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

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.
AuthorsShalea Piteau, Amy Olver, Su-Jin Kim, Kyle Winter, John Andrew Pospisilik, Francis Lynn, Susanne Manhart, Hans-Ulrich Demuth, Madeleine Speck, Raymond A Pederson, Christopher H S McIntosh
JournalBiochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 362 Issue 4 Pg. 1007-12 (Nov 03 2007) ISSN: 0006-291X [Print] United States
PMID17803965 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Receptors, Gastrointestinal Hormone
  • Gastric Inhibitory Polypeptide
  • gastric inhibitory polypeptide receptor
  • Animals
  • Diabetes Mellitus, Type 2 (drug therapy, metabolism)
  • Dose-Response Relationship, Drug
  • Down-Regulation (drug effects)
  • Drug Resistance
  • Gastric Inhibitory Polypeptide (administration & dosage)
  • Hyperglycemia (drug therapy, metabolism)
  • Insulin Resistance
  • Rats
  • Rats, Zucker
  • Receptors, Gastrointestinal Hormone (metabolism)
  • Treatment Outcome

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