Peroxisomal Proliferator-Activated Receptor-γ Upregulates Glucokinase Gene Expression in β-Cells
- Ha-il Kim1,
- Ji-Young Cha1,
- So-Youn Kim1,
- Jae-woo Kim1,
- Kyung Jin Roh2,
- Je-Kyung Seong2,
- Nam Taek Lee3,
- Kang-Yell Choi1,
- Kyung-Sup Kim1 and
- Yong-ho Ahn1
- 1Department of Biochemistry and Molecular Biology, the Institute of Genetic Science, Yonsei University College of Medicine, Seoul, Korea
- 2Department of Laboratory Animal Medicine, Medical Research Center, Yonsei, College of Medicine, Seoul, Korea
- 3Department of Chemistry, Korea Military Academy, Seoul, Korea
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 PPAR-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.
Footnotes
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Address correspondence and reprint requests to Yong-ho Ahn, Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, 134 Shinchon-dong, Seodaemoon-gu, Seoul 120-752, Korea. E-mail: yha111{at}yumc.yonsei.ac.kr.
Received for publication 6 September 2001 and accepted in revised form 26 November 2001.
H.-I.K. and J.-Y.C. contributed equally to this work.
βGK, β-cell-specific GK; DMEM, Dulbecco’s modified Eagle’s medium; EMSA, electrophoretic mobility shift assay; FBS, fetal bovine serum; GK, glucokinase; GSIS, glucose-stimulated insulin secretion; LGK, rat liver-specific GK; MODY, maturity-onset diabetes of the young; PDX-1, pancreatic duodenal homeobox gene-1; PPAR, peroxisomal proliferator-activated receptor; PPRE, peroxisomal proliferator response element; RPA, RNase protection assay; RXR-α, retinoid X receptor-α; TZD, thiazolidinedione.
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