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

Science. 2017 Aug 4;357(6350):507-511. doi: 10.1126/science.aah5582. Epub 2017 Jul 13.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Animals
  • Benzimidazoles
  • Blood Glucose / drug effects
  • Cardiomegaly / chemically induced*
  • Fasting
  • Glucose / metabolism*
  • Glycogen / metabolism
  • Homeostasis / drug effects*
  • Hypoglycemia / chemically induced
  • Imidazoles / adverse effects
  • Imidazoles / chemistry
  • Imidazoles / pharmacology*
  • Insulin / pharmacology
  • Macaca mulatta
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / metabolism
  • Pyridines / adverse effects
  • Pyridines / chemistry
  • Pyridines / pharmacology*

Substances

  • Benzimidazoles
  • Blood Glucose
  • Imidazoles
  • Insulin
  • MK-8722
  • Pyridines
  • Glycogen
  • AMP-Activated Protein Kinases
  • Glucose