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. Significance The presence of extracellular miRNAs in body fluids has been exploited as a brand-new source of biomarkers for different diseases. A fraction of those extracellular miRNAs, contained in extracellular vesicles and exosomes, are additionally being revealed as novel mediators of intercellular communication. Here, we show that systemic injection of exosomes transfected with synthetic miRNAs simulating those enriched in the plasma of obese mice robustly induces glucose intolerance, adipose inflammation, and hepatic steatosis in lean mice. These results support a role for exosomal miRNAs in the modulation of glucose and lipid metabolism in mice and may help us uncover thus far unexplored pathological mechanisms and provide us with novel therapeutic targets.

Bisphenol-A (BPA) is a widespread endocrine-disrupting chemical (EDC) used as the base compound in the manufacture of polycarbonate plastics. It alters pancreatic β-cell function and can be considered a risk factor for type 2 diabetes in rodents. Here we used ERβ−/− mice to study whether ERβ is involved in the rapid regulation of K_ATP channel activity, calcium signals and insulin release elicited by environmentally relevant doses of BPA (1 nM). We also investigated these effects of BPA in β-cells and whole islets of Langerhans from humans. 1 nM BPA rapidly decreased K_ATP channel activity, increased glucose-induced [Ca²⁺]_i signals and insulin release in β-cells from WT mice but not in cells from ERβ−/− mice. The rapid reduction in the K_ATP channel activity and the insulinotropic effect was seen in human cells and islets. BPA actions were stronger in human islets compared to mouse islets when the same BPA concentration was used. Our findings suggest that BPA behaves as a strong estrogen via nuclear ERβ and indicate that results obtained with BPA in mouse β-cells may be extrapolated to humans. This supports that BPA should be considered as a risk factor for metabolic disorders in humans.

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 ± 1.6 to 7.5 ± 1.2%, P < 0.01) and the control group (from 8.0 ± 1.4 to 7.5 ± 0.8%, P < 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 ± 2 to 7.2 ± 1.4% and from 8.1 ± 1.8 to 7.1 ± 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.

OBJECTIVE: Hyperglycemia and hypoglycemia currently are considered risk factors for cardiovascular disease in type 1diabetes. Both acute hyperglycemia and hypoglycemia induce endothelial dysfunction and inflammation, raising the oxidative stress. Glucagon-like peptide 1 (GLP-1) has antioxidant properties, and evidence suggests that it protects endothelial function. RESEARCH DESIGN AND METHODS: The effect of both acute hyperglycemia and acute hypoglycemia in type 1 diabetes, with or without the simultaneous infusion of GLP-1, on oxidative stress (plasma nitrotyrosine and plasma 8-iso prostaglandin F2alpha), inflammation (soluble intercellular adhesion molecule-1 and interleukin-6), and endothelial dysfunction has been evaluated. RESULTS: Both hyperglycemia and hypoglycemia acutely induced oxidative stress, inflammation, and endothelial dysfunction. GLP-1 significantly counterbalanced these effects. CONCLUSIONS: These results suggest a protective effect of GLP-1 during both hypoglycemia and hyperglycemia in type 1 diabetes.

Implementation of regular physical activity helps in the maintenance of a healthy metabolic profile both in humans and mice through molecular mechanisms not yet completely defined. Here, we show that high-intensity interval training (HIIT) modifies the microRNA (miRNA) profile of circulating exosomes in mice, including significant increases in miR-133a and miR-133b. Importantly, treatment of sedentary mice with exosomes isolated from the plasma of trained mice improves glucose tolerance, insulin sensitivity, and decreases plasma levels of triglycerides. Moreover, exosomes isolated from the muscle of trained mice display similar changes in miRNA content, and their administration to sedentary mice reproduces the improvement of glucose tolerance. Exosomal miRNAs up-regulated by HIIT target insulin-regulated transcription factor forkhead box O1 (FoxO1) and, accordingly, expression of FoxO1 is decreased in the liver of trained and exosome-treated mice. Treatment with exosomes transfected with a miR-133b mimic or with a specific siRNA targeting FoxO1 recapitulates the metabolic effects observed in trained mice. Overall, our data suggest that circulating exosomes released by the muscle carry a specific miRNA signature that is modified by exercise and induce expression changes in the liver that impact whole-body metabolic profile. Significance The beneficial metabolic effects of exercise are mediated at least in part by the release of soluble factors by the muscles. Exosomes, small vesicles that facilitate the exchange of biological components among cells and tissues, may constitute one of these factors. Here, we show that exercise triggers the release of exosomes by the trained muscle, carrying a specific miRNA signature that induces gene expression changes in the liver, finally contributing to increased insulin sensitivity. Molecular characterization of exercise-induced exosomal miRNAs and their effects may drive the design of novel therapeutic strategies to alleviate insulin resistance and other aging-related ailments in an increasingly older society.