (HOMA-IR: r = -0.45, P = 0.048; Quicki: r = 0.36, P = 0.12). However, only the relation between M-value(LBM) and chemerin remained significant when adjusting for BMI and fasting insulin levels (r = -0.559, P = 0.016). In conclusion, fasting levels of chemerin might be used as biomarker to identify insulin resistance in healthy men without typical characteristics of metabolic disorders.

Sex steroid-induced changes in circulating monocyte chemoattractant protein-1 levels may contribute to metabolic dysfunction in obese men.

CONTEXT: Low testosterone accompanied by elevated estradiol associates with the development of metabolic dysfunction in men. OBJECTIVE: The aim of the study was to explore the hypothesis that alterations in sex steroid levels induce metabolic dysfunction through adipokines. DESIGN: Circulating levels of sex steroids and 28 adipokines were determined in a cross-sectional study of morbidly obese men and aged-matched controls, as well as in a randomized clinical trial with healthy young men in which obesity-related alterations in sex steroid levels were mimicked by treatment with an aromatase inhibitor plus estradiol patches. RESULTS: Morbidly obese men had lower testosterone levels than normal-weight controls. Estradiol levels were increased in morbidly obese men (without DM2) as compared to normal-weight controls. Circulating levels of multiple proinflammatory cytokines, including IL-1Ra, IL-5, IL-6, IL-10, leptin, monocyte chemoattractant protein 1 (MCP1), and macrophage inflammatory protein 1α, positively associated with estradiol and negatively with testosterone. The associations with estradiol, but not with testosterone, remained significant after adjusting for adipocyte cell size. In a separate clinical trial, the direct adverse effects of lowering testosterone and raising estradiol on MCP1 were substantiated in vivo. CONCLUSIONS: Initial alterations in sex steroid levels may contribute to metabolic dysfunction through adverse effects on adipokine levels in obese men. The direct adverse effects on MCP1, a chemokine highly linked to the development of metabolic dysfunction, were substantiated in a trial mimicking obesity-related alterations of sex steroid levels in healthy young males.

Does low testosterone affect adaptive properties of adipose tissue in obese men?

Obesity and (pre)diabetes in males is associated with low serum testosterone and increased oestradiol levels. It is unknown whether these changes in sex steroids are part of a vicious circle resulting in an increase of risk for metabolic complications of obesity, or whether it presents merely an epiphenomenon. The risk for metabolic complications in obesity seems to be determined by adaptation and integrity of adipose tissue. It is unknown whether the typical changes in sex steroids seen in obese men are desirable or ominous with respect to these functions. However, it might be clinically relevant, as low serum testosterone can be treated, and well with different forms of interventional therapy. The present review provides a short summary on findings, obstacles and future research needed to gain better insight into consequences of changes in sex steroids for adaptation of adipose tissue in obese men.

Endogenous testosterone and cardiovascular disease in healthy men: a meta-analysis.

CONTEXT: The literature provides no clear answer as to whether low endogenous testosterone increases risk of cardiovascular disease (CVD) in healthy men. OBJECTIVE: Our purpose was to estimate the predictive value of testosterone for CVD and to identify study features explaining conflicting results. DATA SOURCES: Articles were identified by a Medline and Embase search and citation tracking. STUDY SELECTION: Eligible were prospective population-based cohort and nested case-control studies of testosterone and atherosclerosis, stroke, myocardial infarction, ischaemic heart disease, death from coronary heart disease or mortality. DATA EXTRACTION: Two independent researchers re-expressed associations of testosterone and CVD in a uniform manner to be used in meta-regression analyses for identification of study features explaining conflicting results, and to estimate the predictive value of testosterone for CVD. RESULTS AND CONCLUSIONS: 19 potentially eligible articles were identified. Overall, a weak independent association was found with an estimated summary RR of 0.89 for a change of one standard deviation in total testosterone level (95% CI 0.83 to 0.96). Age of study population and year of publication modified the relationship between testosterone and CVD. The estimated summary RR was 1.01 (0.95 to 1.08) for studies of men younger than 70 years of age, and 0.84 (0.76 to 0.92) for studies including men over 70 years of age. The latter studies showed a particular pronounced association if published after 1 January 2007. Results were largely confirmed by separate analyses of free- and bioavailable testosterone. The systematic review displayed no association between endogenous testosterone and risk for CVD in middle-aged men. In elderly men, testosterone may weakly protect against CVD. Alternatively, low testosterone may indicate a poor general health.

