title: Reversal of islet GIP receptor down-regulation and resistance to GIP by reducing hyperglycemia in the Zucker rat.
abstract: In type 2 diabetes (T2DM) beta-cell responsiveness to glucose-dependent insulinotropic polypeptide (GIP) is reduced. In a model of T2DM, the VDF Zucker rat, GIP receptor mRNA and protein levels were shown to be down-regulated. Possible restoration of responsiveness to GIP in Zucker rats by reducing hyperglycemia has been examined. ZDF rats with extreme hyperglycemia demonstrated greater islet GIP receptor mRNA down-regulation (94.3+/-3.8%) than ZF rats (48.8+/-22.8%). GIP receptor mRNA levels in ZDF rats returned to 83.0+/-17.9% of lean following normalization of hyperglycemia by phlorizin treatment and pancreas perfusions demonstrated markedly improved GIP responsiveness. Treatment of VDF rats with a DP IV inhibitor (P32/98) resulted in improved glucose tolerance and restored sensitivity to GIP in isolated pancreata. These findings support the proposal that GIP receptor down-regulation in rodent T2DM is secondary to chronic hyperglycemia and that normalization of glycemia can restore GIP sensitivity.
authors.affiliation: University of British Columbia, Department of Cellular & Physiological Sciences, Life Sciences Institute, 2350 Health Sciences Mall, Vancouver, BC, Canada.
authors.forename: Shalea
authors.initials: S
authors.lastname: Piteau
authors.forename: Amy
authors.initials: A
authors.lastname: Olver
authors.forename: Su-Jin
authors.initials: SJ
authors.lastname: Kim
authors.forename: Kyle
authors.initials: K
authors.lastname: Winter
authors.forename: John Andrew
authors.initials: JA
authors.lastname: Pospisilik
authors.forename: Francis
authors.initials: F
authors.lastname: Lynn
authors.forename: Susanne
authors.initials: S
authors.lastname: Manhart
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Demuth
authors.forename: Madeleine
authors.initials: M
authors.lastname: Speck
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Pederson
authors.forename: Christopher H S
authors.initials: CH
authors.lastname: McIntosh
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D004351:Drug Resistance; D005749:Gastric Inhibitory Polypeptide / Q000008:administration & dosage*; D006943:Hyperglycemia / Q000188:drug therapy* / Q000378:metabolism*; D007333:Insulin Resistance; D051381:Rats; D011924:Rats, Zucker; D011964:Receptors, Gastrointestinal Hormone / Q000378:metabolism*; D016896:Treatment Outcome