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Objective: Some obese individuals have normal insulin sensitivity. It is controversial whether this phenotype is associated with increased all-cause mortality risk.Research Design and Methods: Fifteen-year all-cause mortality data were obtained through the Regional Health Registry for 2,011 of 2,074 Caucasian middle-aged individuals of the Cremona Study, a population study on the prevalence of diabetes in Italy. Individuals were divided in four categories according to BMI (nonobese: <30 kg/m²; obese: ≥30 kg/m²) and estimated insulin resistance (insulin sensitive: homeostasis model assessment of insulin resistance <2.5; insulin resistant ≥2.5).Results: Obese insulin-sensitive subjects represented 11% (95% CI 8.1-14.5) of the obese population. This phenotype had similar BMI but lower waist circumference, blood pressure, fasting glucose, triglycerides, and fibrinogen and higher HDL cholesterol than obese insulin-resistant subjects. In the 15-year follow-up, 495 deaths (cardiovascular disease [CVD]: n = 221; cancer: n = 180) occurred. All-cause mortality adjusted for age and sex was higher in the obese insulin-resistant subjects (hazard ratio 1.40 [95% CI 1.08-1.81], P = 0.01) but not in the obese insulin-sensitive subjects (0.99 [0.46-2.11], P = 0.97) when compared with nonobese insulin-sensitive subjects. Also, mortality for CVD and cancer was higher in the obese insulin-resistant subjects but not in the obese insulin-sensitive subjects when compared with nonobese insulin-sensitive subjects.Conclusions: In contrast to obese insulin-resistant subjects, metabolically healthy obese individuals are less common than previously thought and do not show increased all-cause, cancer, and CVD mortality risks in a 15-year follow-up study. [ABSTRACT FROM AUTHOR]

Objective: Monocyte chemoattractant protein-1 (MCP-1/CCL2) is a chemokine involved into the pathogenesis of atherosclerosis and has prognostic value in the acute and chronic phases in patients with acute coronary syndromes.Research Design and Methods: MCP-1/CCL2 concentration was measured in plasma fractions of 363 middle-aged overweight/obese individuals (aged 61 +/- 12 years, BMI 30.1 +/- 6.6 kg/m(2), 15% with type 2 diabetes, and 12% with impaired glucose tolerance) of a population survey carried out in 1990-1991 in Lombardy, Italy (Cremona Study), and cardiovascular disease (CVD) mortality was assessed in 2006 through Regional Health Registry files.Results: At baseline MCP-1/CCL2 was increased in individuals with type 2 diabetes (P < 0.05) and showed significant correlations with biochemical risk markers of atherosclerosis. After 15 years, among the 363 subjects, there were 82 deaths due to CVD. In univariate analysis age, sex, fasting glucose and insulin, fibrinogen, glucose tolerance status, smoking habit, and MCP-1/CCL2 were associated with CVD mortality. Age, sex, fasting serum glucose, MCP-1/CCL2, and smoking habit maintained an independent association with CVD mortality in multiple regression analysis. In a subgroup of 113 subjects in whom data for C-reactive protein (CRP) were available, its level was not predictive of CVD mortality.Conclusions: In middle-aged overweight/obese individuals MCP-1/CCL2 was independently associated with CVD mortality. Further studies will be necessary to establish its role as a surrogate biomarker and as a potential therapeutic target. [ABSTRACT FROM AUTHOR]

Objective: Rapamycin is an immunosuppressive drug currently used to prevent graft rejection in humans, which is considered permissive for tolerance induction. Rapamycin allows expansion of both murine and human naturally occurring CD4(+)CD25(+)FOXP3(+) T regulatory cells (nTregs), which are pivotal for the induction and maintenance of peripheral tolerance. Preclinical murine models have shown that rapamycin enhances nTreg proliferation and regulatory function also in vivo. Objective of this study was to assess whether rapamycin has in vivo effects on human nTregs.Research Design and Methods: nTreg numbers and function were examined in a unique set of patients with type 1 diabetes who underwent rapamycin monotherapy before islet transplantation.Results: We found that rapamycin monotherapy did not alter the frequency and functional features, namely proliferation and cytokine production, of circulating nTregs. However, nTregs isolated from type 1 diabetic patients under rapamycin treatment had an increased capability to suppress proliferation of CD4(+)CD25(-) effector T-cells compared with that before treatment.Conclusions: These findings demonstrate that rapamycin directly affects human nTreg function in vivo, which consists of refitting their suppressive activity, whereas it does not directly change effector T-cell function. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The beta-score is a highly regarded approach to the assessment of transplant functionality. Our aim was to develop an index of beta-cell function that hinges on the pillars of the beta-score (daily insulin requirement and A1C), has a straightforward physiological interpretation, and does not require the execution of an insulin stimulation test. RESEARCH DESIGN AND METHODS: The new index is denoted transplant estimated function (TEF) and is obtained from the daily insulin requirement and A1C. TEF estimates the amount of insulin secreted daily and can be normalized to the number of transplanted islets, thus permitting evaluation of the cost-effectiveness of the transplant. TEF was compared with the area under the curve of C-peptide [AUC(C-pep)] concentration over 24 h, as well as the acute insulin response to intravenous glucose (AIR(glu)) and to arginine (AIR(arg)). The association between TEF and beta-score was also investigated. RESULTS: The correlation of TEF with 24-h AUC(C-pep) was r = 0.73 (P < 0.005), whereas that for beta-score versus 24-h AUC(C-pep) was r = 0.33 (NS). The correlation of TEF with AIR(glu) was r = 0.59 (P < 0.001) and close to that for beta-score versus AIR(glu) (r = 0.65, P < 0.001). The correlation of TEF with AIR(arg) was r = 0.33 (P < 0.005) and was similar to that for beta-score versus AIR(arg) (r = 0.34, P < 0.005). TEF and beta-score were correlated well (r = 0.69, P < 0.0001) and showed similar time profiles. CONCLUSIONS: TEF estimates daily insulin secretion, it is simpler than the beta-score, and its performance against reference indexes of beta-cell secretion is in line with that exhibited by beta-score. TEF can be normalized to the number of transplanted islets and thereby provides a benchmarking tool to evaluate the cost-effectiveness of the transplant. [ABSTRACT FROM AUTHOR]