Systemic pan-AMPK activator MK-8722 improves glucose homeostasis but induces cardiac hypertrophy

• DOI: 10.1126/science.aah5582
• Publication Date: 2017-07-14T01:00:36Z
• Authors: Robert W. Myers; Hong-Ping Guan; Juliann Ehrhart; Aleksandr Petrov; Srinivasa Prahalada; Effie Tozzo; Xiaodong Yang; Marc M. Kurtz; Maria Trujillo; Dinko Gonzalez Tr...; Danqing Feng; Shiyao Xu; George Eiermann; Marie A. Holahan; Daniel Rubins; Stacey Conarello; Xiaoda Niu; Sandra C. Souza; Corin Miller; Jinqi Liu; Ku Lu; Wen Feng; Ying Li; Ronald E. Painter; James A. Milligan; Huaibing He; Franklin Liu; Aimie Ogawa; Douglas Wisniewski; Rory J. Rohm; Liyang Wang; Michelle Bunzel; Ying Qian; Wei Zhu; Hongwu Wang; Bindu Bennet; Lisa LaFranco Sch...; Guillermo E. Fern...; Cai Li; Michael Klimas; Gaochao Zhou; Margaret van Heek; Tesfaye Biftu; Ann Weber; David E. Kelley; Nancy Thornberry; Mark D. Erion; Daniel M. Kemp; Iyassu K. Sebhat
• Keywords: Homeostasis

5'-Adenosine monophosphate-activated protein kinase (AMPK) is a master regulator of energy homeostasis in eukaryotes. Despite three decades investigation, the biological roles AMPK and its potential as drug target remain incompletely understood, largely because lack optimized pharmacological tools. We developed MK-8722, potent, direct, allosteric activator all 12 mammalian complexes. In rodents rhesus monkeys, MK-8722-mediated activation skeletal muscle induced robust, durable, insulin-independent glucose uptake glycogen synthesis, with resultant improvements glycemia no evidence hypoglycemia. These effects translated across species, including diabetic but manifested concomitant cardiac hypertrophy increased without apparent functional sequelae.