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Background: Physical activity (PA)/exercise have become an integral part of the management of type 2 diabetes mellitus (T2DM). However, current guidelines are difficult to put into action in this population due to a number of barriers, especially the lack of acceptable, feasible, and validated behavioral intervention strategies. The present manuscript reports the rationale, study design and methods, and design considerations of the Italian Diabetes and Exercise Study (IDES)-2, a randomized controlled trial testing the efficacy of a behavior change strategy in increasing total daily PA and reducing sedentary time (SED-time) in patients with T2DM., Methods/design: Starting 7 January 2014, the IDES_2 began enrolling 300 patients with known T2DM of at least 1-year duration in three tertiary referral outpatient Diabetes Clinics in Rome. Additional requirements are age 40 to 80 years, body mass index 27 to 40 kg/m(2), sedentary lifestyle, and physically inactive for at least 6 months, ability to walk 1.6 km without assistance, and eligibility after cardiovascular evaluation. Patients are randomized by center and within each center, by age and type of diabetes treatment to either the intervention or the control group. Patients in the intervention (INT) group (n = 150) receive theoretical and practical exercise counseling consisting of aggregated behavior change techniques (one individual theoretical counseling session plus eight twice-a-week individual theoretical and practical exercise counseling sessions) once a year for 3 years. Patients in the control (CON) group (n = 150), receive standard care, including general physician recommendations for daily PA. The primary outcomes are total daily PA and SED-time, as measured objectively by the use of an accelerometer. Secondary outcomes include physical fitness, modifiable cardiovascular risk factors, musculoskeletal disturbances, well-being/depression, and health-related quality of life., Discussion: The behavioral intervention strategy tested in the IDES_2 is based on solid theoretical grounds and uses several behavioral change techniques, two factors which were found to improve effectiveness of behavioral intervention. In addition, physicians and exercise specialists have been specifically trained for counselling/prescribing and supervising PA/exercise, respectively, in subjects suffering from metabolic disorders. Finally, the large sample size, the long study duration, and the objective measurement of PA allow statistically significant and scientifically robust conclusions to be drawn on the feasibility and efficacy of this intervention in T2DM patients., Trial Registration: ClinicalTrials.gov; NCT01600937 ; 10 October 2012.

Aim: To evaluate serum alanine aminotransferase (ALT) activity in a well-characterized group of uncomplicated obese subjects and its correlation with insulin resistance, plasma adiponectin, and leptin concentrations., Methods: One hundred and five uncomplicated obese subjects (87 women, 18 men, age 34.3+/-9.6 years, BMI 39.9+/-8.3 kg/m(2)) were studied. Serum ALT activity was evaluated. Insulin sensitivity was assessed by euglycemic hyperinsulinemic clamp (M index) and fasting insulin. Plasma leptin and adiponectin levels were also measured., Results: Serum ALT concentration in the whole group of uncomplicated obese subjects was 17.73+/-6.33 U/L with none of the subjects presenting ALT levels greater than 43 U/L and only 9 (11%) women and 3 (19%) men showed ALT levels >19 and >30 U/L for women and men, respectively. No significant difference was detected in serum ALT levels between severe obese subjects (BMI >40 kg/m(2)) and those with BMI <40 kg/m(2) (18.63+/-6.25 vs 17.26+/-6.02 U/L). ALT was significantly correlated with fasting insulin (r = 0.485, P = 0.02) and triglycerides (r = 0.358, P = 0.03)., Conclusion: Serum ALT activity is practically normal in uncomplicated obese subjects, independently of their obesity degree. These findings suggest the role of obesity-related comorbidities and not of BMI as main risk factors for elevated ALT levels in obese subjects.

