A novel pathway for regulation of glucose-dependent insulinotropic polypeptide (GIP) receptor expression in beta 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 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.
Lynn
Francis C
FC
Department of Physiology, University of British Columbia, Vancouver Canada, V6T 1Z3.
Thompson
Stephen A
SA
Pospisilik
J Andrew
JA
Ehses
Jan A
JA
Hinke
Simon A
SA
Pamir
Nathalie
N
McIntosh
Christopher H S
CH
Pederson
Raymond A
RA
D000818:Animals; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005227:Fatty Acids / Q000494:pharmacology; D005786:Gene Expression Regulation; D005947:Glucose / Q000494:pharmacology; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D007700:Kinetics; D008954:Models, Biological; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011924:Rats, Zucker; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists; D011964:Receptors, Gastrointestinal Hormone / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000819:agonists; D014158:Transcription, Genetic / Q000187:drug effects
D005227:Fatty Acids; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011964:Receptors, Gastrointestinal Hormone; D014157:Transcription Factors; C041086:gastric inhibitory polypeptide receptor; D005947:Glucose