The effects of a pedometer-based behavioral modification program with telephone support on physical activity and sedentary behavior in type 2 diabetes patients.

OBJECTIVE: Effectiveness of a behavioral modification program on physical activity (PA) and sedentary behavior in diabetes patients. METHODS: Ninety-two patients were randomly assigned to an intervention or control group. The 24-weeks intervention consisted of a face-to-face session, pedometer and seven telephone follow-ups. Mean selection criteria were 35-75 years; 25-35 kg/m(2); ≤ 12% HbA1c, treated for type 2 diabetes; no PA limitations. PA and sedentary behavior were measured by pedometer, accelerometer and questionnaire over the short- (24 weeks) and intermediate- (1 year) term. RESULTS: The intervention group increased their steps/day by 2744, their total PA by 23 min/day (p<0.001) and decreased their sedentary behavior by 23 min/day (p<0.05) post-intervention. After 1 year the intervention group still had an increase of 1872 steps/day, 11 min/day total PA and a decrease of 12 min/day in sedentary behavior (p<0.001). CONCLUSION: This pedometer-based behavioral modification program with telephone support showed lasting positive effects on steps/day, PA and sedentary behavior. PRACTICE IMPLICATIONS: This study tested a convenient way to increase PA among type 2 diabetes patients.

Combined gene and protein expression of hormone-sensitive lipase and adipose triglyceride lipase, mitochondrial content, and adipocyte size in subcutaneous and visceral adipose tissue of morbidly obese men.

AIMS: Lipotoxicity in obesity might be a failure of adipocytes to respond sufficiently adequate to persistent energy surplus. To evaluate the role of lipolytic enzymes or mitochondria in lipotoxicity, we studied expression levels of genes and proteins involved in lipolysis and mitochondrial DNA (mtDNA) content. METHODS: As differences in lipid metabolism between men and women are extremely complex, we recruited only men (lean and morbidly obese) and collected subcutaneous and visceral adipose tissue during abdominal surgery for real-time PCR gene expression, protein expression, and microscopic study. RESULTS: Although mRNA levels of hormone-sensitive lipase (HSL) and adipose triglyceride lipase (ATGL) were increased in visceral adipose tissue of morbidly obese men, this was not paralleled by alterations in protein expression and phosphorylation of HSL and ATGL. mtDNA content of visceral adipose tissue was increased in morbidly obese men as compared to lean controls (p < 0.013). Positive correlations were observed between visceral adipocyte size and serum triacylglycerol (r = 0.6, p < 0.007) as well as between visceral adipocyte size and CRP (r = 0.6, p < 0.009) in analyses performed separately in obese men. CONCLUSION: Lipotoxicity of morbidly obese men might be related to the quantitative impact of the visceral fat depot rather than to important dysregulation of involved lipolytic enzymes or adipocyte mitochondria.

Sex steroids affect triglyceride handling, glucose-dependent insulinotropic polypeptide, and insulin sensitivity: a 1-week randomized clinical trial in healthy young men.

OBJECTIVE: To evaluate metabolic effects of sex steroids in nonfasting and fasting conditions, independent from changes in body composition. RESEARCH DESIGN AND METHODS: A randomized clinical trial was performed to create contrasting sex steroid levels in healthy young men: by letrozole (aromatase inhibitor) to lower estradiol (E(2)) and increase testosterone (group T, n = 10) versus letrozole plus E(2) patches to lower T and raise E(2) (group E, n = 10). Mixed meals and hyperinsulinemic-euglycemic clamps were performed before and after a 1-week treatment period. RESULTS: Following intervention, the postprandial triglyceride response displayed a diverging response with a decline in group T and an increase in group E; the postprandial glucose-dependent insulinotropic polypeptide (GIP) response increased in group T. Insulin sensitivity increased in group T but remained unaltered in group E. CONCLUSIONS: In healthy young men, short-term changes in sex steroids affect postprandial triglyceride and GIP response and insulin sensitivity.

