Repositioning the Role of Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) on the TRAIL to the Development of Diabetes Mellitus: An Update of Experimental and Clinical Evidence.

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a member of the TNF protein superfamily, represents a multifaceted cytokine with unique biological features including both proapoptotic and pro-survival effects in different cell types depending on receptor interactions and local stimuli. Beyond its extensively studied anti-tumor and immunomodulatory properties, a growing body of experimental and clinical evidence over the past two decades suggests a protective role of TRAIL in the development of type 1 (T1DM) and type 2 (T2DM) diabetes mellitus. This evidence can be briefly summarized by the following observations: (i) acceleration and exacerbation of T1DM and T2DM by TRAIL blockade or genetic deficiency in animal models, (ii) prevention and amelioration of T1DM and T2DM with recombinant TRAIL treatment or systemic TRAIL gene delivery in animal models, (iii) significantly reduced circulating soluble TRAIL levels in patients with T1DM and T2DM both at disease onset and in more advanced stages of diabetes-related complications such as cardiovascular disease and diabetic nephropathy, (iv) increase of serum TRAIL levels in diabetic patients after initiation of antidiabetic treatment and metabolic improvement. To explore the underlying mechanisms and provide mechanistic links between TRAIL and diabetes, a number of animal and in vitro studies have reported direct effects of TRAIL on several tissues involved in diabetes pathophysiology such as pancreatic islets, skeletal muscle, adipose tissue, liver, kidney, and immune and vascular cells. Residual controversy remains regarding the effects of TRAIL on adipose tissue homeostasis. Although the existing evidence is encouraging and paves the way for investigating TRAIL-related interventions in diabetic patients with cardiometabolic abnormalities, caution is warranted in the extrapolation of animal and in vitro data to the clinical setting, and further research in humans is imperative in order to uncover all aspects of the TRAIL-diabetes relationship and delineate its therapeutic implications in metabolic disease.

Intermittent Energy Restriction, Weight Loss and Cardiometabolic Risk: A Critical Appraisal of Evidence in Humans.

Dietary patterns with intermittent energy restriction (IER) have been proposed as an attractive alternative to continuous energy restriction (CER) for the management of obesity and its associated comorbidities. The most widely studied regimens of IER comprise energy restriction on two days per week (5:2), alternate-day energy restriction by 60-70% (ADF), and timely restriction of energy intake during a specific time window within the day (TRF; time-restricted feeding). Although there is some evidence to suggest that IER can exert beneficial effects on human cardiometabolic health, yet is apparently not superior compared to CER, there are still some critical issues/questions that warrant further investigation: (i) high-quality robust scientific evidence regarding the long-term effects of IER (safety, efficacy, compliance) is limited since the vast majority of intervention studies had a duration of less than 6 months; (ii) whether the positive effects of IER are independent of or actually mediated by weight loss remains elusive; (iii) it remains unknown whether IER protocols are a safe recommendation for the general population; (iv) data concerning the impact of IER on ectopic fat stores, fat-free mass, insulin resistance and metabolic flexibility are inconclusive; (v) the cost-effectiveness of IER dietary regimens has not been adequately addressed; (vi) direct head-to-head studies comparing different IER patterns with variable macronutrient composition in terms of safety and efficacy are scarce; and (vii) evidence is limited with regard to the efficacy of IER in specific populations, including males, the elderly and patients with morbid obesity and diabetes mellitus. Until more solid evidence is available, individualization and critical perspective are definitely warranted to determine which patients might benefit the most from an IER intervention, depending on their personality traits and most importantly comorbid health conditions.

Important Considerations for the Treatment of Patients with Diabetes Mellitus and Heart Failure from a Diabetologist's Perspective: Lessons Learned from Cardiovascular Outcome Trials.

