title: Activation of the cAMP-PKA pathway Antagonizes Metformin Suppression of Hepatic Glucose Production.
abstract: 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.
authors.affiliation: From the Division of Metabolism, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, heling@jhmi.edu.
authors.forename: Ling
authors.initials: L
authors.lastname: He
authors.affiliation: From the Division of Metabolism, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287.
authors.forename: Evan
authors.initials: E
authors.lastname: Chang
authors.affiliation: From the Division of Metabolism, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287.
authors.forename: Jinghua
authors.initials: J
authors.lastname: Peng
authors.affiliation: From the Division of Metabolism, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287.
authors.forename: Hongying
authors.initials: H
authors.lastname: An
authors.affiliation: Departments of Medicine and.
authors.forename: Sara M
authors.initials: SM
authors.lastname: McMillin
authors.affiliation: Pediatrics, Rutgers-Robert Wood Johnson Medical School, New Brunswick, New Jersey 08901, and.
authors.forename: Sally
authors.initials: S
authors.lastname: Radovick
authors.affiliation: Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland 20892.
authors.forename: Constantine A
authors.initials: CA
authors.lastname: Stratakis
authors.affiliation: Departments of Medicine and.
authors.forename: Fredric E
authors.initials: FE
authors.lastname: Wondisford
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D019943:Amino Acid Substitution; D000818:Animals; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000235:genetics / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D005947:Glucose / Q000235:genetics / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D020125:Mutation, Missense
chemical_list: D008687:Metformin; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D055372:AMP-Activated Protein Kinases; D005947:Glucose
keywords: AMP-activated kinase (AMPK); aspirin; glucogenesis; liver; metformin; protein kinase A (PKA)