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

5′-Adenosine monophosphate–activated protein kinase (AMPK) is a master regulator of energy homeostasis in eukaryotes. Despite three decades of investigation, the biological roles of AMPK and its potential as a drug target remain incompletely understood, largely because of a lack of optimized pharmac...

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Published in:Science (American Association for the Advancement of Science) 2017-08, Vol.357 (6350), p.507-511
Main Authors: Myers, Robert W., Guan, Hong-Ping, Ehrhart, Juliann, Petrov, Aleksandr, Prahalada, Srinivasa, Tozzo, Effie, Yang, Xiaodong, Kurtz, Marc M., Trujillo, Maria, Trotter, Dinko Gonzalez, Feng, Danqing, Xu, Shiyao, Eiermann, George, Holahan, Marie A., Rubins, Daniel, Conarello, Stacey, Niu, Xiaoda, Souza, Sandra C., Miller, Corin, Liu, Jinqi, Lu, Ku, Feng, Wen, Li, Ying, Painter, Ronald E., Milligan, James A., He, Huaibing, Liu, Franklin, Ogawa, Aimie, Wisniewski, Douglas, Rohm, Rory J., Wang, Liyang, Bunzel, Michelle, Qian, Ying, Zhu, Wei, Wang, Hongwu, Bennet, Bindu, Scheuch, Lisa LaFranco, Fernandez, Guillermo E., Li, Cai, Klimas, Michael, Zhou, Gaochao, van Heek, Margaret, Biftu, Tesfaye, Weber, Ann, Kelley, David E., Thornberry, Nancy, Erion, Mark D., Kemp, Daniel M., Sebhat, Iyassu K.
Format: Article
Language:English
Subjects:
Activation
Adenosine
Adenosine kinase
Adenosine monophosphate
Adenosine triphosphate
Allosteric properties
AMP
AMP-Activated Protein Kinases - metabolism
Animal models
Animals
ATP
Blood glucose
Blood Glucose - drug effects
Cardiomegaly - chemically induced
Complications
Diabetes
Diabetes mellitus
Energy balance
Energy levels
Enlargement
Eukaryotes
Fasting
Glucose
Glucose - metabolism
Glycogen
Glycogen - metabolism
Heart
Heart diseases
Homeostasis
Homeostasis - drug effects
Hypertrophy
Hypoglycemia
Hypoglycemia - chemically induced
Imidazoles - adverse effects
Imidazoles - chemistry
Imidazoles - pharmacology
Insulin
Insulin - pharmacology
Kinases
Macaca mulatta
Male
Mammals
Metabolic disorders
Mice
Mice, Inbred C57BL
Monkeys
Muscle, Skeletal - drug effects
Muscle, Skeletal - metabolism
Muscles
Pharmacology
Protein kinase
Pyridines - adverse effects
Pyridines - chemistry
Pyridines - pharmacology
Rodents
Skeletal muscle
Synthesis
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Summary:5′-Adenosine monophosphate–activated protein kinase (AMPK) is a master regulator of energy homeostasis in eukaryotes. Despite three decades of investigation, the biological roles of AMPK and its potential as a drug target remain incompletely understood, largely because of a lack of optimized pharmacological tools. We developed MK-8722, a potent, direct, allosteric activator of all 12 mammalian AMPK complexes. In rodents and rhesus monkeys, MK-8722–mediated AMPK activation in skeletal muscle induced robust, durable, insulin-independent glucose uptake and glycogen synthesis, with resultant improvements in glycemia and no evidence of hypoglycemia. These effects translated across species, including diabetic rhesus monkeys, but manifested with concomitant cardiac hypertrophy and increased cardiac glycogen without apparent functional sequelae.
ISSN:0036-8075
1095-9203
DOI:10.1126/science.aah5582