Heart failure (HF) represents an important cardiovascular complication of type 2 diabetes mellitus (T2DM) associated with substantial morbidity and mortality, and is emphasized in recent cardiovascular outcome trials (CVOTs) as a critical outcome for patients with T2DM. Treatment of T2DM in patients with HF can be challenging, considering that these patients are usually elderly, frail and have extensive comorbidities, most importantly chronic kidney disease. The complexity of medical regimens, the high risk clinical characteristics of patients and the potential of HF therapies to interfere with glucose metabolism, and conversely the emerging potential of some antidiabetic agents to modulate HF outcomes, are only some of the challenges that need to be addressed in the framework of a team-based personalized approach. The presence of established HF or the high risk of developing HF in the future has influenced recent guideline recommendations and can guide therapeutic decision making. Metformin remains first-line treatment for overweight T2DM patients at moderate cardiovascular risk. Although not contraindicated, metformin is no longer considered as first-line therapy for patients with established HF or at risk for HF, since there is robust scientific evidence that treatment with other glucose-lowering agents such as sodium-glucose cotransporter 2 inhibitors (SGLT2i) should be prioritized in this population due to their strong and remarkably consistent beneficial effects on HF outcomes.

Experimental hypogonadism: insulin resistance, biochemical changes and effect of testosterone substitution.

Background We sought to clarify the role of testosterone substitution in terms of insulin resistance and metabolic profile dysregulation in hypogonadism. Methods Twenty-nine male Wistar rats aged 11-12 weeks were divided in three groups: control (C, n = 10), sham operation; orchiectomy (ORX, n = 9); and orchiectomy + testosterone substitution (ORX+T, n = 10). Blood samples were obtained at day 1 (operation), after 10 days (intramuscular T injection 100 µg/100 g b.w.), 25 days (second T injection) and 40 days (sacrifice). Results Hormonal replacement significantly attenuated the negative effect of orchiectomy on insulin resistance as indicated by the successive changes in both insulin levels (1.44 ± 2.94 vs. 4.10 ± 2.47 vs. 1.78 ± 0.68 ng/mL, for D1, D10 and D40, respectively; p = 0.028 and p = 0.022, respectively) and HOMA-IR index (1.36 ± 2.75 vs. 3.68 ± 1.87 vs. 1.74 ± 0.69 ng/mL, for D1, D10 and D40, respectively; p = 0.024 and p = 0.026, respectively) in the ORX+T group. Irisin levels peaked at the 10th postoperative day and were decreased at the end of the experiment (0.27 ± 0.11 vs. 0.85 ± 0.54 vs. 0.02 ± 0.07 ng/mL for D1, D10 and D40, respectively; p = 0.028 in both cases), whereas resistin levels did not differ. Experimental hypogonadism results in an unfavorable lipid profile and insulin resistance, which is not observed when the ORX animals are substituted for T.

The Effect of the Oral Administration of Leucine on Endothelial Function, Glucose and Insulin Concentrations in Healthy Subjects.

OBJECTIVE: The aim of our study was to investigate the potential differential effect of hyperglycaemia and hyperinsulinaemia induced by glucose infusion alone and in combination with leucine consumption on endothelial function in healthy individuals. METHODS: Ten male volunteers were examined in random order twice. In one visit, they consumed 250 ml water (baseline) and 30 min later glucose was infused iv. In the other visit, they consumed 250 ml water with 25 g of leucine and 30 min later the same amount of glucose was infused. Serum glucose and insulin were measured at baseline and every 10 min after glucose infusion for 1 h. Endothelial function was evaluated by measurement of flow mediated vasodilatation (FMD) at baseline, 10 and 60 min after glucose infusion. RESULTS: In both visits, glucose levels increased to the same degree, whereas insulin response was significantly higher after leucine administration. FMD values declined significantly compared to baseline 10 min after glucose infusion in the control visit (6.9±2.7 vs. 3.2±3.5%, respectively, p=0.006), while no significant change was observed when glucose infusion was followed by leucine consumption. CONCLUSIONS: Acute hyperglycaemia impairs endothelial function in healthy male individuals. Leucine administration prevents hyperglycaemia-mediated endothelial dysfunction probably due to enhanced insulin secretion.

Roux-en-Y Gastric Bypass Is More Effective than Sleeve Gastrectomy in Improving Postprandial Glycaemia and Lipaemia in Non-diabetic Morbidly Obese Patients: a Short-term Follow-up Analysis.

