Cited 79 time in
Cited 77 time in
Selective Chemical Inhibition of PGC-1 alpha Gluconeogenic Activity Ameliorates Type 2 Diabetes
- Selective Chemical Inhibition of PGC-1 alpha Gluconeogenic Activity Ameliorates Type 2 Diabetes
- Sharabi K.; Lin H.; Tavares C.D.J.; Dominy J.E.; Camporez J.P.; Perry R.J.; Schilling R.; Rines A.K.; Lee, Jae Min; Hickey, Marc; Bennion M.; Palmer M.; Nag P.P.; Bittker J.A.; Perez J.; Jedrychowski M.P.; Ozcan U.; Gygi S.P.; Kamenecka T.M.; Shulman G.I.; Schreiber S.L.; Griffin P.R.; Puigserver P.
- DGIST Authors
- Lee, Jae Min
- Issue Date
- Cell, 169(1), 148-160.e15
- Article Type
- AlphaLisa; drug discovery; GCN5; glucagon; gluconeogenesis; hepatic glucose production; insulin resistance; PGC-1alpha; protein acetylation; type 2 diabetes
- 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. © 2017 Elsevier Inc.
- Cell Press
- Related Researcher
Aging, Metabolism and Physiology Lab
There are no files associated with this item.
- Department of New BiologyAging, Metabolism and Physiology Lab1. Journal Articles
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.