Ectopic expression of GIP in pancreatic β-cells maintains enhanced insulin secretion in mice with complete absence of proglucagon-derived peptides

Diabetes. 2013 Feb;62(2):510-8. doi: 10.2337/db12-0294. Epub 2012 Oct 25.


Glucagon and glucagon-like peptide-1 (GLP-1) are produced in pancreatic α-cells and enteroendocrine L-cells, respectively, in a tissue-specific manner from the same precursor, proglucagon, that is encoded by glucagon gene (Gcg), and play critical roles in glucose homeostasis. Here, we studied glucose homeostasis and β-cell function of Gcg-deficient mice that are homozygous for a Gcg-GFP knock-in allele (Gcg(gfp/gfp)). The Gcg(gfp/gfp) mice displayed improved glucose tolerance and enhanced insulin secretion, as assessed by both oral glucose tolerance test (OGTT) and intraperitoneal glucose tolerance test (IPGTT). Responses of glucose-dependent insulinotropic polypeptide (GIP) to both oral and intraperitoneal glucose loads were unexpectedly enhanced in Gcg(gfp/gfp) mice, and immunohistochemistry localized GIP to pancreatic β-cells of Gcg(gfp/gfp) mice. Furthermore, secretion of GIP in response to glucose was detected in isolated islets of Gcg(gfp/gfp) mice. Blockade of GIP action in vitro and in vivo by cAMP antagonism and genetic deletion of the GIP receptor, respectively, almost completely abrogated enhanced insulin secretion in Gcg(gfp/gfp) mice. These results indicate that ectopic GIP expression in β-cells maintains insulin secretion in the absence of proglucagon-derived peptides (PGDPs), revealing a novel compensatory mechanism for sustaining incretin hormone action in islets.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cyclic AMP / antagonists & inhibitors
  • Gastric Inhibitory Polypeptide / biosynthesis*
  • Gastric Inhibitory Polypeptide / genetics
  • Gene Deletion
  • Gene Knock-In Techniques
  • Glucagon-Like Peptide-1 Receptor
  • Glucose Intolerance / genetics
  • Glucose Intolerance / metabolism
  • Glucose Tolerance Test
  • Homeostasis / genetics
  • Homeostasis / physiology
  • Immunohistochemistry
  • Incretins / metabolism
  • Insulin / metabolism*
  • Insulin Secretion
  • Insulin-Secreting Cells / cytology
  • Insulin-Secreting Cells / metabolism*
  • Male
  • Mice
  • Peptide Fragments / metabolism*
  • Proglucagon / analysis
  • Proglucagon / metabolism*
  • Receptors, Gastrointestinal Hormone / genetics
  • Receptors, Glucagon / metabolism


  • Glp1r protein, mouse
  • Glucagon-Like Peptide-1 Receptor
  • Incretins
  • Insulin
  • Peptide Fragments
  • Receptors, Gastrointestinal Hormone
  • Receptors, Glucagon
  • Proglucagon
  • Gastric Inhibitory Polypeptide
  • gastric inhibitory polypeptide receptor
  • Cyclic AMP