Obesity is frequently associated with metabolic disease. Here, we show that obesity changes the miRNA profile of plasma exosomes in mice, including increases in miR-122, miR-192, miR-27a-3p, and miR-27b-3p. Importantly, treatment of lean mice with exosomes isolated from obese mice induces glucose intolerance and insulin resistance. Moreover, administration of control exosomes transfected with obesity-associated miRNA mimics strongly induces glucose intolerance in lean mice and results in central obesity and hepatic steatosis. Expression of the candidate target gene Ppara is decreased in white adipose tissue but not in the liver of mimic-treated (MIMIC) mice, and this is accompanied by increased circulating free fatty acids and hypertriglyceridemia. Treatment with a specific siRNA targeting Ppara transfected into exosomes recapitulates the phenotype induced by obesity-associated miRNAs. Importantly, simultaneously reducing free fatty acid plasma levels in MIMIC mice with either the lipolysis inhibitor acipimox or the PPARα agonist fenofibrate partially protects against these metabolic alterations. Overall, our data highlight the central role of obesity-associated exosomal miRNAs in the etiopathogeny of glucose intolerance and dyslipidemia.

Background Progressive β-cell failure is a characteristic feature of type 2 diabetes; consequently, β-cell secretagogues are useful for achieving sufficient glycaemic control. The European GUIDE study is the first large-scale head-to-head comparison of two sulphonylureas designed for once-daily administration used under conditions of everyday clinical practice.Design Eight hundred and forty-five type 2 diabetic patients were randomized to either gliclazide modified release (MR) 30 -120 mg daily or glimepiride 1 -6 mg daily as monotherapy or in combination with their current treatment (metformin or an α-glucosidase inhibitor) according to a double-blind, 27-week, parallel-group design. Efficacy was evaluated by HbA1c and safety by hypoglycaemic episodes using the European Agency definition.Results HbA 1c decreased similarly in both groups from 8·4% to 7·2% on gliclazide MR and from 8·2% to 7·2% on glimepiride. Approximately 50% of the patients achieved HbA1c levels less than 7%, and 25% less than 6·5%. The mean difference between groups of the final HbA 1c was −0·06% (noninferiority test P < 0·0001). No hypoglycaemia requiring external assistance occurred. Hypoglycaemia with blood glucose level < 3 mmol L −1 occurred significantly less frequently (P = 0·003) with gliclazide MR (3·7% of patients) compared with glimepiride (8·9% of patients). The distribution of the sulphonylurea doses was similar in both groups.Conclusions This study provides new insights into therapeutic strategies using sulphonylureas. It shows that gliclazide MR is at least as effective as glimepiride, either as monotherapy or in combination. The safety of gliclazide MR was significantly better, demonstrating approximately 50% fewer confirmed hypoglycaemic episodes in comparison with glimepiride.

OBJECTIVE -To evaluate whether the continuous glucose monitoring system (CGMS; MiniMed, Sylmar, CA) is useful for investigating the incidence of unrecognized hypoglycemias in type 1 and type 2 diabetic patients and for improving metabolic control in type 1 diabetic patients. RESEARCH DESIGN AND METHODS-A total of 70 diabetic subjects (40 type 1 and 30 type 2 subjects) were monitored using the CGMS. The number of unrecognized hypoglycemias was registered. Furthermore, the 40 type 1 diabetic patients whose treatment was modified in accordance with the information obtained from the CGMS were compared with a control group of 35 different type 1 diabetic patients using intensive capillary glucose measurements. HbA 1c levels were measured before the monitoring period and 3 months later.RESULTS -The CGMS detected unrecognized hypoglycemias in 62.5% of the type 1 diabetic patients and in 46.6% of the type 2 diabetic patients. We found that 73.7% of all events occurred at night. HbA 1c concentrations decreased significantly in both the group of type 1 diabetic subjects monitored with the CGMS (from 8.3 Ϯ 1.6 to 7.5 Ϯ 1.2%, P Ͻ 0.01) and the control group (from 8.0 Ϯ 1.4 to 7.5 Ϯ 0.8%, P Ͻ 0.01). The greatest reduction was observed in the subgroup of patients who started continuous subcutaneous insulin infusion therapy, both in the CGMS-monitored and control groups (from 9.4 Ϯ 2 to 7.2 Ϯ 1.4% and from 8.1 Ϯ 1.8 to 7.1 Ϯ 0.6%, respectively).CONCLUSIONS -The CGMS is useful for detecting unrecognized hypoglycemias in type 1 and type 2 diabetic subjects; however, it is not better than standard capillary glucose measurements for improving metabolic control of type 1 diabetic subjects, regardless of the therapeutic regimen. Diabetes Care 26:1153-1157, 2003S ome relevant prospective studies have demonstrated that good metabolic control of diabetes decreases the risk of chronic complications (1,2).Intensive therapeutic regimens with multiple insulin injections (MIIs) combined with frequent measurements of capillary blood glucose levels are known to be the most useful ways of achieving good metabolic control. It is also known that intensive regimens can increase the number of hypoglycemias and that the perception of autonomic symptomatology may decrease over time.It is often difficult to achieve optimal control (3,4), despite intensive insulin therapy and frequent self-monitoring of blood glucose, partly because of the limitations of the glycemic profile obtained from intermittent fingersticks (5). A new Holter-style sensor system recently came on the market (continuous glucose monitoring system [CGMS]; MiniMed) for continuously measuring glucose concentrations in subcutaneous tissue (6). This system has been validated by several reports (7,8) and has been shown to provide a good correlation between blood and interstitial glucose levels (9 -11). The continuous glucose profile obtained using this system is easy for physicians to interpret, thus patient treatment can be modified and glucose control improved. Recent studies have show...