ABSTRACT: Background: Peroxisome proliferator-activated receptor (PPAR) regulates the expression of fatty acid metabolism genes and is thought to play a role in the regulation of insulin secretion and lipid detoxification. We have examined the mechanism whereby glucose decreases PPAR gene expression in the pancreatic β-cell.Methods: INS832/13 β-cell and isolated rat islets were incubated at 3 and 20 mM glucose for 18 h in the absence or presence of adenosine monophosphate (AMP)-activated protein kinase (AMPK) activators and inhibitors, as well as p38 mitogen-activated protein kinase (p38 MAPK) inhibitors. In another set of experiments, INS832/13 were infected with an adenovirus expressing a dominant-negative form of AMPK. PPAR expression levels were measured by reverse transcription polymerase chain reaction and Western blot.Results: Elevated glucose reduced the abundance of the PPAR transcript and protein, and its target genes acyl-coenzyme A (CoA) oxidase (ACO) and uncoupling protein 2 (UCP-2) in INS832/13 β-cell and isolated rat islets. Glucose reduced AMPK activity, while the AMPK activators 5-amino-4-imidazolecarboxamide riboside and metformin increased PPAR expression and suppressed the action of glucose. By contrast, the AMPK inhibitor compound C mimicked the glucose effect. A dominant negative form of AMPK reduced the PPAR, ACO and UCP-2 transcripts to the same extent as elevated glucose. Pharmacological evidence indicated that glucose-regulated PPAR expression does not involve p38 MAPK, a target of AMPK in several cell types.Conclusions: The results indicate that glucose represses PPAR gene expression via AMPK, but not via p38 MAPK in the β-cell.
Journal of Diabetes 11/2009; 1(4):263 - 272.