Low fasting triglycerides: hallmark of the healthy large hip?

Body fat distribution modulates risk for type 2 diabetes mellitus. We evaluated potentially involved metabolic risk factors. In a population of 282 male and 157 female healthy subjects (data from the San Antonio and the European Group of Insulin Resistance (EGIR) study cohorts), we evaluated associations between body fat distribution (assessed by waist and hip circumference) and parameters of lipid- and glucose metabolism, including clamp measurements of insulin sensitivity. After stratification for BMI, fasting triglycerides were lower in the presence of a large hip, and higher in a large waist. Persons with the largest BMI (3rd tertile) showed a difference in triglyceride levels of 1.5 vs. 2.4 mmol/l in large vs. small hip circumference groups (P < 0.038), and a difference of 1.5 vs. 1.2 mmol/l in large vs. small waist circumference groups (P < 0.025). A similar analysis did not reveal a difference in insulin sensitivity. Linear regression analyses confirmed the findings; they revealed negative associations between triglycerides and hip, and (for women borderline statistically significant) positive associations between triglycerides and waist, after adjustment for BMI, mutual confounding, and age (beta +/- s.e.; men: -0.48 +/- 0.005, P < 0.001, and 0.21 +/- 0.005, P < 0.05; women: -0.78 +/- 0.007, P < 0.001, and 0.24 +/- 0.005, P < 0.065), respectively. Linear regression analyses revealed similar opposite associations with high-density lipoprotein (HDL)-cholesterol, though not with glucose, insulin, or insulin sensitivity as measured with the clamp method. In our study population of healthy persons, body fat distribution is associated with fasting triglycerides and HDL-cholesterol, and not with insulin sensitivity. Metabolic risk of unfavorable body fat distribution may be modulated by lower triglyceride storage capacity.

Fasting-based estimates of insulin sensitivity in overweight and obesity: a critical appraisal.

OBJECTIVE: To identify simple methods to estimate the degree of insulin resistance. RESEARCH METHODS AND PROCEDURES: The performance of a wide range of fasting-based index estimates of insulin sensitivity was compared by receiver operating characteristic analysis (area under curves and their 95% confidence intervals) against the M value from euglycemic insulin clamp studies collected in the San Antonio (non-Hispanic whites and Hispanic residents of San Antonio, TX) and European Group for the Study of Insulin Resistance (non-diabetic white Europeans) databases (n = 638). RESULTS: Insulin resistance differed substantially between lean (BMI < 25 kg/m2), overweight or obese (BMI > or = 25 kg/m2), and type 2 diabetic individuals. Estimates of insulin resistance were, therefore, assessed in each group separately. In the overweight and obese subgroup (n = 302), the receiver operating characteristic performance of fasting-based indices varied from 0.72 (0.62 to 0.82), in the case of the insulin/glucose ratio, to 0.80 (0.72 to 0.88) in the case of Belfiore free fatty acids. One superior method could not be identified; the confidence intervals overlapped, and no statistically significant differences emerged. All indices performed better when using the whole study population, with fasting plasma insulin, homeostatic model assessment, insulin/glucose ratio, quantitative insulin sensitivity check index, glucose/insulin ratio, Belfiore glycemia, revised quantitative insulin sensitivity check index, McAuley index, and Belfiore free fatty acids showing area under curves of 0.83, 0.90, 0.66, 0.90, 0.66, 0.90, 0.85, 0.83, and 0.86, respectively, because of the inclusion of very insulin sensitive (lean) and very insulin resistant cases (diabetic subjects). DISCUSSION: In conclusion, a superior fasting-based index estimate to distinguish between the presence and absence of insulin resistance in overweight and obesity could not be identified despite the use of the large datasets.