Induction of miR-132 and miR-212 Expression by Glucagon-Like Peptide 1 (GLP-1) in Rodent and Human Pancreatic β-Cells

Mol Endocrinol. 2015 Sep;29(9):1243-53. doi: 10.1210/me.2014-1335. Epub 2015 Jul 28.

Abstract

Better understanding how glucagon-like peptide 1 (GLP-1) promotes pancreatic β-cell function and/or mass may uncover new treatment for type 2 diabetes. In this study, we investigated the potential involvement of microRNAs (miRNAs) in the effect of GLP-1 on glucose-stimulated insulin secretion. miRNA levels in INS-1 cells and isolated rodent and human islets treated with GLP-1 in vitro and in vivo (with osmotic pumps) were measured by real-time quantitative PCR. The role of miRNAs on insulin secretion was studied by transfecting INS-1 cells with either precursors or antisense inhibitors of miRNAs. Among the 250 miRNAs surveyed, miR-132 and miR-212 were significantly up-regulated by GLP-1 by greater than 2-fold in INS-1 832/3 cells, which were subsequently reproduced in freshly isolated rat, mouse, and human islets, as well as the islets from GLP-1 infusion in vivo in mice. The inductions of miR-132 and miR-212 by GLP-1 were correlated with cAMP production and were blocked by the protein kinase A inhibitor H-89 but not affected by the exchange protein activated by cAMP activator 8-pCPT-2'-O-Me-cAMP-AM. GLP-1 failed to increase miR-132 or miR-212 expression levels in the 832/13 line of INS-1 cells, which lacks robust cAMP and insulin responses to GLP-1 treatment. Overexpression of miR-132 or miR-212 significantly enhanced glucose-stimulated insulin secretion in both 832/3 and 832/13 cells, and restored insulin responses to GLP-1 in INS-1 832/13 cells. GLP-1 increases the expression of miRNAs 132 and 212 via a cAMP/protein kinase A-dependent pathway in pancreatic β-cells. Overexpression of miR-132 or miR-212 enhances glucose and GLP-1-stimulated insulin secretion.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cyclic AMP / analogs & derivatives
  • Cyclic AMP / biosynthesis
  • Cyclic AMP / genetics
  • Cyclic AMP / pharmacology
  • Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors
  • Diabetes Mellitus, Type 2 / metabolism
  • Glucagon-Like Peptide 1 / pharmacology*
  • Glucose / metabolism
  • Humans
  • Insulin / metabolism
  • Insulin Secretion
  • Insulin-Secreting Cells / cytology
  • Insulin-Secreting Cells / metabolism*
  • Isoquinolines / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs / biosynthesis*
  • MicroRNAs / genetics
  • Protein Kinase Inhibitors / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Sulfonamides / pharmacology

Substances

  • 8-(4-chlorophenylthio)-2'-O-methyladenosine-3',5'-monophosphate acetoxymethyl ester
  • Insulin
  • Isoquinolines
  • MIRN132 microRNA, human
  • MIRN132 microRNA, mouse
  • MIRN132 microRNA, rat
  • MIRN212 microRNA, human
  • MIRN212 microRNA, mouse
  • MIRN212 microRNA, rat
  • MicroRNAs
  • Protein Kinase Inhibitors
  • Sulfonamides
  • Glucagon-Like Peptide 1
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • Glucose
  • N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide