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Diabetes. 2010 Jun;59(6):1445-50. doi: 10.2337/db09-1655. Epub 2010 Mar 23.

Physiologic and pharmacologic modulation of glucose-dependent insulinotropic polypeptide (GIP) receptor expression in beta-cells by peroxisome proliferator-activated receptor (PPAR)-gamma signaling: possible mechanism for the GIP resistance in type 2 diabetes.

Author information

  • 1Division of Endocrinology, Diabetes, and Metabolism and the Department of Medicine, University of Vermont, Burlington, Vermont, USA.

Abstract

OBJECTIVE:

We previously showed that peroxisome proliferator-activated receptor (PPAR)-gamma in beta-cells regulates pdx-1 transcription through a functional PPAR response element (PPRE). Gene Bank blast for a homologous nucleotide sequence revealed the same PPRE within the rat glucose-dependent insulinotropic polypeptide receptor (GIP-R) promoter sequence. We investigated the role of PPARgamma in GIP-R transcription.

RESEARCH DESIGN AND METHODS:

Chromatin immunoprecipitation assay, siRNA, and luciferase gene transcription assay in INS-1 cells were performed. Islet GIP-R expression and immunohistochemistry studies were performed in pancreas-specific PPARgamma knockout mice (PANC PPARgamma(-/-)), normoglycemic 60% pancreatectomy rats (Px), normoglycemic and hyperglycemic Zucker fatty (ZF) rats, and mouse islets incubated with troglitazone.

RESULTS:

In vitro studies of INS-1 cells confirmed that PPAR-gamma binds to the putative PPRE sequence and regulates GIP-R transcription. In vivo verification was shown by a 70% reduction in GIP-R protein expression in islets from PANC PPARgamma(-/-) mice and a twofold increase in islets of 14-day post-60% Px Sprague-Dawley rats that hyperexpress beta-cell PPARgamma. Thiazolidinedione activation (72 h) of this pathway in normal mouse islets caused a threefold increase of GIP-R protein and a doubling of insulin secretion to 16.7 mmol/l glucose/10 nmol/l GIP. Islets from obese normoglycemic ZF rats had twofold increased PPARgamma and GIP-R protein levels versus lean rats, with both lowered by two-thirds in ZF rats made hyperglycemic by 60% Px.

CONCLUSIONS:

Our studies have shown physiologic and pharmacologic regulation of GIP-R expression in beta-cells by PPARgamma signaling. Also disruption of this signaling pathway may account for the lowered beta-cell GIP-R expression and resulting GIP resistance in type 2 diabetes.

PMID:
20332343
[PubMed - indexed for MEDLINE]
PMCID:
PMC2874705
Free PMC Article

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