A novel pathway for regulation of glucose-dependent insulinotropic polypeptide (GIP) receptor expression in beta cells

FASEB J. 2003 Jan;17(1):91-3. doi: 10.1096/fj.02-0243fje. Epub 2002 Nov 15.


Glucose-dependent insulinotropic polypeptide (GIP) is secreted postprandially and acts in concert with glucose to stimulate insulin secretion from the pancreas. Here, we describe a novel pathway for the regulation of GIP receptor (GIPR) expression within clonal beta-cell lines, pancreatic islets, and in vivo. High (25 mM) glucose was able to significantly reduce GIPR mRNA levels in INS(832/13) cells after only 6 h. In contrast, palmitic acid (2 mM) and WY 14643 (100 microM) stimulated approximate doublings of GIPR expression in INS(832/13) cells under low (5.5 mM), but not high (25 mM), glucose conditions, suggesting that fat can regulate GIPR expression via PPARalpha in a glucose-dependent manner. Both MK-886, an antagonist of PPARalpha, and a dominant negative form of PPARalpha transfected into INS(832/13) cells caused a significant reduction in GIPR expression in low, but not high, glucose conditions. Finally, in hyperglycemic clamped rats, there was a 70% reduction in GIPR expression in the islets and a 71% reduction in GIP-stimulated insulin secretion from the perfused pancreas. Thus, evidence is presented that the GIPR is controlled at normoglycemia by the fatty acid load on the islet; however, when exposed to hyperglycemic conditions, the GIPR is down-regulated, which may contribute to the decreased responsiveness to GIP that is observed in type 2 diabetes.

MeSH terms

  • Animals
  • Cell Line
  • Dose-Response Relationship, Drug
  • Down-Regulation*
  • Fatty Acids / pharmacology
  • Gene Expression Regulation
  • Glucose / pharmacology
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / metabolism*
  • Kinetics
  • Models, Biological
  • RNA, Messenger / biosynthesis
  • Rats
  • Rats, Zucker
  • Receptors, Cytoplasmic and Nuclear / agonists
  • Receptors, Gastrointestinal Hormone / genetics
  • Receptors, Gastrointestinal Hormone / metabolism*
  • Signal Transduction*
  • Transcription Factors / agonists
  • Transcription, Genetic / drug effects


  • Fatty Acids
  • RNA, Messenger
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Gastrointestinal Hormone
  • Transcription Factors
  • gastric inhibitory polypeptide receptor
  • Glucose