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

Myers, Robert W.; Guan, Hong-Ping; Ehrhart, Juliann; Petrov, Aleksandr; Prahalada, Srinivasa; Tozzo, Effie; Yang, Xiaodong; Kurtz, Marc M.; Trujillo, Maria; Gonzalez Trotter, Dinko; 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; LaFranco Scheuch, Lisa; 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.

doi:10.1126/science.aah5582

Cited by 352Metabolism, Diabetes, and CancerNatural Antidiabetic Agents StudiesPeroxisome Proliferator-Activated Receptors

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

Myers, Robert W., Guan, Hong-Ping, Ehrhart, Juliann, Petrov, Aleksandr, Prahalada, Srinivasa, Tozzo, Effie, Yang, Xiaodong, Kurtz, Marc M. +41 more·2017·Science

DOI 10.1126/science.aah5582

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Abstract

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.

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Some pharmacological AMPK activators, such as MK-8722, cause cardiac hypertrophy, which is considered the main side effect of pharmacological pan-AMPK activation.
“However, some pharmacological AMPK activators, such as MK-8722 [203], cause cardiac hypertrophy, which is considered the main side effect of pharmacological pan-AMPK activation [17].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [17]
Hepatic gluconeogenesis is inhibited by AMPK activation, which also enhances insulin sensitivity, muscle glucose absorption, and fatty acid oxidation.
“Hepatic gluconeogenesis is inhibited by AMPK activation, which also enhances insulin sensitivity, muscle glucose absorption, and fatty acid oxidation (103, 104).”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [103]
AMPK is activated through metabolic stress and acts as a cellular regulator of lipid and glucose metabolism.
“AMPK is activated through metabolic stress and acts as a cellular regulator of lipid and glucose metabolism (102, 103).”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [103]

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Page /1 14 AMP-activated protein kinase and metabolic control
Exp, H., Viollet, B., & Andréelli, F. (2015)

Authors: Myers, R. W., Guan, H.-P., Ehrhart, J., Petrov, A., Prahalada, S., Tozzo, E., Yang, X., Kurtz, M. M., Trujillo, M., Gonzalez Trotter, D., Feng, D., Xu, S., Eiermann, G., Holahan, M. A., Rubins, D., Conarello, S., Niu, X., Souza, S. C., Miller, C., Liu, J., Lu, K., Feng, W., Li, Y., Painter, R. E., Milligan, J. A., He, H., Liu, F., Ogawa, A., Wisniewski, D., Rohm, R. J., Wang, L., Bunzel, M., Qian, Y., Zhu, W., Wang, H., Bennet, B., LaFranco Scheuch, L., Fernandez, G. E., Li, C., Klimas, M., Zhou, G., van Heek, M., Biftu, T., Weber, A., Kelley, D. E., Thornberry, N., Erion, M. D., Kemp, D. M., & Sebhat, I. K.
Affiliations: Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
Translational Imaging and Biomarkers Departments, Merck Research Laboratories, West Point, PA 19486, USA.
Safety Assessment and Laboratory Animal Resources, Merck Research Laboratories, West Point, PA 19486, USA.
In Vivo Pharmacology, Merck Research Laboratories, Kenilworth, NJ 07033, USA.
Corresponding author: Myers, Robert W.
Guan, Hong-Ping
Souza, Sandra C.
Sebhat, Iyassu K.
ORCID: Myers, Robert W.
Guan, Hong-Ping
Petrov, Aleksandr
Prahalada, Srinivasa
Tozzo, Effie
Kurtz, Marc M.
Trujillo, Maria
Holahan, Marie A.
Rubins, Daniel
Niu, Xiaoda
Souza, Sandra C.
Miller, Corin
Liu, Jinqi
Li, Ying
Milligan, James A.
He, Huaibing
Liu, Franklin
Ogawa, Aimie
Wisniewski, Douglas
Wang, Liyang
Bunzel, Michelle
Qian, Ying
Zhu, Wei
Wang, Hongwu
Bennet, Bindu
LaFranco Scheuch, Lisa
Klimas, Michael
Zhou, Gaochao
Biftu, Tesfaye
Weber, Ann
Kelley, David E.
Thornberry, Nancy
Sebhat, Iyassu K.
Venue: Science
Publisher: American Association for the Advancement of Science (AAAS)
Published: 2017-08-04
Volume: 357
Issue: 6350
Pages: 507-511
ISSN: 0036-8075 (ISSN-L)
1095-9203
DOI: 10.1126/science.aah5582
OpenAlex: W2735200095
Cited by: 346
References: 30
Citations by year: 2026: 38 · 2025: 47 · 2024: 37 · 2023: 31 · 2022: 37 · 2021: 43 · 2020: 38 · 2019: 29 · 2018: 30 · 2017: 16
FWCI: 13.00
Type: journal article
Language: en
Open access: closed
Locations: Science (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Natural Antidiabetic Agents Studies
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
Keywords: AMPK, allosteric activators, glucose homeostasis, insulin-independent glucose uptake, glycogen synthesis, skeletal muscle, cardiac hypertrophy, cardiac glycogen, diabetes mellitus, rhesus monkeys, energy homeostasis
MeSH terms: Animals, Benzimidazoles, Blood Glucose, Fasting, Glucose, Glycogen, Cardiomegaly, Homeostasis, Hypoglycemia, Imidazoles, Insulin, Macaca mulatta, Male, Mice, Inbred C57BL, Pyridines, Muscle, Skeletal, Mice, AMP-Activated Protein Kinases

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

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