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

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; Wenlin Li; Erick Kindt; Marc Foretz; Benoit Viollet; Jessica Ward; Ravi G Kurumbail; Amit S Kalgutkar; Jørgen Wojtaszewski; Kimberly O Cameron; Russell A Miller

doi:10.1016/j.cmet.2017.04.010

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

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 BlatnikWenlin Li, Erick Kindt, Marc Foretz, Benoit Viollet, Jessica Ward, Ravi G Kurumbail, Amit S Kalgutkar, Jørgen Wojtaszewski, Kimberly O Cameron, Russell A Miller

August Krogh Sektionen for Molekylær Fysiologi

108 Citationer (Scopus)

Abstract

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.

Originalsprog	Engelsk
Tidsskrift	Cell Metabolism
Vol/bind	25
Udgave nummer	5
Sider (fra-til)	1147-1159, e1-e10
Antal sider	23
ISSN	1550-4131
DOI	https://doi.org/10.1016/j.cmet.2017.04.010
Status	Udgivet - 2 maj 2017

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10.1016/j.cmet.2017.04.010

http://www.cell.com/article/S1550413117302152/pdf

Citationsformater

Cokorinos, E. C., Delmore, J., Reyes, A. R., Albuquerque, B., Kjøbsted, R., Jørgensen, N. O., Tran, J.-L., Jatkar, A., Cialdea, K., Esquejo, R. M., Meissen, J., Calabrese, M. F., Cordes, J., Moccia, R., Tess, D., Salatto, C. T., Coskran, T. M., Opsahl, A. C., Flynn, D., ... Miller, R. A. (2017). Activation of skeletal muscle AMPK promotes glucose disposal and glucose lowering in non-human primates and mice. Cell Metabolism, 25(5), 1147-1159, e1-e10. https://doi.org/10.1016/j.cmet.2017.04.010

Cokorinos, EC, Delmore, J, Reyes, AR, Albuquerque, B, Kjøbsted, R , Jørgensen, NO, Tran, J-L, Jatkar, A, Cialdea, K, Esquejo, RM, Meissen, J, Calabrese, MF, Cordes, J, Moccia, R, Tess, D, Salatto, CT, Coskran, TM, Opsahl, AC, Flynn, D, Blatnik, M, Li, W, Kindt, E, Foretz, M, Viollet, B, Ward, J, Kurumbail, RG, Kalgutkar, AS, Wojtaszewski, J, Cameron, KO & Miller, RA 2017, 'Activation of skeletal muscle AMPK promotes glucose disposal and glucose lowering in non-human primates and mice', Cell Metabolism, bind 25, nr. 5, s. 1147-1159, e1-e10. https://doi.org/10.1016/j.cmet.2017.04.010

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abstract = "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.",

keywords = "AMPK, Diabetes, Glucose uptake, Pharmacology",

author = "Cokorinos, {Emily C} and Jake Delmore and Reyes, {Allan R} and Bina Albuquerque and Rasmus Kj{\o}bsted and J{\o}rgensen, {Nicolas Oldenburg} and Jean-Luc Tran and Aditi Jatkar and Katherine Cialdea and Esquejo, {Ryan M} and John Meissen and Calabrese, {Matthew F} and Jason Cordes and Robert Moccia and David Tess and Salatto, {Christopher T} and Coskran, {Timothy M} and Opsahl, {Alan C} and Declan Flynn and Matthew Blatnik and Wenlin Li and Erick Kindt and Marc Foretz and Benoit Viollet and Jessica Ward and Kurumbail, {Ravi G} and Kalgutkar, {Amit S} and J{\o}rgen Wojtaszewski and Cameron, {Kimberly O} and Miller, {Russell A}",

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AU - Cokorinos, Emily C

AU - Delmore, Jake

AU - Reyes, Allan R

AU - Albuquerque, Bina

AU - Kjøbsted, Rasmus

AU - Jørgensen, Nicolas Oldenburg

AU - Tran, Jean-Luc

AU - Jatkar, Aditi

AU - Cialdea, Katherine

AU - Esquejo, Ryan M

AU - Meissen, John

AU - Calabrese, Matthew F

AU - Cordes, Jason

AU - Moccia, Robert

AU - Tess, David

AU - Salatto, Christopher T

AU - Coskran, Timothy M

AU - Opsahl, Alan C

AU - Flynn, Declan

AU - Blatnik, Matthew

AU - Li, Wenlin

AU - Kindt, Erick

AU - Foretz, Marc

AU - Viollet, Benoit

AU - Ward, Jessica

AU - Kurumbail, Ravi G

AU - Kalgutkar, Amit S

AU - Wojtaszewski, Jørgen

AU - Cameron, Kimberly O

AU - Miller, Russell A

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N2 - 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.

AB - 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.

KW - AMPK

KW - Diabetes

KW - Glucose uptake

KW - Pharmacology

U2 - 10.1016/j.cmet.2017.04.010

DO - 10.1016/j.cmet.2017.04.010

M3 - Journal article

C2 - 28467931

SN - 1550-4131

VL - 25

SP - 1147-1159, e1-e10

JO - Cell Metabolism

JF - Cell Metabolism

IS - 5

ER -

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

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