PURPOSE: We aimed to compare the effects of Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) on postprandial glucose and lipid metabolism in addition to weight loss and fasting metabolic profile, in non-diabetic patients undergoing bariatric surgery. METHODS: Seventy-one patients were consecutively recruited and studied preoperatively, 3 and 6 months after surgery. Of these, 28 underwent RYGB (7 males, age 38 ± 9 years, BMI 46.9 ± 5.0 kg/m2), and 43 SG (9 males, age 38 ± 9 years, BMI 50.2 ± 7.0 kg/m2). A semi-liquid mixed meal was consumed, and blood samples were taken before, and every 30 min after meal ingestion up to 180 min postprandially, for measurement of glucose, insulin, and lipids. The overall postprandial response was assessed as area under the concentration-time curve (AUC). RESULTS: Baseline metabolic parameters were similar between RYGB and SG. Both groups experienced comparable weight loss, and a similar improvement in fasting glucose, insulin, and insulin resistance. Total and LDL cholesterol levels were lower at 6 months after RYGB compared to SG, while there was no difference in HDL cholesterol or triglycerides. Glucose AUC was lower after RYGB compared to SG at both 3 (p = 0.008) and 6 months (p = 0.016), without any difference in postprandial insulin response. Triglyceride AUC was also lower in RYGB vs. SG at 3 and 6 months (p ≤ 0.001). CONCLUSIONS: RYGB is superior to SG in improving postprandial glycaemia and lipaemia and cholesterol profile 6 months postoperatively in non-diabetic, severely obese patients. These findings imply procedure-specific effects, such as the malabsorptive nature of RYGB, and less likely a different incretin postoperative response.

Defining the Optimal Dietary Approach for Safe, Effective and Sustainable Weight Loss in Overweight and Obese Adults.

Various dietary approaches with different caloric content and macronutrient composition have been recommended to treat obesity in adults. Although their safety and efficacy profile has been assessed in numerous randomized clinical trials, reviews and meta-analyses, the characteristics of the optimal dietary weight loss strategy remain controversial. This mini-review will provide general principles and practical recommendations for the dietary management of obesity and will further explore the components of the optimal dietary intervention. To this end, various dietary plans are critically discussed, including low-fat diets, low-carbohydrate diets, high-protein diets, very low-calorie diets with meal replacements, Mediterranean diet, and diets with intermittent energy restriction. As a general principle, the optimal diet to treat obesity should be safe, efficacious, healthy and nutritionally adequate, culturally acceptable and economically affordable, and should ensure long-term compliance and maintenance of weight loss. Setting realistic goals for weight loss and pursuing a balanced dietary plan tailored to individual needs, preferences, and medical conditions, are the key principles to facilitate weight loss in obese patients and most importantly reduce their overall cardiometabolic risk and other obesity-related comorbidities.

Comparison of health-related quality of Life (HRQOL) among patients with pre-diabetes, diabetes and normal glucose tolerance, using the 15D-HRQOL questionnaire in Greece: the DEPLAN study.

BACKGROUND: Diabetes mellitus is usually preceded by a pre-diabetic stage before the clinical presentation of the disease, the influence of which on persons' quality of life is not adequately elucidated. The purpose of this study was to compare the Health-Related Quality of Life (HRQOL) of persons with pre-diabetes with that of diabetes or normal glucose tolerance (NGT), using the validated HRQOL-15D questionnaire. METHODS: The HRQOL-15D scores of 172 people with pre-diabetes (108 with Impaired Fasting Glucose [IFG], 64 with Impaired Glucose Tolerance [IGT], aged 58.3 ± 10.3 years) and 198 with NGT (aged 54.4 ± 10.1 years) from the Greek part of the DEPLAN study (Diabetes in Europe - Prevention using Lifestyle, Physical Activity and Nutritional Intervention), were compared to 100 diabetes patients' scores (aged 60.9 ± 12.5 years, diabetes duration 17.0 ± 10.0 years, HbA1c 7.2 ± 1.2%), derived from the outpatient Diabetes Clinic of a University Hospital. RESULTS: The diabetes patients' HRQOL-15D score (0.8605) was significantly lower than the pre-diabetes' (0.9008) and the controls' (0.9092) (p < 0.001). There were no differences in the total score between the controls and the group with pre-diabetes. However, examination of individual parameters of the score showed that people with IGT had lower scores compared to the control group, as related to the parameters of "mobility" and "psychological distress". No differences were found in any component of the HRQOL-15D score between the control group and the IFG group, nor between the two groups with pre-diabetes (IFG vs. IGT). CONCLUSIONS: Persons with pre-diabetes had a similar HRQOL score with healthy individuals, and a higher score than persons with diabetes. Specific components of the score, however, were lower in the IGT group compared to the controls. These findings help clarify the issue of HRQOL of persons with pre-diabetes and its possible impact on prevention.

