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

Francis C. Lynn, Stephen A. Thompson, J. Andrew Pospisilik, Jan A. Ehses, Simon A. Hinke, Nathalie Pamir, Christopher H S McIntosh, Raymond A. Pederson

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)91-93
Number of pages3
JournalThe FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume17
Issue number1
StatePublished - 2003
Externally publishedYes

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Glucose
PPAR alpha
L 663536
Peptides
Pancreas
Insulin
Palmitic Acid
gastric inhibitory polypeptide receptor
Medical problems
Islets of Langerhans
Type 2 Diabetes Mellitus
Rats
Fatty Acids
Fats
Cells
Cell Line
Messenger RNA

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A novel pathway for regulation of glucose-dependent insulinotropic polypeptide (GIP) receptor expression in beta cells. / Lynn, Francis C.; Thompson, Stephen A.; Pospisilik, J. Andrew; Ehses, Jan A.; Hinke, Simon A.; Pamir, Nathalie; McIntosh, Christopher H S; Pederson, Raymond A.

In: The FASEB journal : official publication of the Federation of American Societies for Experimental Biology, Vol. 17, No. 1, 2003, p. 91-93.

Research output: Contribution to journalArticle

Lynn, Francis C. ; Thompson, Stephen A. ; Pospisilik, J. Andrew ; Ehses, Jan A. ; Hinke, Simon A. ; Pamir, Nathalie ; McIntosh, Christopher H S ; Pederson, Raymond A. / A novel pathway for regulation of glucose-dependent insulinotropic polypeptide (GIP) receptor expression in beta cells. In: The FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2003 ; Vol. 17, No. 1. pp. 91-93.
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