MicroRNAs contribute to compensatory β cell expansion during pregnancy and obesity

Pregnancy and obesity are frequently associated with diminished insulin sensitivity, which is normally compensated for by an expansion of the functional beta cell mass that prevents chronic hyperglycemia and development of diabetes mellitus. The molecular basis underlying compensatory beta cell mass expansion is largely unknown. We found in rodents that beta cell mass expansion during pregnancy and obesity is associated with changes in the expression of several islet microRNAs, including miR-338-3p. In isolated pancreatic islets, we recapitulated the decreased miR-338-3p level observed in gestation and obesity by activating the G protein-coupled estrogen receptor GPR30 and the glucagon-like peptide 1 (GLP1) receptor. Blockade of miR-338-3p in beta cells using specific anti-miR molecules mimicked gene expression changes occurring during beta cell mass expansion and resulted in increased proliferation and improved survival both in vitro and in vivo. These findings point to a major role for miR-338-3p in compensatory beta cell mass expansion occurring under different insulin resistance states.