Metabolic effects of Crocus sativus and protective action against non-alcoholic fatty liver disease in diabetic rats.

Non-alcoholic fatty liver disease (NAFLD) is the result of the accumulation of adipose tissue deposits in the liver and it is associated with type 2 diabetes. Crocus sativus (saffron) is known for its antioxidant and its potential hypoglycemic effects. We investigated the role of saffron on NAFLD in diabetic rats. Thirty adult male rats were allocated into three groups; control (n=10), which received normal diet; streptozotocin (STZ) group (n=10), which received normal chow diet, 10% fructose in their drinking water and STZ (40 mg/kg body weight; STZ-saffron group (n=10), which followed the same dietary and pharmacological pattern as STZ group and were additionally supplemented with saffron (100 mg/kg/day). Metabolic profile was measured and histopathological examination of the liver was evaluated. STZ group exhibited the highest glucose levels at the end of the experiment (P<0.05), while there was no difference between control and STZ-saffron group (584 vs. 213 mg/dl vs. 209 mg/dl, respectively). STZ group revealed higher percentage of steatosis (5-33%) when compared to the other two groups (P<0.005). Saffron exhibits both hypoglycemic and hepatoprotective actions. Yet, further studies enlightening the exact mechanisms of saffron's mode of actions are required.

Association of plasma fetuin-a levels with peripheral arterial disease and lower extremity arterial calcification in subjects with type 2 diabetes mellitus.

AIMS: Fetuin-A is a hepatic glycoprotein that is involved in insulin resistance and atherosclerosis. Herein we examined the association of plasma fetuin-A levels with peripheral arterial disease (PAD) in patients with type 2 diabetes mellitus (T2DM). MATERIAL AND METHODS: A total of 71 patients with T2DM and 57 non-diabetic individuals were recruited. Diagnosis of PAD was based on the absence of triphasic waveform at pedal arteries, while ankle-brachial index (ABI) was calculated. Radiographs of both feet and ankles were taken for the assessment of lower extremity arterial calcification (LEAC). Plasma fetuin-A levels were measured using ELISA. RESULTS: Patients with T2DM had higher fetuin-A levels than non-diabetic participants. Participants with diabetes and PAD had lower fetuin-A levels than non-PAD diabetic patients. In subjects with T2DM fetuin-A levels were associated with ABI. Multivariate analysis demonstrated that in patients with T2DM the odds of PAD increased with long diabetes duration, smoking, presence of arterial hypertension and dyslipidemia, as well as with lower fetuin-A levels. A trend towards higher fetuin-A levels in subjects with less severe LEAC was found. CONCLUSION: Plasma fetuin-A levels are lower in patients with T2DM and PAD and are associated with PAD, irrespective of traditional cardiovascular risk factors. Moreover, fetuin-A may be involved in arterial calcification.

The effect of slow spaced eating on hunger and satiety in overweight and obese patients with type 2 diabetes mellitus.

BACKGROUND: Slow spaced eating is associated with improved satiety and gut hormone responses in normal-weight participants. This crossover study compared the effect of slow and rapid eating patterns on hunger, fullness, glucose, insulin, and the appetite-related gut hormones peptide YY (PYY), glucagon-like peptide-1 (GLP-1), and ghrelin in overweight and obese participants with type 2 diabetes mellitus (T2DM). METHODS: 20 overweight and obese participants with T2DM on metformin were recruited. A test meal of 300 mL ice-cream was consumed in random order in two different sessions by each participant; meal duration was 5 or 30 min. Fullness and hunger as assessed by visual analog scales (VAS), and glucose, insulin, PYY, GLP-1, and ghrelin were measured at baseline and at 30 min intervals after meal termination for 3 h. RESULTS: Fullness VAS ratings were significantly higher at the 90', 120', 150', and 180' time points and hunger ratings were lower at 90', 150', and 180' for the 30 min meal. The area under the curve (AUC) for fullness was higher after the 30 min meal than after the 5 min meal (11 943.7±541.2 vs 10 901.0±568.8 mm min, p=0.003) whereas the hunger AUC was lower (4442.9±328 vs 4966.7±347.5 mm min, p=0.012). There were no differences in glucose, insulin, PYY, GLP-1, and ghrelin responses. CONCLUSIONS: Slow spaced eating increased fullness and decreased hunger ratings in overweight and obese participants with T2DM, without the improvement in gut hormone responses found in normal-weight participants. Slow spaced eating may be a useful prevention strategy, but might also help curb food intake in those already suffering from obesity and diabetes.

