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Adipose tissue is now recognized to have a multitude of functions that are of importance in the regulation of energy balance and substrate metabolism. Different hormones, in particular insulin and catecholamines, govern the storage and utilization of energy in the triglyceride depots. In addition, adipocytes produce several different substances with endocrine or paracrine functions, which regulate the overall energetic homeostasis. With excess energy storage, obesity develops, leading to increased risk for type 2 diabetes and cardiovascular disease. The distribution of body fat appears to be even more important than the total amount of fat. Abdominal and, in particular, visceral adiposity is strongly linked to insulin resistance, type 2 diabetes, hypertension and dyslipidaemia, leading to increased risk of cardiovascular disease. The adverse metabolic impact of visceral fat has been attributed to distinct biological properties of adipocytes in this depot compared with other adipose tissue depots. Indeed, regional variations in the metabolic activity of fat cells have been observed. Furthermore, expression studies aiming at defining the unique biological properties of adipose tissues from distinct anatomical sites have identified depot-related differences in the protein content of fat-produced molecules. In this review we wish to summarize important results from the literature and also some recent data from our own work. The main scope is to describe the biological functions of adipose tissue, and to focus on metabolic, hormonal, and signalling differences between fat depots. [ABSTRACT FROM AUTHOR]

beta-cell dysfunction is an early pathophysiological defect in type 2 diabetes mellitus. Conventional secretagogues, although effective in increasing insulin secretion, may be associated with undesirable side effects, including hypoglycemia, abnormalities in cardiovascular responses, and beta-cell apoptosis. Glucagon-like peptide(GLP)-1 is an incretin hormone displaying glucose-dependent stimulation of insulin secretion, trophic effects on the pancreatic beta-cells, and inhibitory effects on gastrointestinal motility, which has been shown to ameliorate hyperglycemia and reduce glycemic excursions. However, after parenteral administration native GLP-1 is rapidly degraded by plasma dipeptydil peptidase (DPP)-IV. Hence, degradation-resistant, long-acting GLP-1 receptor agonists have been proposed as novel agents for diabetes therapy. Alternatively, inhibitionof DPP-IV-mediated GLP-1 degradation represents another approach for exploiting GLP-1 beneficial effects on metabolic control. This review will summarize the biological effects of GLP-1, the general features of GLP-1 mimetics and DPP-IV inhibitors, and the promising results of recently published clinical trials testing these compounds for the treatment of type 2 diabetes. [ABSTRACT FROM AUTHOR]

Aims: Postprandial hyperglycaemia in patients with Type 2 diabetes mellitus has been linked to the development of cardiovascular disease. This study compared the effects of mealtime (thrice-daily) nateglinide with once-daily glyburide on postprandial glucose levels in patients with Type 2 diabetes and postprandial hyperglycaemia. Methods: Patients with Type 2 diabetes aged ‡ 21 years with 2-h postprandial glucose levels ‡ 11.1 mmol ⁄ l, HbA1c of 6.5–8.5% (48–69 mmol⁄ mol) and BMIof 22–30 kg ⁄m2 were randomized to 6 weeks’ double-blind treatment with nateglinide 120 mg three times daily prior tomeals, or glyburide 5 mg once daily before breakfast. The primary endpoint was the baselineadjusted change in plasma glucose frompreprandial (fasting plasma glucose) to 2-h postprandial glucose levels (2-h postprandial glucose excursion) at 6 weeks. Results: Patients were randomized to nateglinide (n = 122) or glyburide (n = 110).The treatment groups were similar in terms of age, gender, BMI, fasting plasma glucose, 2-h postprandial glucose and HbA1c. At endpoint, nateglinide recipients had significantly greater reductions than those receiving glyburide in both the 2-h ()2.4 vs.)1.6 mmol ⁄ l;P = 0.02)and1-h()1.7 vs. )0.9 mmol⁄ l; P = 0.016) postprandial glucose excursions.Adverse events,most commonly symptomatic hypoglycaemia,were reported in26%of recipients of glyburide and22%of recipients of nateglinide. Episodes of suspected mild hypoglycaemiawere reported in 24% of recipients of glyburide and 10% of recipients of nateglinide. Conclusions: Nateglinide leads to greater reductions in postprandial glucose excursions and is associated with a lower risk of hypoglycaemia than glyburide in this selected population of patients with Type 2 diabetes. [ABSTRACT FROM AUTHOR]

