Reversal of islet GIP receptor down-regulation and resistance to GIP by reducing hyperglycemia in the Zucker rat

Biochem Biophys Res Commun. 2007 Nov 3;362(4):1007-12. doi: 10.1016/j.bbrc.2007.08.115. Epub 2007 Aug 29.


In type 2 diabetes (T2DM) beta-cell responsiveness to glucose-dependent insulinotropic polypeptide (GIP) is reduced. In a model of T2DM, the VDF Zucker rat, GIP receptor mRNA and protein levels were shown to be down-regulated. Possible restoration of responsiveness to GIP in Zucker rats by reducing hyperglycemia has been examined. ZDF rats with extreme hyperglycemia demonstrated greater islet GIP receptor mRNA down-regulation (94.3+/-3.8%) than ZF rats (48.8+/-22.8%). GIP receptor mRNA levels in ZDF rats returned to 83.0+/-17.9% of lean following normalization of hyperglycemia by phlorizin treatment and pancreas perfusions demonstrated markedly improved GIP responsiveness. Treatment of VDF rats with a DP IV inhibitor (P32/98) resulted in improved glucose tolerance and restored sensitivity to GIP in isolated pancreata. These findings support the proposal that GIP receptor down-regulation in rodent T2DM is secondary to chronic hyperglycemia and that normalization of glycemia can restore GIP sensitivity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / metabolism*
  • Dose-Response Relationship, Drug
  • Down-Regulation / drug effects
  • Drug Resistance
  • Gastric Inhibitory Polypeptide / administration & dosage*
  • Hyperglycemia / drug therapy*
  • Hyperglycemia / metabolism*
  • Insulin Resistance
  • Rats
  • Rats, Zucker
  • Receptors, Gastrointestinal Hormone / metabolism*
  • Treatment Outcome


  • Receptors, Gastrointestinal Hormone
  • Gastric Inhibitory Polypeptide
  • gastric inhibitory polypeptide receptor