title: Two weeks of metformin treatment induces AMPK-dependent enhancement of insulin-stimulated glucose uptake in mouse soleus muscle.
abstract: Metformin-induced activation of the 5'-AMP-activated protein kinase (AMPK) has been associated with enhanced glucose uptake in skeletal muscle, but so far no direct causality has been examined. We hypothesized that an effect of in vivo metformin treatment on glucose uptake in mouse skeletal muscles is dependent on AMPK signaling. Oral doses of metformin or saline treatment were given to muscle-specific kinase dead (KD) AMPKα2 mice and wild-type (WT) littermates either once or chronically for 2 wk. Soleus and extensor digitorum longus muscles were used for measurements of glucose transport and Western blot analyses. Chronic treatment with metformin enhanced insulin-stimulated glucose uptake in soleus muscles of WT (∼45%, P < 0.01) but not of AMPK KD mice. Insulin signaling at the level of Akt protein expression or Thr(308) and Ser(473) phosphorylation was not changed by metformin treatment. Insulin signaling at the level of Akt and TBC1D4 protein expression as well as Akt Thr(308)/Ser(473) and TBC1D4 Thr(642)/Ser(711) phosphorylation were not changed by metformin treatment. Also, protein expressions of Rab4, GLUT4, and hexokinase II were unaltered after treatment. The acute metformin treatment did not affect glucose uptake in muscle of either of the genotypes. In conclusion, we provide novel evidence for a role of AMPK in potentiating the effect of insulin on glucose uptake in soleus muscle in response to chronic metformin treatment.
authors.affiliation: Molecular Physiology Group, August Krogh Centre, Department of Nutrition, Exercise and Sport Sciences, University of Copenhagen, Copenhagen, Denmark;
authors.forename: Jonas Møller
authors.initials: JM
authors.lastname: Kristensen
authors.affiliation: Molecular Physiology Group, August Krogh Centre, Department of Nutrition, Exercise and Sport Sciences, University of Copenhagen, Copenhagen, Denmark;
authors.forename: Jonas T
authors.initials: JT
authors.lastname: Treebak
authors.affiliation: Institute of Sports Medicine, Department of Orthopedic Surgery M, Bispebjerg Hospital and Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; and.
authors.forename: Peter
authors.initials: P
authors.lastname: Schjerling
authors.affiliation: Research Division, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts.
authors.forename: Laurie
authors.initials: L
authors.lastname: Goodyear
authors.affiliation: Molecular Physiology Group, August Krogh Centre, Department of Nutrition, Exercise and Sport Sciences, University of Copenhagen, Copenhagen, Denmark; jwojtaszewski@nexs.ku.dk.
authors.forename: Jørgen F P
authors.initials: JF
authors.lastname: Wojtaszewski
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D005260:Female; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D007328:Insulin / Q000008:administration & dosage*; D008687:Metformin / Q000008:administration & dosage*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D013997:Time Factors
chemical_list: D051275:Glucose Transporter Type 4; D007328:Insulin; D008687:Metformin; C534978:Prkaa2 protein, mouse; D055372:AMP-Activated Protein Kinases; D005947:Glucose
keywords: AMPK; glucose uptake; insulin; metformin; skeletal muscle