Pioglitazone (PIO) is an agonist of peroxisome proliferator-activated receptor-γ (PPARγ) which is predominantly expressed in adipose tissue and improves insulin sensitivity in patients with type 2 diabetes (T2D). We hypothesized that PIO effects are mediated, at least in part, by changes in the cargo composition (specifically, miRNAs) of circulating exosomes. We tested this hypothesis in a 3-month trial in which 24 patients with T2D who were well-controlled (HbA1c ≤ 7.0%) with diet/exercise or metformin were randomized to either PIO or placebo (PLA) treatment (NCT00656864). Levels of 42 miRNAs expressed in adipocyte exosomes were measured in exosomes isolated from fasting plasma samples obtained before and after treatment. Levels of exosomal miR-374b-5p, miR-20a-5p, miR-7-5p, and miR-195-5p changed significantly (fold change > 1.5, P < 0.05, FDR < 0.17) in response to PIO treatment relative to PLA (Figure). Changes in exosomal miRNAs correlated with changes in fasting glucose and insulin levels (r > 0.4, P < 0.05, FDR < 0.1). These data suggest that the change in the abundance of specific miRNAs in circulating exosomes may serve as a biomarker of response to PIO and that exosomal miR-374b-5p, miR-20a-5p, miR-7-5p, and miR-195-5p might play mechanistic roles in long-range inter-organ crosstalk.
Y.O. Nunez Lopez: None. R.E. Pratley: Other Relationship; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eisai Inc., GlaxoSmithKline plc., Janssen Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Inc., Ligand Pharmaceuticals, Inc., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk Inc., Pfizer Inc., Sanofi-Aventis, Takeda Development Center Americas, Inc..