Objective: The existence of healthy obese subjects has been suggested but not clearly reported. We sought to address the prevalence of uncomplicated obesity and adverse risk factors in a large Italian obese population., Research Methods and Procedures: This was a cross-sectional study of a population of consecutive Italian obese subjects. We studied 681 obese subjects (514 women and 167 men), with a mean age of 41.1+/-13.9 years (range, 16 to 77 years), mean BMI of 40.2+/-7.6 kg/m2 (range, 30 to 89.8 kg/m2), and a history of obesity for 20.5+/-7 years (range, 10.5 to 30 years). Anthropometric, metabolic, cardiac, and obesity-related risk factors were evaluated., Results: The prevalence of uncomplicated subjects was 27.5%, independent of BMI and duration of obesity. The youngest group of obese subjects showed a higher, but not statistically significantly higher, prevalence of uncomplicated obesity. No statistical difference for the prevalence of impaired fasting glucose, glucose intolerance, high triglycerides, high total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol among BMI categories (from mild to extremely severe obesity degree) was found. Obese subjects with BMI>50 kg/m2 showed a higher prevalence of high blood pressure only when they were compared with the group with a BMI of 30 to 35 kg/m2 (p<0.01). Obese subjects with BMI>40 kg/m2 showed a higher prevalence of hyperinsulinemia than subjects with BMI 30 to 35 kg/m2 (p<0.01)., Discussion: This study shows that a substantial part of an Italian obese population has uncomplicated obesity, and the prevalence of adverse risk factors in this sample is unexpectedly low and partially independent of obesity degree. Uncomplicated obesity could represent a well-defined clinical entity.

Several genetic variants of peroxisome proliferator-activated receptor-gamma2 (PPAR-gamma2) have been identified, among which Pro12Ala, a missense mutation in exon 2, is highly prevalent in Caucasian populations. Up to now, conflicting results with regard to the association between this mutation and complex traits, such as obesity, insulin sensitivity and Type 2 diabetes, have been reported. We investigated the influence of the Pro12Ala polymorphism of PPAR-gamma2 on insulin sensitivity in a large Italian population sample, n=1215, in whom extensive clinical and biochemical analyses were performed. To estimate the insulin sensitivity status, the homeostasis model assessment of insulin resistance (HOMA-IR) was calculated; in the obese/overweight subjects an oral glucose tolerance test (OGTT) was also performed and the Matsuda insulin sensitivity index (ISI) calculated. The insulin secretion index (homeostasis model assessment of percent beta-cell function, HOMA-beta%) was utilized to evaluate beta-cell function. The effect of the Pro12Ala polymorphism on quantitative variables was tested using multiple linear regression analysis. X12Ala (either Pro12Ala or Ala12Ala) genotype was associated with significantly lower fasting insulin levels compared to Pro/Pro (P=0.01 after correction for multiple comparisons) in all subjects. Consistent with this finding, significantly lower HOMA-IR was observed in X12Ala carriers (P=0.013 after correction for multiple comparisons) in all cohort. Moreover, no significant interaction effect was observed between body mass index and X12Ala polymorphism and between gender and X12Ala polymorphism in modulating insulin sensitivity. Our observations substantially extend previous findings and demonstrated that X12Ala variant is significantly associated with greater insulin sensitivity.

Objective: A massive amount of fat tissue, as that observed in obese subjects with BMI over 50 kg/m(2), could affect cardiac morphology and performance, but few data on this issue are available. We sought to evaluate cardiac structure and function in uncomplicated severely obese subjects., Research Methods and Procedures: We studied 55 uncomplicated severely obese patients, 40 women, 15 men, mean age 35.5 +/- 10.2 years, BMI 51.2 +/- 8.8 kg/m(2), range 43 to 81 kg/m(2), with a history of fat excess of at least 10 years, and 55 age-matched normal-weight subjects (40 women, 15 men, mean BMI 23.8 +/- 1.2 kg/m(2)) as a control group. Each subject underwent an echocardiogram to evaluate left ventricular (LV) mass and geometry and systolic and diastolic function., Results: Severely obese subjects showed greater LV mass and indexed LV mass than normal-weight subjects (p < 0.01 for all parameters). Nevertheless, LV mass was appropriate for sex, height(2.7), and stroke work in most (77%) uncomplicated severely obese subjects. In addition, no significant difference in LV mass indices and LV mass appropriateness between obese subjects with BMI > or = 50 kg/m(2) and those with BMI < or = 50 kg/m(2) was found. Obese subjects also showed higher ejection fraction and midwall shortening than normal-weight subjects (p = 0.05 and p < 0.01, respectively), suggesting a hyperdynamic systolic function. No significant difference in systolic performance between obese subjects with BMI > or = 50 kg/m(2) and those with BMI < or = 50 kg/m(2) was seen., Discussion: Our data show that uncomplicated severe obesity, despite the massive fat tissue amount, is associated largely with adapted and appropriate changes in cardiac structure and function.

