Abstract：
: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.
journal_name
Celljournal_title
Cellauthors
Sharabi K,Lin H,Tavares CDJ,Dominy JE,Camporez JP,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,Grdoi
10.1016/j.cell.2017.03.001subject
Has Abstractpub_date
2017-03-23 00:00:00pages
148-160.e15issue
1eissn
0092-8674issn
1097-4172pii
S0092-8674(17)30249-0journal_volume
169pub_type
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