Peroxisomal proliferator-activated receptor-γ upregulates glucokinase gene expression in β-cells

Abstract

Thiazolidinediones, synthetic ligands of peroxisomal proliferator-activated receptor-γ (PPAR-γ), improve peripheral insulin sensitivity and glucose-stimulated insulin secretion in pancreatic β-cells. To explore the role of PPAR-γ in glucose sensing of β-cells, we have dissected the β-cell-specific glucokinase (βGK) promoter, which constitutes glucose-sensing apparatus in pancreatic β-cells, and identified a peroxisomal proliferator response element (PPRE) in the promoter. The βGK-PPRE is located in the region between +47 and +68 bp. PPAR-γ/retinoid X receptor-α heterodimer binds to the element and activates the βGK promoter. The βGK promoter lacking or having mutations in PPRE cannot be activated by PPAR-γ. PPAR-γ activates the βGK promoter in β-cells as well as non-β-cells. Furthermore, troglitazone increases endogenous GK expression and its enzyme activity in β-cell lines. These results indicate that PRAR-γ can regulate GK expression in β-cells. Taking these results together with our previous work, we conclude that PPAR-γ regulates gene expression of glucose-sensing apparatus and thereby improves glucose-sensing ability of β-cells, contributing to the restoration of β-cell function in type 2 diabetic subjects by troglitazone.