Activation of skeletal muscle AMPK promotes glucose disposal and glucose lowering in non-human primates and mice

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

Emily C Cokorinos, Jake Delmore, Allan R Reyes, Bina Albuquerque, Rasmus Kjøbsted, Nicolas Oldenburg Jørgensen, Jean-Luc Tran, Aditi Jatkar, Katherine Cialdea, Ryan M Esquejo, John Meissen, Matthew F Calabrese, Jason Cordes, Robert Moccia, David Tess, Christopher T Salatto, Timothy M Coskran, Alan C Opsahl, Declan Flynn, Matthew Blatnik & 10 andre Wenlin Li, Erick Kindt, Marc Foretz, Benoit Viollet, Jessica Ward, Ravi G Kurumbail, Amit S Kalgutkar, Jørgen Wojtaszewski, Kimberly O Cameron, Russell A Miller

The AMP-activated protein kinase (AMPK) is a potential therapeutic target for metabolic diseases based on its reported actions in the liver and skeletal muscle. We evaluated two distinct direct activators of AMPK: a non-selective activator of all AMPK complexes, PF-739, and an activator selective for AMPK β1-containing complexes, PF-249. In cells and animals, both compounds were effective at activating AMPK in hepatocytes, but only PF-739 was capable of activating AMPK in skeletal muscle. In diabetic mice, PF-739, but not PF-249, caused a rapid lowering of plasma glucose levels that was diminished in the absence of skeletal muscle, but not liver, AMPK heterotrimers and was the result of an increase in systemic glucose disposal with no impact on hepatic glucose production. Studies of PF-739 in cynomolgus monkeys confirmed translation of the glucose lowering and established activation of AMPK in skeletal muscle as a potential therapeutic approach to treat diabetic patients.

OriginalsprogEngelsk
TidsskriftCell Metabolism
Vol/bind25
Udgave nummer5
Sider (fra-til)1147-1159, e1-e10
Antal sider23
ISSN1550-4131
DOI
StatusUdgivet - 2017

Bibliografisk note

CURIS 2017 NEXS 124

ID: 177383146