Aims: The aim of the study was to evaluate and compare continuous subcutaneous insulin infusion (CSII) use in pediatric and adult age groups. Methods: Data were collected with a questionnaire sent by e-mail to CSII-experienced Diabetes Centers. The questionnaire assessed: (1) number of CSII-treated patients; (2) patient demographic data and characteristics; (3) structure and organization of Diabetes Centers providing CSII therapy; (4) pump characteristics (conventional pump, sensor-augmented pump); and (5) CSII dropouts. Results: A total of 217 out of 1093 Italian centers participated: 51 pediatric (23.5 %) and 166 (76.5 %) adult centers (AP). Compared to a survey performed in 2005, there was a significant increase in the number of pediatric units when compared to adult units (112 vs 37 %, respectively, p < 0.05). Pediatric age is characterized by a greater concern for quality of life and injections, and a higher dropout rate (10.6 vs 8.9 %) mainly related to pump wearability and site reactions. A complete diabetes-care team is associated with a superior use of technology (fewer dropouts, increased CGM and advanced bolus use) which is, however, still used in a small percentage of patients. Conclusions: In Italy, the number of CSII-treated pediatric patients (PP) is growing more significantly when compared to adults. Only 60 % of all patients are using advanced functions and 20 % are using CGMs continuously. This confirms the great interest in diabetes technology that is growing in pediatric diabetologists. However, much improvement is warranted in the organization and specialized training of pediatric, adult and transitional facilities. [ABSTRACT FROM AUTHOR]

Objectives Poorer control of risk factors for cardiovascular disease ( CVD) has been reported in diabetic women, as compared with diabetic men. It has been proposed that this finding is due to gender disparities in treatment intensity. We investigated this hypothesis in a large contemporary cohort of subjects with type 2 diabetes. Design Observational, cross-sectional study. Subjects and setting Consecutive patients with type 2 diabetes from the Renal Insufficiency And Cardiovascular Events ( RIACE) Italian multicentre study ( n = 15 773), attending 19 hospital-based diabetes clinics in 2007-2008. Main outcome measures Traditional CVD risk factors, macro- and microvascular complications and current glucose-, lipid- and blood pressure ( BP)-lowering treatments were assessed. Results Although CVD was more prevalent in men, women showed a less favourable CVD risk profile and worse performance in achieving treatment targets for haemoglobin A1c, LDL, HDL and non- HDL cholesterol, systolic blood pressure ( BP) and in particular obesity [body mass index ( BMI) and waist circumference], but not for triglycerides and diastolic BP. However, women were more frequently receiving pharmacological treatment for hypertension and to a lesser extent hyperglycaemia and dyslipidaemia than men, and female gender remained an independent predictor of unmet therapeutic targets after adjustment for confounders such as treatments, BMI, duration of diabetes and, except for the systolic BP goal, age. Conclusions In women with type 2 diabetes from the RIACE cohort, a more adverse CVD risk profile and a higher likelihood of failing treatment targets, compared with men, were not associated with treatment differences. This suggests that factors other than gender disparities in treatment intensity are responsible. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the rate and determinants of concordance between advanced diabetic retinopathy (DR) and chronic kidney disease (CKD), as assessed by both albuminuria and estimated glomerular filtration rate (eGFR), in the large cohort of the Renal Insufficiency And Cardiovascular Events (RIACE) Italian multicenter study.Research Design and Methods: Patients with type 2 diabetes (n = 15,773) visiting consecutively 19 hospital-based diabetes clinics in years 2007 and 2008 were examined. DR was assessed by dilated fundoscopy. CKD was defined based on albuminuria and eGFR.Results: CKD was present in 58.64% of subjects with advanced DR, whereas advanced DR was detectable only in 15.28% of individuals with any CKD and correlated with the albuminuric CKD phenotypes more than with the nonalbuminuric phenotype. Age, male sex, diabetes duration, hemoglobin A(1c), hypertension, triglycerides, previous cardiovascular disease, and, inversely, HDL-cholesterol correlated independently with the presence of any CKD in individuals with advanced DR; correlates differed according to the presence of albuminuria, reduced eGFR, or both. Conversely, factors associated with the presence of advanced DR in subjects with any CKD were diabetes treatment, previous cardiovascular disease, albuminuria, and, inversely, smoking, eGFR, and age at diagnosis.Conclusions: Concordance of CKD with advanced DR is low in subjects with type 2 diabetes, and CKD without advanced DR is more frequent than isolated advanced DR, at variance with type 1 diabetes. Factors independently associated with the presence of any CKD in individuals with advanced DR differ, at least in part, from those correlating with the presence of advanced DR in subjects with any CKD and by CKD phenotype. [ABSTRACT FROM AUTHOR]

