A novel pathway for regulation of glucose‐dependent insulinotropic polypeptide receptor expression in β‐cells

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 β‐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 μM) stimulated approximate doublings of GIPR expression in INS(832/13) cells under low (5.5 mM), but not high (25 mM), glucose conditons, suggesting that fat can regulate GIPR expression via PPARα in a glucose‐dependent manner. Both MK‐886, an antagonist of PPARα, and a dominant negative form of PPARα 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.