Postprandial stimulation of insulin release by glucose-dependent insulinotropic polypeptide (GIP). Effect of a specific glucose-dependent insulinotropic polypeptide receptor antagonist in the rat

J Clin Invest. 1996 Dec 1;98(11):2440-5. doi: 10.1172/JCI119060.


Glucose-dependent insulinotropic polypeptide (GIP) is a 42-amino acid peptide produced by K cells of the mammalian proximal small intestine and is a potent stimulant of insulin release in the presence of hyperglycemia. However, its relative physiological importance as a postprandial insulinotropic agent is unknown. Using LGIPR2 cells stably transfected with rat GIP receptor cDNA, GIP (1-42) stimulation of cyclic adenosine monophosphate (cAMP) production was inhibited in a concentration-dependent manner by GIP (7-30)-NH2. Competition binding assays using stably transfected L293 cells demonstrated an IC50 for GIP receptor binding of 7 nmol/liter for GIP (1-42) and 200 nmol/liter for GIP (7-30)-NH2, whereas glucagonlike peptide-1 (GLP-1) binding to its receptor on ++betaTC3 cells was minimally displaced by GIP (7-30)-NH2. In fasted anesthetized rats, GIP (1-42) stimulated insulin release in a concentration-dependent manner, an effect abolished by the concomitant intraperitoneal administration of GIP (7-30)-NH2 (100 nmol/ kg). In contrast, glucose-, GLP-1-, and arginine-stimulated insulin release were not affected by GIP (7-30)-NH2. In separate experiments, GIP (7-30)-NH2 (100 nmol/kg) reduced postprandial insulin release in conscious rats by 72%. It is concluded that GIP (7-30)-NH2 is a GIP-specific receptor antagonist and that GIP plays a dominant role in mediating postprandial insulin release.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Line
  • Cyclic AMP / metabolism
  • Fasting
  • Gastric Inhibitory Polypeptide / pharmacology*
  • Insulin / metabolism*
  • Insulin Secretion
  • Kinetics
  • Male
  • Peptide Fragments / pharmacology
  • Postprandial Period
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Gastrointestinal Hormone / biosynthesis
  • Receptors, Gastrointestinal Hormone / physiology*
  • Recombinant Proteins / biosynthesis
  • Recombinant Proteins / metabolism
  • Structure-Activity Relationship
  • Swine
  • Transfection


  • Insulin
  • Peptide Fragments
  • Receptors, Gastrointestinal Hormone
  • Recombinant Proteins
  • Gastric Inhibitory Polypeptide
  • gastric inhibitory polypeptide receptor
  • Cyclic AMP