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Cell DOI:10.1016/j.cell.2017.03.001

Selective Chemical Inhibition of PGC-1α Gluconeogenic Activity Ameliorates Type 2 Diabetes.

Publication TypeJournal Article
Year of Publication2017
AuthorsSharabi, K, Lin, H, Tavares, CDJ, Dominy, JE, Camporez, JPaulo, Perry, RJ, Schilling, R, Rines, AK, Lee, J, Hickey, M, Bennion, M, Palmer, M, Nag, PP, Bittker, JA, Perez, J, Jedrychowski, MP, Ozcan, U, Gygi, SP, Kamenecka, TM, Shulman, GI, Schreiber, SL, Griffin, PR, Puigserver, P
Date Published2017 03 23
KeywordsAcetylation, Animals, Blood Glucose, Cells, Cultured, Diabetes Mellitus, Type 2, Gluconeogenesis, Glucose, Hepatocyte Nuclear Factor 4, Hepatocytes, High-Throughput Screening Assays, Hypoglycemic Agents, Insulin Resistance, Mice, p300-CBP Transcription Factors, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha

Type 2 diabetes (T2D) is a worldwide epidemic with a medical need for additional targeted therapies. Suppression of hepatic glucose production (HGP) effectively ameliorates diabetes and can be exploited for its treatment. We hypothesized that targeting PGC-1α acetylation in the liver, a chemical modification known to inhibit hepatic gluconeogenesis, could be potentially used for treatment of T2D. Thus, we designed a high-throughput chemical screen platform to quantify PGC-1α acetylation in cells and identified small molecules that increase PGC-1α acetylation, suppress gluconeogenic gene expression, and reduce glucose production in hepatocytes. On the basis of potency and bioavailability, we selected a small molecule, SR-18292, that reduces blood glucose, strongly increases hepatic insulin sensitivity, and improves glucose homeostasis in dietary and genetic mouse models of T2D. These studies have important implications for understanding the regulatory mechanisms of glucose metabolism and treatment of T2D.


Alternate JournalCell
PubMed ID28340340
PubMed Central IDPMC5398763
Grant ListF32 DK102293 / DK / NIDDK NIH HHS / United States
R03 DA032468 / DA / NIDA NIH HHS / United States
U54 HG005032 / HG / NHGRI NIH HHS / United States
R24 DK080261 / DK / NIDDK NIH HHS / United States
R01 DK040936 / DK / NIDDK NIH HHS / United States
R01 DK069966 / DK / NIDDK NIH HHS / United States
U2C DK059635 / DK / NIDDK NIH HHS / United States