CIRCULATING ADIPOCYTE-DERIVED EXOSOMAL MICRORNAs ASSOCIATED WITH DECREASED INSULIN RESISTANCE AFTER GASTRIC BYPASS

OBJECTIVE: Exosomes from obese adipose contain dysregulated microRNAs linked to insulin signaling, as compared to lean controls, providing a direct connection between adiposity and insulin resistance. The current study tested the hypotheses that gastric bypass surgery and its subsequent weight loss would normalize adipocyte-derived-exosomal microRNAs associated with insulin signaling and the associated metabolome related to glucose homeostasis. METHODS: African-American female subjects with obesity (N=6; age: 38.5±6.8 years; BMI: 51.2±8.8 kg/m(2)) were tested before and one year after surgery. Insulin resistance (HOMA), serum metabolomics and global microRNA profiles of circulating adipocyte-derived exosomes were evaluated via ANCOVA and correlational analyses. RESULTS: One-year post-surgery, patients showed decreased BMI (−18.6±5.1 kg/m(2); p<0.001), ameliorated insulin resistance (HOMA: 1.94±0.6 pre-surgery, 0.49±0.1 post-surgery; p<0.001), and altered metabolites including branched chain amino acids. Biological pathways analysis of predicted mRNA targets of 168 surgery-responsive microRNAs (p<0.05) identified the insulin signaling pathway (p=1.27E-10; 52/138 elements), among others, in our dataset. The insulin signaling pathway was also a target of 10 microRNAs correlated to changes in HOMA (p<0.05; r>0.4), and 48 microRNAs correlated to changes in BCAA levels. CONCLUSIONS: These data indicate that circulating adipocyte-derived exosomes are modified following gastric bypass surgery and correlate to improved post-surgery insulin resistance

Metabolically protective cytokines adiponectin and fibroblast growth factor-21 are increased by acute overfeeding in healthy humans

Context: Circulating levels of metabolically protective and adverse cytokines are altered in obese humans and rodent models. However, it is not clear whether these cytokines are altered rapidly in response to over-nutrition, or as a later consequence of the obese state. Methods: Forty sedentary healthy individuals were examined prior to and at 3 and 28 days of high fat overfeeding (+1250 kCal/day, 45% fat). Insulin sensitivity (hyperinsulinaemic-euglycaemic clamp), adiposity, serum levels of adiponectin and fibroblast growth factor-21 (FGF21), fatty acid binding protein-4 (FABP4), lipocalin-2 and plasminogen activator factor-1 (PAI1) were assessed. Statistics were performed by repeated measures ANOVA. Results: Overfeeding increased weight, body fat and liver fat, fasting glucose, insulin and reduced insulin sensitivity by clamp (all P <0.05). Metabolically protective cytokines, adiponectin and FGF21 were increased at day 3 of overfeeding (P ≤0.001) and adiponectin was also elevated at day 28 (P=0.001). FABP4, lipocalin-2 and PAI-1 were not changed by overfeeding at either time point. Conclusion: Metabolically protective cytokines, adiponectin and FGF-21, were increased by over nutrition and weight gain in healthy humans, despite increases in insulin resistance. We speculate that this was in attempt to maintain glucose homeostasis in a state of nutritional excess. PAI-I, FABP4 and lipocalin 2 were not altered by overfeeding suggesting that changes in these cytokines may be a later consequence of the obese state.Leonie K. Heilbronn, Lesley V. Campbell, Aimin Xu, Dorit Samocha-Bone

Receptor antibodies as novel therapeutics for diabetes

Antibodies to receptors can block or mimic hormone action. Taking advantage of receptor isoforms, co-receptors and other receptor modulating proteins, antibodies and other designer ligands can enhance tissue specificity and provide new approaches to the therapy of diabetes and other diseases