MicroRNAs contribute to compensatory β cell expansion during pregnancy and obesity

J Clin Invest. 2012 Oct;122(10):3541-51. doi: 10.1172/JCI64151. Epub 2012 Sep 10.

Abstract

Pregnancy and obesity are frequently associated with diminished insulin sensitivity, which is normally compensated for by an expansion of the functional β cell mass that prevents chronic hyperglycemia and development of diabetes mellitus. The molecular basis underlying compensatory β cell mass expansion is largely unknown. We found in rodents that β 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 β cells using specific anti-miR molecules mimicked gene expression changes occurring during β 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 β cell mass expansion occurring under different insulin resistance states.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptation, Physiological / physiology*
  • Animals
  • Cells, Cultured / drug effects
  • Cells, Cultured / metabolism
  • Cytokines / biosynthesis
  • Cytokines / genetics
  • Estradiol / analogs & derivatives
  • Estradiol / pharmacology
  • Estradiol / physiology
  • Estrogen Antagonists / pharmacology
  • Female
  • Fulvestrant
  • Gene Expression Regulation / physiology
  • Glucagon-Like Peptide 1 / physiology
  • Glucagon-Like Peptide-1 Receptor
  • Insulin Resistance / physiology*
  • Islets of Langerhans / growth & development*
  • Islets of Langerhans / metabolism
  • Islets of Langerhans / pathology*
  • Male
  • Mice
  • Mice, Mutant Strains
  • MicroRNAs / biosynthesis
  • MicroRNAs / genetics
  • MicroRNAs / physiology*
  • Obesity / pathology*
  • Obesity / physiopathology
  • Organ Size / drug effects
  • Postpartum Period / metabolism
  • Pregnancy / metabolism
  • Pregnancy / physiology*
  • Rats
  • Rats, Wistar
  • Receptors, G-Protein-Coupled / agonists
  • Receptors, G-Protein-Coupled / biosynthesis
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, Glucagon / agonists
  • Receptors, Glucagon / deficiency
  • Signal Transduction / drug effects
  • Signal Transduction / physiology

Substances

  • Cytokines
  • Estrogen Antagonists
  • Glp1r protein, mouse
  • Glp1r protein, rat
  • Glucagon-Like Peptide-1 Receptor
  • Gper1 protein, rat
  • MIRN144 microRNA, rat
  • MIRN338 microRNA, rat
  • MIRN451 microRNA, rat
  • MicroRNAs
  • Receptors, G-Protein-Coupled
  • Receptors, Glucagon
  • Fulvestrant
  • Estradiol
  • Glucagon-Like Peptide 1