title: Nutrient Excess and AMPK Downregulation in Incubated Skeletal Muscle and Muscle of Glucose Infused Rats.
abstract: We have previously shown that incubation for 1h with excess glucose or leucine causes insulin resistance in rat extensor digitorum longus (EDL) muscle by inhibiting AMP-activated protein kinase (AMPK). To examine the events that precede and follow these changes, studies were performed in rat EDL incubated with elevated levels of glucose or leucine for 30min-2h. Incubation in high glucose (25mM) or leucine (100μM) significantly diminished AMPK activity by 50% within 30min, with further decreases occurring at 1 and 2h. The initial decrease in activity at 30min coincided with a significant increase in muscle glycogen. The subsequent decreases at 1h were accompanied by phosphorylation of αAMPK at Ser485/491, and at 2h by decreased SIRT1 expression and increased PP2A activity, all of which have previously been shown to diminish AMPK activity. Glucose infusion in vivo, which caused several fold increases in plasma glucose and insulin, produced similar changes but with different timing. Thus, the initial decrease in AMPK activity observed at 3h was associated with changes in Ser485/491 phosphorylation and SIRT1 expression and increased PP2A activity was a later event. These findings suggest that both ex vivo and in vivo, multiple factors contribute to fuel-induced decreases in AMPK activity in skeletal muscle and the insulin resistance that accompanies it.
authors.affiliation: Department of Medicine, Section of Endocrinology and Diabetes, Boston University Medical Center, Boston, Massachusetts, United States of America.
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Coughlan
authors.affiliation: Department of Medicine, Section of Endocrinology and Diabetes, Boston University Medical Center, Boston, Massachusetts, United States of America.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Balon
authors.affiliation: Department of Medicine, Section of Endocrinology and Diabetes, Boston University Medical Center, Boston, Massachusetts, United States of America.
authors.forename: Rudy J
authors.initials: RJ
authors.lastname: Valentine
authors.affiliation: Department of Medicine, Section of Endocrinology and Diabetes, Boston University Medical Center, Boston, Massachusetts, United States of America.
authors.forename: Robert
authors.initials: R
authors.lastname: Petrocelli
authors.affiliation: Department of Medicine, Section of Endocrinology and Diabetes, Boston University Medical Center, Boston, Massachusetts, United States of America.
authors.forename: Vera
authors.initials: V
authors.lastname: Schultz
authors.affiliation: Diabetes and Obesity Program, Garvan Institute of Medical Research and School of Medical Sciences, University of NSW, Sydney, Australia.
authors.forename: Amanda
authors.initials: A
authors.lastname: Brandon
authors.affiliation: Diabetes and Obesity Program, Garvan Institute of Medical Research and School of Medical Sciences, University of NSW, Sydney, Australia.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Cooney
authors.affiliation: Diabetes and Obesity Program, Garvan Institute of Medical Research and School of Medical Sciences, University of NSW, Sydney, Australia.
authors.forename: Edward W
authors.initials: EW
authors.lastname: Kraegen
authors.affiliation: Department of Medicine, Section of Endocrinology and Diabetes, Boston University Medical Center, Boston, Massachusetts, United States of America.
authors.forename: Neil B
authors.initials: NB
authors.lastname: Ruderman
authors.affiliation: Department of Medicine, Section of Endocrinology and Diabetes, Boston University Medical Center, Boston, Massachusetts, United States of America.
authors.forename: Asish K
authors.initials: AK
authors.lastname: Saha
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000824:Animal Nutritional Physiological Phenomena; D000818:Animals; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000378:metabolism; D015870:Gene Expression; D005947:Glucose / Q000008:administration & dosage / Q000378:metabolism*; D006003:Glycogen / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism*; D054409:Nicotinamide Phosphoribosyltransferase / Q000378:metabolism; D010084:Oxidation-Reduction; D010766:Phosphorylation; D051381:Rats; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism
chemical_list: D006003:Glycogen; D054409:Nicotinamide Phosphoribosyltransferase; D000071679:Glycogen Synthase Kinase 3 beta; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D038362:Glycogen Synthase Kinase 3; D055372:AMP-Activated Protein Kinases; D056564:Sirtuin 1; D000103:Acetyl-CoA Carboxylase; D005947:Glucose