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

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Science  13 Jul 2017:
eaah5582
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 investigations over three decades, the biological roles of AMPK and its potential as a drug target remain incompletely understood, due largely to the lack of optimized pharmacological tools. We now report MK-8722, a potent, direct, allosteric activator of all twelve mammalian AMPK complexes. In rodents and rhesus monkeys, MK-8722-mediated AMPK activation in skeletal muscle induces robust, durable, insulin-independent glucose uptake and glycogen synthesis, with resultant improvements in glycemia and no evidence of hypoglycemia. These effects translate across species, including diabetic rhesus monkeys, but manifest with concomitant cardiac hypertrophy and increased cardiac glycogen without apparent functional sequelae.

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