The insulin signaling cascade was investigated in rat myocardium in vivo in the presence of streptozocin (STZ)-induced diabetes and after diabetes treatment by islet transplantation under the kidney capsule. The levels of insulin-stimulated tyrosine phosphorylation of the insulin receptor beta-subunit, insulin receptor substrate (IRS)-2, and p52(Shc) were increased in diabetic compared with control heart, whereas tyrosine phosphorylation of IRS-1 was unchanged. The amount of the p85 subunit of phosphatidylinositol 3-kinase (PI 3-kinase) and the level of PI 3-kinase activity associated with IRS-2 were also elevated in diabetes, whereas no changes in IRS-1-associated PI 3-kinase were observed. Insulin-induced phosphorylation of Akt on Thr-308 was increased fivefold in diabetic heart, whereas Akt phosphorylation on Ser-473 was normal. In contrast with Akt phosphorylation, insulin-induced phosphorylation of glycogen synthase kinase (GSK)-3, a major cellular substrate of Akt, was markedly reduced in diabetes. In islet-transplanted rats, the majority of the alterations in insulin-signaling proteins found in diabetic rats were normalized, but insulin stimulation of IRS-2 tyrosine phosphorylation and association with PI 3-kinase was blunted. In conclusion, in the diabetic heart, 1) IRS-1, IRS-2, and p52(Shc) are differently altered, 2) the levels of Akt phosphorylation on Ser-473 and Thr-308, respectively, are not coordinately regulated, and 3) the increased activity of proximal-signaling proteins (i.e., IRS-2 and PI 3-kinase) is not propagated distally to GSK-3. Islet transplantation under the kidney capsule is a potentially effective therapy to correct several diabetes-induced abnormalities of insulin signaling in cardiac muscle but does not restore the responsiveness of all signaling reactions to insulin. [ABSTRACT FROM AUTHOR]

Insulin-dependent diabetes in rats is characterized by abnormalities of post-binding insulin signaling reactions that are not fully corrected by exogenous insulin therapy. The aim of this study was to investigate the effects of islet transplantation on insulin signaling in skeletal muscle and myocardium of streptozocin (STZ)-induced diabetic rats. Control rats, untreated diabetic rats, and diabetic rats transplanted with syngeneic islets under the kidney capsule were studied. Compared with controls, diabetic rats were characterized by multiple insulin signaling abnormalities in skeletal muscle, which included 1) increased insulin-stimulated tyrosine phosphorylation of the insulin receptor beta-subunit and insulin receptor substrates IRS-1 and IRS-2, 2) increased substrate tyrosine phosphorylation in the basal state, 3) a decreased amount of IRS-1 protein, 4) markedly elevated basal and insulin-stimulated phosphatidylinositol (PI) 3-kinase activity in anti-IRS-1 immunoprecipitates from total tissue extracts, and 5) increased PI 3-kinase activity in low-density microsomes. A similar augmentation of insulin receptor and substrate tyrosine phosphorylation in response to STZ-diabetes was also found in myocardium, although with lower magnitude than that found in skeletal muscle. In addition, STZ-diabetes resulted in decreased IRS-1 and increased IRS-2 protein levels in myocardium. Islet transplantation fully corrected the diabetes-induced changes in protein tyrosine phosphorylation and PI 3-kinase activity and normalized IRS-1 and IRS-2 protein content in both skeletal muscle and myocardium. Thus, insulin delivered into the systemic circulation by pancreatic islets transplanted under the kidney capsule can adequately correct altered insulin signaling mechanisms in insulinopenic diabetes. [ABSTRACT FROM AUTHOR]

Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted from entero-endocrine L cells in response to ingested nutrients. The most important action of GLP-1 is the enhancement of glucose-stimulated insulin secretion by beta-cells mediated by activation of the GLP-1 G-protein-coupled receptor. Additionally, GLP-1 receptor activation on beta-cells may contribute to regulate beta-cell proliferation, neogenesis and survival. Other non-tropic beta-cell effects of this hormone include inhibition of gastric emptying, glucagon secretion, food intake, and stimulation of peripheral glucose uptake. However, in addition to actions that contribute to glucose homeostasis, GLP-1 appears to exert relevant actions on other tissues not considered classic metabolic regulators of glucose homeostasis, such as the heart and lungs. Due to the pleiotropic actions of GLP-1, incretin-based therapies represent not only an expanding pharmacological area to manage hyperglycemia in type 2 diabetes but also potentially attractive tools to address tissue dysfunction in diabetes and other human diseases. [ABSTRACT FROM AUTHOR]