Osteocalcin induces release of glucagon-like peptide-1 and thereby stimulates insulin secretion in mice

PLoS One. 2013;8(2):e57375. doi: 10.1371/journal.pone.0057375. Epub 2013 Feb 20.

Abstract

The uncarboxylated form (ucOC), but not the γ-carboxylated form (GlaOC), of the bone-derived protein osteocalcin stimulates insulin secretion and regulates energy metabolism in insulin target tissues. Glucagon-like peptide-1 (GLP-1) is an insulin secretagogue that is released from the gut in response to food intake. We have now found that Gprc6a, a putative ucOC receptor, is expressed in epithelial cells of the mouse small intestine as well as in STC-1 enteroendocrine cells. Secretion of GLP-1 by STC-1 cells was stimulated by ucOC but not by GlaOC. The serum GLP-1 concentration in mice was increased by intraperitoneal or oral administration of ucOC, whereas GlaOC was effective in this regard only after oral application. Serum insulin levels were also increased by ucOC, and this effect was potentiated by an inhibitor of dipeptidyl peptidase IV and blocked by a GLP-1 receptor antagonist. Intravenous injection of ucOC in mice increased the serum GLP-1 concentration, and also increased the serum level of insulin. Our results suggest that ucOC acts via Gprc6a to induce GLP-1 release from the gut, and that the stimulatory effect of ucOC on insulin secretion is largely mediated by GLP-1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Cell Line
  • Dipeptidyl Peptidase 4 / metabolism
  • Dipeptidyl-Peptidase IV Inhibitors / pharmacology
  • Enteroendocrine Cells / cytology
  • Enteroendocrine Cells / drug effects*
  • Enteroendocrine Cells / metabolism
  • Gene Expression Regulation / drug effects
  • Glucagon-Like Peptide 1 / blood
  • Glucagon-Like Peptide 1 / genetics*
  • Glucagon-Like Peptide-1 Receptor
  • Injections, Intravenous
  • Insulin / agonists
  • Insulin / blood
  • Insulin / metabolism*
  • Insulin Secretion
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Osteocalcin / metabolism
  • Osteocalcin / pharmacology*
  • Protein Isoforms / metabolism
  • Protein Isoforms / pharmacology
  • Receptors, G-Protein-Coupled / genetics*
  • Receptors, G-Protein-Coupled / metabolism
  • Receptors, Glucagon / antagonists & inhibitors
  • Receptors, Glucagon / genetics
  • Receptors, Glucagon / metabolism
  • Signal Transduction / drug effects

Substances

  • Dipeptidyl-Peptidase IV Inhibitors
  • GPRC6A protein, mouse
  • Glp1r protein, mouse
  • Glucagon-Like Peptide-1 Receptor
  • Insulin
  • Protein Isoforms
  • Receptors, G-Protein-Coupled
  • Receptors, Glucagon
  • Osteocalcin
  • Glucagon-Like Peptide 1
  • Dipeptidyl Peptidase 4

Grant support

This work was supported by KAKENHI from Japan Society for Promotion of Science to MH (24229009), JG (23792127), HT (24592805) and MM (24592804). AM is a Research Fellow (RPD program) of Japan Society for the Promotion of Science. The Uehara Memorial Foundation (to AM). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.