Metabolic syndrome is related to multiple cardiovascular risk factors. Visceral adipose tissue (VAT) plays a key role in metabolic syndrome. Easy detection of VAT could be an important tool to increase knowledge of metabolic syndrome. The objective of this study was to study the relationship of echocardiographic epicardial adipose tissue to anthropometric and clinical parameters of metabolic syndrome. We selected 72 consecutive subjects, 46.5 +/- 17.4 yr of age, with a body mass index between 22 and 47 kg/m(2). Each subject underwent transthoracic echocardiogram to measure epicardial fat thickness on right ventricle and magnetic resonance imaging to calculate visceral adipose tissue. Anthropometric, metabolic, and cardiac parameters were also evaluated. Echocardiographic epicardial adipose tissue showed a very good correlation with magnetic resonance imaging abdominal VAT and epicardial fat measurement (Bland-Altman plot and linear regression). Multiple regression analysis showed that waist circumference (r(2) = 0.428; P = 0.01), diastolic blood pressure (r(2) = 0. 387; P = 0.02), and fasting insulin (r(2) = 0.387; P = 0.03) were the strongest independent variables correlated with epicardial adipose tissue. Echocardiographic epicardial adipose tissue could be applied as an easy and reliable imaging indicator of VAT and cardiovascular risk.

Gastric bypass has been reported to be associated with markedly suppressed plasma ghrelin levels, suggesting that it is one of the possible weight-reducing factors related to this procedure. The aim of this study was the evaluation of plasma ghrelin levels in patients who had undergone laparoscopic Roux-en-Y gastric bypass (LRYGBP) and laparoscopic adjustable silicone gastric banding (LASGB). Normoweight, obese subjects and patients who had undergone total gastrectomy were used as controls. In this cross-sectional study, we selected 10 subjects who underwent LASGB, 11 subjects with LRYGBP, 10 obese subjects, eight patients with total gastrectomy, and eight normoweight subjects. Plasma ghrelin, insulin, and glucose profiles were determined before and after breakfast and lunch. Obese subjects showed a ghrelin plasma level significantly lower than normoweight subjects (407.3 +/- 21.6 vs. 813 +/- 72.4 pg/ml, P < 0.01). Patients with LRYGBP showed baseline ghrelin levels lower than LASGB (213.5 +/- 73.9 vs. 314.2 +/- 84.3 pg/ml, P = 0.04). Both groups of patients who underwent bariatric surgical procedures also had ghrelin lower than normoweight and obese subjects (P < 0.01 and P < 0.05, respectively). Patients with total gastrectomy showed plasmatic ghrelin levels extremely lower than those in all other groups (32.6 +/- 18.7 pg/ml, P < 0.001 for all). The ghrelin profile in both groups of subjects who underwent LRYGBP and LASGB did not show any meal-related changes as observed in obese and normoweight control groups. Significant difference in plasma ghrelin levels between LRYGBP and LASGB was found, suggesting that both procedures could induce weight loss by different mechanisms in which ghrelin could be involved.

Objective: We studied uncomplicated obesity as a model to evaluate the influence of insulin sensitivity per se on left ventricular mass (LVM) and geometry., Research Methods and Procedures: We selected 50 obese subjects (BMI > 30 kg/m(2); 38 women and 12 men; mean age, 38.4 +/- 10 years; BMI, 36.4 +/- 10.5 kg/m(2)) with normal blood pressure, glucose tolerance, and plasmatic lipid levels. Thirty lean subjects formed the control group. Each subject underwent euglycemic insulin clamp (7 pmol/min per kg) to evaluate whole body glucose use (M index) and echocardiogram to calculate LVM and indexed LVM., Results: Insulin-resistant obese subjects had higher LVM, LVM/h(2.7), LVM/body surface area, and LVM/fat-free mass(kg) (p = 0.001; p = <0.001 p = 0.001, and p = 0.04, respectively) than obese subjects with normal insulin sensitivity. Multivariate regression analysis showed that M index was the strongest independent correlate of LVM (r(2) = 0.34; p = 0.03)., Discussion: Our findings showed that insulin resistance, in uncomplicated obesity, is associated with an increased LVM and precocious changes of left ventricular geometry, whereas preserved insulin sensitivity is not associated with increased LVM.

Objective: To validate transthoracic echocardiography as an easy and reliable imaging method for visceral adipose tissue (VAT) prediction. VAT is recognized as an important indicator of high cardiovascular and metabolic risk. Several methods are applied to estimate VAT, with different results., Research Methods and Procedures: We selected 60 healthy subjects (29 women, 31 men, 49.5 +/- 16.2 years) with a wide range of body mass indexes. Each subject underwent transthoracic echocardiogram and magnetic resonance imaging (MRI) to measure epicardial fat thickness on the right ventricle. Measurements of epicardial adipose tissue thickness were obtained from the same echocardiographic and MRI views and points. MRI was also used to measure VAT cross-sectional areas at the level of L4 to L5. Anthropometric indexes were also measured., Results: Subjects with predominant visceral fat accumulation showed higher epicardial adipose tissue thickness than subjects with predominant peripheral fat distribution: 9.97 +/- 2.88 vs. 4.34 +/- 1.98 (p = 0.005) and 7.19 +/- 2.74 vs. 3.43 +/- 1.64 (p = 0.004) in men and women, respectively. Simple linear regression analysis showed an excellent correlation between epicardial adipose tissue and waist circumference (r = 0.895, p = 0.01) and MRI abdominal VAT (r = 0.864, p = 0.01). Multiple regression analysis showed that epicardial adipose tissue thickness (r(2) = 0.442, p = 0.02) was the strongest independent variable correlated to MRI VAT. Bland test confirmed the good agreement between the two methods., Discussion: Epicardial adipose tissue showed a strong correlation with anthropometric and imaging measurements of VAT. Hence, transthoracic echocardiography could be an easy and reliable imaging method for VAT prediction.

Objective: To evaluate whether or not "uncomplicated" obesity (without associated comorbidities) is really associated with cardiac abnormalities., Research Methods and Procedures: We evaluated cardiac parameters in obese subjects with long-term obesity, normal glucose tolerance, normal blood pressure, and regular plasma lipids. We selected 75 obese patients [body mass index (BMI) >30 kg/m(2)], who included 58 women and 17 men (mean age, 33.7 +/- 11.9 years; BMI, 37.8 +/- 5.5 kg/m(2)) with a > or =10-year history of excess fat, and 60 age-matched normal-weight controls, who included 47 women and 13 men (mean age, 32.7 +/- 10.4 years; BMI, 23.1 +/- 1.4 kg/m(2)). Each subject underwent an oral glucose tolerance test to exclude impaired glucose tolerance or diabetes mellitus, bioelectrical impedance analysis to calculate fat mass and fat-free mass, and echocardiography., Results: Obese patients presented diastolic function impairment, hyperkinetic systole, and greater aortic root and left atrium compared with normal subjects. No statistically significant differences between obese subjects and normal subjects were found in indexed left ventricular mass (LVM/body surface area, LVM/height(2.7), and LVM/fat-free mass(kg)), and no changes in left ventricular geometry were observed. No statistically significant differences in cardiac parameters between extreme (BMI > 40 kg/m(2)) and mild obesity (BMI < 35 kg/m(2)) were observed., Discussion: In conclusion, our data showed that obesity, in the absence of glucose intolerance, hypertension, and dyslipidemia, seems to be associated only with an impairment of diastolic function and hyperkinetic systole, and not with left ventricular hypertrophy.