Study of postprandial lipaemia in type 2 diabetes mellitus: exenatide versus liraglutide.

Therapeutic approaches based on the actions of the incretin hormone GLP-1 have been widely established in the management of T2DM. Nevertheless, much less research has been aimed at elucidating the role of GLP-1 in lipid metabolism and in particular postprandial dyslipidemia. Exenatide and liraglutide are two GLP-1 receptor agonists which are currently available as subcutaneously administered treatment for T2DM but their chronic effects on postprandial lipaemia have not been well investigated. The aim of this study is to examine the effect of treatment with either liraglutide or exenatide for two weeks on postprandial lipaemia in obese subjects with T2DM. This study was a single-center, two-armed, randomized, controlled 2-week prospective intervention trial in 20 subjects with T2DM. Patients were randomized to receive either liraglutide or exenatide treatment and underwent a standardized meal tolerance test early in the morning after 10 h fast at baseline (visit 1, beginning of treatment) and after a two-week treatment period (visit 2). Exenatide and liraglutide both appear to be equally effective in lowering postprandial lipaemia after the first administration and after a two-week treatment. The mechanisms which lead to this phenomenon, which seem to be independent of gastric emptying, are yet to be studied.

Relationship between autonomic nervous system function and continuous interstitial glucose measurement in patients with type 2 diabetes.

AIMS: The Aim of the present study was to examine whether there is a relationship between autonomic nervous system function and glycemic variability (GV) in patients with type 2 diabetes (T2D). METHODS: A total of 50 (29 males) patients with T2D (mean age 58.4 ± 9.9 years, median diabetes duration 5.5 [IQR 2.0-9.25] years), on oral antidiabetic agents, underwent ECG recording and subcutaneous glucose monitoring, simultaneously and continuously, for 24 hours. RESULTS: After adjustment for HbA1c and diabetes duration, total power of heart rate variability (HRV) was inversely associated with the standard deviation of the mean interstitial tissue glucose (MITG) and with the M-value during the entire recording (r: -0.29, P = 0.052; r: -0.30, P = 0.047, resp.) and during the night (r: -0.29, P = 0.047; r: -0.31, P = 0.03, resp.). Most of the HRV time-domain indices were significantly correlated with standard deviation of the MITG and the M-value. These correlations were stronger for the HRV recordings during the night. No significant association was found between HRV parameters and MAGE. CONCLUSIONS: HRV is inversely associated with GV in patients with T2D, which might be a sign of causation between GV and autonomic dysfunction. Prospective studies are needed to further investigate the importance of GV in the pathogenesis of long-term complications of diabetes.

Association of lean body mass with cardiometabolic risk factors in healthy postmenopausal women.

OBJECTIVE: Aim of this study was to investigate the association of total and regional lean body mass (LBM) with cardiometabolic risk factors in healthy obese and nonobese postmenopausal women. METHODS: A total of 150 postmenopausal women (age 54 ± 7 years, BMI 29.6 ± 5.8 kg/m2) underwent a comprehensive assessment of cardiometabolic risk, including metabolic syndrome (MS). Body composition analysis was performed with Dual-energy X-ray Absorptiometry, and multiple height-adjusted indices of total and regional LBM were evaluated. RESULTS: After controlling for age, diet, physical activity, and total fat mass, most indices of total, central, and peripheral LBM displayed significant positive correlations with cardiometabolic risk factors. Most associations were no longer significant after controlling for waist circumference, with the only exception of lean mass in the arms, which remained significantly associated with the presence and severity of MS (number of MS abnormalities), independently of central adiposity. A significant additive interaction was found between lean mass in the arms and waist circumference in increasing the prevalence of MS. CONCLUSIONS: LBM is unfavorably associated with cardiometabolic risk factors in healthy postmenopausal women. Whether LBM, especially in arms, is associated with cardiometabolic health independently of central fat distribution in postmenopausal women, merits further investigation.

Effect of atorvastatin on baroreflex sensitivity in subjects with type 2 diabetes and dyslipidaemia.

