MicroRNAs contribute to compensatory β cell expansion during pregnancy and obesity

• Published in: The Journal of clinical investigation Vol. 122; no. 10; pp. 3541 - 3551
• Main Authors: Jacovetti, Cécile, Abderrahmani, Amar, Parnaud, Géraldine, Jonas, Jean-Christophe, Peyot, Marie-Line, Cornu, Marion, Laybutt, Ross, Meugnier, Emmanuelle, Rome, Sophie, Thorens, Bernard, Prentki, Marc, Bosco, Domenico, Regazzi, Romano
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.10.2012
• Subjects: Adaptation, Physiological - physiology; Animals; Care and treatment; Causes of; 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; Genetic aspects; 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; Life Sciences; Male; Mice; Mice, Mutant Strains; MicroRNA; MicroRNAs - biosynthesis; MicroRNAs - genetics; MicroRNAs - physiology; Obesity; Obesity - pathology; Obesity - physiopathology; Organ Size - drug effects; Pancreatic beta cells; Physiological aspects; Postpartum Period - metabolism; Pregnancy; 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; Belgium; France; Switzerland; DIABETES-MELLITUS; PANCREATIC-ISLETS; PROTEIN-COUPLED RECEPTOR; PROBE LEVEL; INSULIN-SECRETION; MASS; ESTROGEN; PROLIFERATION; PLACENTAL-LACTOGEN; EXPRESSION
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI64151

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.