Peroxisomal proliferator-activated receptor-gamma upregulates glucokinase gene expression in beta-cells.
Thiazolidinediones, synthetic ligands of peroxisomal proliferator-activated receptor-gamma (PPAR-gamma), improve peripheral insulin sensitivity and glucose-stimulated insulin secretion in pancreatic beta-cells. To explore the role of PPAR-gamma in glucose sensing of beta-cells, we have dissected the beta-cell-specific glucokinase (betaGK) promoter, which constitutes glucose-sensing apparatus in pancreatic beta-cells, and identified a peroxisomal proliferator response element (PPRE) in the promoter. The betaGK-PPRE is located in the region between +47 and +68 bp. PPAR-gamma/retinoid X receptor-alpha heterodimer binds to the element and activates the betaGK promoter. The betaGK promoter lacking or having mutations in PPRE cannot be activated by PPAR-gamma. PPAR-gamma activates the betaGK promoter in beta-cells as well as non-beta-cells. Furthermore, troglitazone increases endogenous GK expression and its enzyme activity in beta-cell lines. These results indicate that PPAR-gamma can regulate GK expression in beta-cells. Taking these results together with our previous work, we conclude that PPAR-gamma regulates gene expression of glucose-sensing apparatus and thereby improves glucose-sensing ability of beta-cells, contributing to the restoration of beta-cell function in type 2 diabetic subjects by troglitazone.
Kim
Ha-il
HI
Department of Biochemistry and Molecular Biology, the Institute of Genetic Science, Yonsei University College of Medicine, Seoul, Korea.
Cha
Ji-Young
JY
Kim
So-Youn
SY
Kim
Jae-woo
JW
Roh
Kyung Jin
KJ
Seong
Je-Kyung
JK
Lee
Nam Taek
NT
Choi
Kang-Yell
KY
Kim
Kyung-Sup
KS
Ahn
Yong-ho
YH
D000818:Animals; D002460:Cell Line; D002839:Chromans / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D019281:Dimerization; D004789:Enzyme Activation / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D005941:Glucokinase / Q000235:genetics*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007515:Islets of Langerhans / Q000201:enzymology*; D051379:Mice; D016297:Mutagenesis, Site-Directed; D011401:Promoter Regions, Genetic; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism / Q000502:physiology*; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D020218:Response Elements; D047488:Retinoid X Receptors; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D015533:Transcriptional Activation; D014162:Transfection; D000077288:Troglitazone
D002839:Chromans; D007004:Hypoglycemic Agents; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D004247:DNA; D005941:Glucokinase; D000077288:Troglitazone