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Suppression of Peroxisome Proliferator-Activated Receptor -Coactivator-1 Normalizes the Glucolipotoxicity-Induced Decreased BETA2/NeuroD Gene Transcription and Improved Glucose Tolerance in Diabetic Rats

Department of Endocrinology and Metabolism (J.-W.K., Y.-H.Y., K.-S.H., J.-H.C., S.-H.K., K.-H.S., H.-Y.S., K.-H.Y.), The Catholic University of Korea, Seoul 137-040, Korea; Department of Anatomy (H.S.-K.), Ajou University, School of Medicine, Suwon 442-749, Korea; and Department of Internal Medicine (I.-K.L.), Kyungbuk University School of Medicine, Daegu 718-851, Korea

Address all correspondence and requests for reprints to: Kun-Ho Yoon, M.D., Ph.D., Department of Internal Medicine, The Catholic University of Korea, Kangnam St. Mary’s Hospital, Seoul 137-040, Korea. E-mail: yoonk{at}catholic.ac.kr.

Peroxisome proliferator-activated receptor -coactivator-1 (PGC-1) is significantly elevated in the islets of animal models of diabetes. However, the molecular mechanism has not been clarified. We investigated whether the suppression of PGC-1 expression protects against β-cell dysfunction in vivo and determined the mechanism of action of PGC-1 in β-cells. The studies were performed in glucolipotixicity-induced primary rat islets and INS-1 cells. In vitro and in vivo approaches using adenoviruses were used to evaluate the role of PGC-1 in glucolipotoxicity-associated β-cell dysfunction. The expression of PGC-1 in cultured β-cells increased gradually with glucolipotoxicity. The overexpression of PGC-1 also suppressed the expression of the insulin and β-cell E-box transcription factor (BETA2/NeuroD) genes, which was reversed by PGC-1 small interfering RNA (siRNA). BETA2/NeuroD, p300-enhanced BETA2/NeuroD, and insulin transcriptional activities were significantly suppressed by Ad-PGC-1 but were rescued by Ad-siPGC-1. PGC-1 binding at the glucocorticoid receptor site on the BETA2/NeuroD promoter increased in the presence of PGC-1. Ad-siPGC-1 injection through the celiac arteries of 90% pancreatectomized diabetic rats improved their glucose tolerance and maintained their fasting insulin levels. The suppression of PGC-1 expression protects the glucolipotoxicity-induced β-cell dysfunction in vivo and in vitro. A better understanding of the functions of molecules such as PGC-1, which play key roles in intracellular fuel regulation, could herald a new era of the treatment of patients with type 2 diabetes mellitus by providing protection from glucolipotoxicity, which is an important cause of the development and progression of the disease.