In this prospective study, we examined the effect of atorvastatin treatment on baroreflex sensitivity (BRS) in subjects with type 2 diabetes. A total of 79 patients with type 2 diabetes with dyslipidaemia were recruited. A total of 46 subjects were enrolled to atorvastatin 10 mg daily and low-fat diet and 33 patients to low-fat diet only. BRS was assessed non-invasively using the sequence method at baseline, 3, 6 and 12 months. Treatment with atorvastatin increased BRS after 12 months (from 6.46 ± 2.79 ms/mmHg to 8.05 ± 4.28 ms/mmHg, p = 0.03), while no effect was seen with low-fat diet. Further sub-analysis according to obesity status showed that BRS increased significantly only in the non-obese group (p = 0.036). A low dose of atorvastatin increased BRS in non-obese subjects with type 2 diabetes and dyslipidaemia after 1-year treatment. This finding emphasizes the beneficial effect of atorvastatin on cardiovascular system, beyond the lipid-lowering effects.

Regional fat distribution and cardiometabolic risk in healthy postmenopausal women.

BACKGROUND: Regional fat distribution is an important determinant of cardiometabolic risk after menopause. The aim of the present study was to investigate the association between indices of fat distribution obtained by Dual-energy X-ray Absorptiometry (DXA) and representative cardiometabolic risk factors in a cohort of healthy postmenopausal women. METHODS: In this cross-sectional study, cardiometabolic risk factors were correlated with a variety of central and peripheral fat depots obtained by DXA, in a total of 150 postmenopausal women, free of diabetes and cardiovascular disease (age 54 ± 7 years, BMI 29.6 ± 5.8 kg/m(2), mean ± 1 SD). RESULTS: After adjusting for age and total adiposity, DXA-derived indices of central and peripheral fat distribution displayed opposite associations (positive versus negative) with the examined cardiometabolic risk factors. In multivariate regression analysis, thoracic fat mass % was an independent predictor of blood pressure, HOMA index and triglycerides, abdominal fat mass % was an independent predictor of high sensitivity C-reactive protein, and abdominal-to-gluteofemoral fat ratio was an independent predictor of high density lipoprotein cholesterol. An index of peripheral fat distribution, gluteofemoral fat mass %, proved to be the most important determinant of metabolic syndrome (Odds Ratio 0.76, 95% confidence intervals 0.67-0.87, p<0.001), independent of total and central adiposity. CONCLUSION: DXA-derived indices of regional fat distribution such as thoracic, abdominal and gluteofemoral fat, correlate significantly with cardiometabolic risk factors in healthy postmenopausal women, and may serve as clinically useful tools for evaluating cardiometabolic risk after menopause.

Dietary sodium, potassium, and alcohol: key players in the pathophysiology, prevention, and treatment of human hypertension.

Western industrialized societies are currently experiencing an epidemic expansion of hypertension (HTN), which extends alarmingly even to children and adolescents. HTN constitutes an independent risk factor for cardiorenal disease and represents an extremely common comorbidity of diabetes and obesity. Numerous randomized clinical trials and meta-analyses have provided robust scientific evidence that reduced dietary salt intake, increased dietary potassium intake, moderation of alcohol consumption, optimal weight maintenance, and the adoption of "heart-friendly" dietary patterns such as the Dietary Approaches to Stop Hypertension or the Mediterranean diet can effectively lower blood pressure. Interestingly, the susceptibility of blood pressure to nutritional interventions is greatly variable among individuals, depending on age, race, genetic background, and comorbidities. The purpose of this review is to provide a comprehensive overview of currently available scientific evidence in the constantly evolving field of diet and HTN, placing particular emphasis on the key role of dietary sodium, dietary potassium, and alcohol intake in the pathophysiology, prevention, and treatment of human hypertension.

Body composition determinants of metabolic phenotypes of obesity in nonobese and obese postmenopausal women.

