Journal
DIABETES
Volume 59, Issue 6, Pages 1445-1450Publisher
AMER DIABETES ASSOC
DOI: 10.2337/db09-1655
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Funding
- National Institutes of Health [DK56818, DK68329]
- Juvenile Diabetes Research Foundation
- Iacocca Foundation
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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 PPAR gamma in GIP-R transcription. RESEARCH DESIGN AND METHODS-Chromatin immuno-precipitation 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 PPAR gamma knockout mice (PANC PPAR gamma(-/-)), normoglycemic 60% pancreatectomy rats (Px), normoglycemic and hyperglycemic Zucker fatty (ZE) 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 PPAR gamma(-/-) mice and a twofold increase in islets of 14-day post-60% Px Sprague-Dawley rats that hyperexpress beta-cell PPAR gamma. 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 PPAR gamma and GIP-R protein levels versus lean rats, with both lowered by two-thirds in ZE rats made hyperglycemic by 60% Px. CONCLUSIONS-Our studies have shown physiologic and pharmacologic regulation of GIP-R expression in beta-cells by PPAR gamma 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. Diabetes 59:1445-1450, 2010
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