TY - JOUR
T1 - Activation of the cAMP-PKA pathway antagonizes metformin suppression of hepatic glucose production
AU - He, Ling
AU - Chang, Evan
AU - Peng, Jinghua
AU - An, Hongying
AU - McMillin, Sara M.
AU - Radovick, Sally
AU - Stratakis, Constantine A.
AU - Wondisford, Fredric E.
N1 - Funding Information:
This work was supported in part by grants from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health: R00DK085142 (to L. H.), R01DK107641 (to L. H.), and R01DK063349 (to F. E. W.).
Publisher Copyright:
© 2016 by The American Society for Biochemistry and Molecular Biology, Inc. Published in the U.S.A.
PY - 2016/5/13
Y1 - 2016/5/13
N2 - Metformin is the most commonly prescribed oral anti-diabetic agent worldwide. Surprisingly, about 35% of diabetic patients either lack or have a delayed response to metformin treatment, and many patients become less responsive to metformin over time. It remains unknown how metformin resistance or insensitivity occurs. Recently, we found that therapeutic metformin concentrations suppressed glucose production in primary hepatocytes through AMPK; activation of the cAMP-PKA pathway negatively regulates AMPK activity by phosphorylating AMPKα subunit at Ser-485, which in turn reduces AMPK activity. In this study, we find that metformin failed to suppress glucose production in primary hepatocytes with constitutively activated PKA and did not improve hyperglycemia in mice with hyperglucagonemia. Expression of the AMPKα1(S485A) mutant, which is unable to be phosphorylated by PKA, increased both AMPKα activation and the suppression of glucose production in primary hepatocytes treated with metformin. Intriguingly, salicylate/ aspirin prevents the phosphorylation of AMPKα at Ser-485, blocks cAMP-PKA negative regulation of AMPK, and improves metformin resistance. We propose that aspirin/salicylate may augment metformin's hepatic action to suppress glucose production.
AB - Metformin is the most commonly prescribed oral anti-diabetic agent worldwide. Surprisingly, about 35% of diabetic patients either lack or have a delayed response to metformin treatment, and many patients become less responsive to metformin over time. It remains unknown how metformin resistance or insensitivity occurs. Recently, we found that therapeutic metformin concentrations suppressed glucose production in primary hepatocytes through AMPK; activation of the cAMP-PKA pathway negatively regulates AMPK activity by phosphorylating AMPKα subunit at Ser-485, which in turn reduces AMPK activity. In this study, we find that metformin failed to suppress glucose production in primary hepatocytes with constitutively activated PKA and did not improve hyperglycemia in mice with hyperglucagonemia. Expression of the AMPKα1(S485A) mutant, which is unable to be phosphorylated by PKA, increased both AMPKα activation and the suppression of glucose production in primary hepatocytes treated with metformin. Intriguingly, salicylate/ aspirin prevents the phosphorylation of AMPKα at Ser-485, blocks cAMP-PKA negative regulation of AMPK, and improves metformin resistance. We propose that aspirin/salicylate may augment metformin's hepatic action to suppress glucose production.
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U2 - 10.1074/jbc.M116.719666
DO - 10.1074/jbc.M116.719666
M3 - Article
C2 - 27002150
AN - SCOPUS:84969180647
VL - 291
SP - 10562
EP - 10570
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 20
ER -