OBJECTIVE: Although obesity is typically associated with increased cardiovascular risk, a subset of obese individuals display a normal metabolic profile ("metabolically healthy obese," MHO) and conversely, a subset of nonobese subjects present with obesity-associated cardiometabolic abnormalities ("metabolically obese nonobese," MONO). The aim of this cross-sectional study was to identify the most important body composition determinants of metabolic phenotypes of obesity in nonobese and obese healthy postmenopausal women. DESIGN AND METHODS: We studied a total of 150 postmenopausal women (age 54 ± 7 years, mean ± 1 SD). Based on a cardiometabolic risk score, nonobese (body mass index [BMI] ≤ 27) and obese women (BMI > 27) were classified into "metabolically healthy" and "unhealthy" phenotypes. Total and regional body composition was assessed with dual-energy X-ray absorptiometry (DXA). RESULTS: In both obese and nonobese groups, the "unhealthy" phenotypes were characterized by frequent bodyweight fluctuations, higher biochemical markers of insulin resistance, hepatic steatosis and inflammation, and higher anthropometric and DXA-derived indices of central adiposity, compared with "healthy" phenotypes. Indices of total adiposity, peripheral fat distribution and lean body mass were not significantly different between "healthy" and "unhealthy" phenotypes. Despite having increased fat mass, MHO women exhibited comparable cardiometabolic parameters with healthy nonobese, and better glucose and lipid levels than MONO. Two DXA-derived indices, trunk-to-legs and abdominal-to-gluteofemoral fat ratio were the major independent determinants of the "unhealthy" phenotypes in our cohort. CONCLUSIONS: The "metabolically obese phenotype" is associated with bodyweight variability, multiple cardiometabolic abnormalities and an excess of central relative to peripheral fat in postmenopausal women. DXA-derived centrality ratios can discriminate effectively between metabolic subtypes of obesity in menopause.

Cigarette Smoking Is Associated with Prolongation of the QTc Interval Duration in Patients with Type 2 Diabetes Mellitus.

Aims. Aim of the study was to evaluate the effect of smoking on autonomic nervous system (ANS) activity and QTc interval duration in patients with Type 2 diabetes mellitus (T2DM). Methods. A total of 70 patients with T2DM (35 chronic smokers, 35 nonsmokers) treated with oral antidiabetic medications underwent continuous ECG Holter monitoring for 24 hours and analysis of time- and frequency-domain measures of heart rate variability (HRV). HRV over short time was also assessed using the deep breathing test. In addition, baroreflex sensitivity (BRS) was evaluated using the spontaneous sequence method. The mean QTc interval was measured from the 24-hour ECG recordings. Results. Smokers had lower body mass index (BMI) and exhibited higher 24-hour mean heart rate. There was no difference regarding all measures of ANS activity between the two groups. Smokers showed increased mean QTc duration during the 24 hours (439.25 ± 26.95 versus 425.05 ± 23.03 ms, P = 0.021) as well as in both day (439.14 ± 24.31 ms, P = 0.042) and night periods (440.91 ± 32.30 versus 425.51 ± 24.98 ms, P = 0.033). The association between smoking status and mean QTc interval persisted after adjusting for BMI. Conclusions. Cigarette smoking is associated with prolongation of the QTc interval in patients with T2DM by a mechanism independent of ANS dysfunction.

The effect of hyperhomocysteinemia on aortic distensibility in healthy individuals.

OBJECTIVE: Elevated plasma homocysteine (HCY) levels have been associated with increased risk for cardiovascular disease. Aortic distensibility and aortic pulse wave velocity (PWV) are indices of aortic elasticity. The potential effect of acute hyperhomocysteinemia (HHCY) on the elastic properties of the aorta in healthy individuals is not known. The aim of the present study was to determine the effect of acute methionine-induced HHCY on aortic distensibility and PWV in healthy individualsand the effect of acute HHCY on myocardial performance of the left ventricle (Tei index). METHODS: Thirty healthy volunteers were included in this crossover study. An oral methionine (100 mg/kg) or water load was given in random order on separate days at weekly intervals. Aortic distensibility and Tei index were determined non-invasively by ultrasonography at baseline and 3 h after methionine or water consumption, while PWV was measured by applanation tonometry at baseline and every 1 h for the same time interval. RESULTS: Oral methionine induced an increase in total plasma HCY concentrations (P < 0.001), whereas HCY concentrations did not change after water consumption. Aortic distensibility decreased 3 h after methionine load (P < 0.001) and Tei index increased (P < 0.001), suggesting worsening compared with baseline values. Water consumption had no effect on aortic distensibility or Tei index values. PWV values did not change after either methionine or water consumption. CONCLUSIONS: Acute methionine-induced HHCY reduces aortic distensibility and worsens myocardial performance in healthy individuals. Further research is warranted to examine in the long term the direct effects of HHCY on cardiovascular function and the indirect effects on structural remodeling.