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A novel pathway for regulation of glucose‐dependent insulinotropic polypeptide receptor expression in β‐cells
Author(s) -
Lynn Francis C.,
Thompson Stephen A.,
Pospisilik J. Andrew,
Ehses Jan A.,
Hinke Simon A.,
Pamir Nathalie,
McIntosh Christopher H. S.,
Pederson Raymond A.
Publication year - 2003
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.02-0243fje
Subject(s) - medicine , endocrinology , pancreas , islet , receptor , gastric inhibitory polypeptide , pancreatic islets , downregulation and upregulation , biology , insulin , secretion , carbohydrate metabolism , chemistry , biochemistry , gene , glucagon
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.