Activation of skeletal muscle AMPK promotes glucose disposal and glucose lowering in non-human primates and mice
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Activation of skeletal muscle AMPK promotes glucose disposal and glucose lowering in non-human primates and mice. / Cokorinos, Emily C; Delmore, Jake; Reyes, Allan R; Albuquerque, Bina; Kjøbsted, Rasmus; Jørgensen, Nicolas Oldenburg; Tran, Jean-Luc; Jatkar, Aditi; Cialdea, Katherine; Esquejo, Ryan M; Meissen, John; Calabrese, Matthew F; Cordes, Jason; Moccia, Robert; Tess, David; Salatto, Christopher T; Coskran, Timothy M; Opsahl, Alan C; Flynn, Declan; Blatnik, Matthew; Li, Wenlin; Kindt, Erick; Foretz, Marc; Viollet, Benoit; Ward, Jessica; Kurumbail, Ravi G; Kalgutkar, Amit S; Wojtaszewski, Jørgen; Cameron, Kimberly O; Miller, Russell A.
In: Cell Metabolism, Vol. 25, No. 5, 2017, p. 1147-1159, e1-e10.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Activation of skeletal muscle AMPK promotes glucose disposal and glucose lowering in non-human primates and mice
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
N1 - CURIS 2017 NEXS 124
PY - 2017
Y1 - 2017
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
VL - 25
SP - 1147-1159, e1-e10
JO - Cell Metabolism
JF - Cell Metabolism
SN - 1550-4131
IS - 5
ER -
ID: 177383146