title: Intact Regulation of the AMPK Signaling Network in Response to Exercise and Insulin in Skeletal Muscle of Male Patients With Type 2 Diabetes: Illumination of AMPK Activation in Recovery From Exercise.
abstract: Current evidence on exercise-mediated AMPK regulation in skeletal muscle of patients with type 2 diabetes (T2D) is inconclusive. This may relate to inadequate segregation of trimeric complexes in the investigation of AMPK activity. We examined the regulation of AMPK and downstream targets ACC-β, TBC1D1, and TBC1D4 in muscle biopsy specimens obtained from 13 overweight/obese patients with T2D and 14 weight-matched male control subjects before, immediately after, and 3 h after exercise. Exercise increased AMPK α2β2γ3 activity and phosphorylation of ACCβ Ser(221), TBC1D1 Ser(237)/Thr(596), and TBC1D4 Ser(704) Conversely, exercise decreased AMPK α1β2γ1 activity and TBC1D4 Ser(318)/Thr(642) phosphorylation. Interestingly, compared with preexercise, 3 h into exercise recovery, AMPK α2β2γ1 and α1β2γ1 activity were increased concomitant with increased TBC1D4 Ser(318)/Ser(341)/Ser(704) phosphorylation. No differences in these responses were observed between patients with T2D and control subjects. Subjects were also studied by euglycemic-hyperinsulinemic clamps performed at rest and 3 h after exercise. We found no evidence for insulin to regulate AMPK activity. Thus, AMPK signaling is not compromised in muscle of patients with T2D during exercise and insulin stimulation. Our results reveal a hitherto unrecognized activation of specific AMPK complexes in exercise recovery. We hypothesize that the differential regulation of AMPK complexes plays an important role for muscle metabolism and adaptations to exercise.
authors.affiliation: Section of Molecular Physiology, August Krogh Centre, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Rasmus
authors.initials: R
authors.lastname: Kjøbsted
authors.affiliation: Department of Endocrinology, Odense University Hospital, Odense, Denmark.
authors.forename: Andreas J T
authors.initials: AJ
authors.lastname: Pedersen
authors.affiliation: Section of Molecular Physiology, August Krogh Centre, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Janne R
authors.initials: JR
authors.lastname: Hingst
authors.affiliation: Department of Endocrinology, Odense University Hospital, Odense, Denmark Section of Molecular Diabetes and Metabolism, Institute of Molecular Medicine and Institute of Clinical Research, University of Southern Denmark, Odense, Denmark.
authors.forename: Rugivan
authors.initials: R
authors.lastname: Sabaratnam
authors.affiliation: Section of Molecular Physiology, August Krogh Centre, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Jesper B
authors.initials: JB
authors.lastname: Birk
authors.affiliation: Department of Endocrinology, Odense University Hospital, Odense, Denmark Section of Molecular Diabetes and Metabolism, Institute of Molecular Medicine and Institute of Clinical Research, University of Southern Denmark, Odense, Denmark.
authors.forename: Jonas M
authors.initials: JM
authors.lastname: Kristensen
authors.affiliation: Department of Endocrinology, Odense University Hospital, Odense, Denmark Section of Molecular Diabetes and Metabolism, Institute of Molecular Medicine and Institute of Clinical Research, University of Southern Denmark, Odense, Denmark.
authors.forename: Kurt
authors.initials: K
authors.lastname: Højlund
authors.affiliation: Section of Molecular Physiology, August Krogh Centre, Department of Nutrition, Exercise and Sports, Faculty of Science, 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*; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D001642:Bicycling; D001706:Biopsy; D015992:Body Mass Index; D015331:Cohort Studies; D003131:Combined Modality Therapy; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D015444:Exercise; D005221:Fatigue / Q000209:etiology / Q000517:prevention & control; D020690:GTPase-Activating Proteins / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007328:Insulin / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009765:Obesity / Q000150:complications / Q000628:therapy; D050177:Overweight / Q000150:complications / Q000628:therapy; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D052097:Quadriceps Muscle; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D020690:GTPase-Activating Proteins; D007004:Hypoglycemic Agents; D007328:Insulin; C526441:TBC1D1 protein, human; C518767:TBC1D4 protein, human; D055372:AMP-Activated Protein Kinases; C520105:ACACB protein, human; D000103:Acetyl-CoA Carboxylase