title: Exercise Increases Human Skeletal Muscle Insulin Sensitivity via Coordinated Increases in Microvascular Perfusion and Molecular Signaling.
abstract: Insulin resistance is a major health risk, and although exercise clearly improves skeletal muscle insulin sensitivity, the mechanisms are unclear. Here we show that initiation of a euglycemic-hyperinsulinemic clamp 4 h after single-legged exercise in humans increased microvascular perfusion (determined by contrast-enhanced ultrasound) by 65% in the exercised leg and 25% in the rested leg (P< 0.05) and that leg glucose uptake increased 50% more (P< 0.05) in the exercised leg than in the rested leg. Importantly, infusion of the nitric oxide synthase inhibitor l-NG-monomethyl-l-arginine acetate (l-NMMA) into both femoral arteries reversed the insulin-stimulated increase in microvascular perfusion in both legs and abrogated the greater glucose uptake in the exercised compared with the rested leg. Skeletal muscle phosphorylation of TBC1D4 Ser318and Ser704and glycogen synthase activity were greater in the exercised leg before insulin and increased similarly in both legs during the clamp, and l-NMMA had no effect on these insulin-stimulated signaling pathways. Therefore, acute exercise increases insulin sensitivity of muscle by a coordinated increase in insulin-stimulated microvascular perfusion and molecular signaling at the level of TBC1D4 and glycogen synthase in muscle. This secures improved glucose delivery on the one hand and increased ability to take up and dispose of the delivered glucose on the other hand.
authors.affiliation: Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Denmark.
authors.forename: Kim A
authors.initials: KA
authors.lastname: Sjøberg
authors.affiliation: Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Denmark.
authors.forename: Christian
authors.initials: C
authors.lastname: Frøsig
authors.affiliation: Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Denmark.
authors.forename: Rasmus
authors.initials: R
authors.lastname: Kjøbsted
authors.affiliation: Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Denmark.
authors.forename: Lykke
authors.initials: L
authors.lastname: Sylow
authors.affiliation: Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Denmark.
authors.forename: Maximilian
authors.identifier: 0000-0002-8069-9055
authors.initials: M
authors.lastname: Kleinert
authors.affiliation: Institute of Sport, Exercise and Active Living (ISEAL), Victoria University, Melbourne, Victoria, Australia.|College of Health and Biomedicine, Victoria University, Melbourne, Victoria, Australia.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Betik
authors.affiliation: Institute of Sport, Exercise and Active Living (ISEAL), Victoria University, Melbourne, Victoria, Australia.|Institute for Physical Activity and Nutrition, Deakin University, Geelong, Victoria, Australia.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Shaw
authors.affiliation: Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Denmark.
authors.forename: Bente
authors.initials: B
authors.lastname: Kiens
authors.affiliation: Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Denmark.
authors.forename: Jørgen F P
authors.initials: JFP
authors.lastname: Wojtaszewski
authors.affiliation: Menzies Research Institute Tasmania, University of Tasmania, Hobart, Tasmania, Australia.
authors.forename: Stephen
authors.initials: S
authors.lastname: Rattigan
authors.affiliation: Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Denmark glenn.mcconell@vu.edu.au erichter@nexs.ku.dk.
authors.forename: Erik A
authors.initials: EA
authors.lastname: Richter
authors.affiliation: Institute of Sport, Exercise and Active Living (ISEAL), Victoria University, Melbourne, Victoria, Australia glenn.mcconell@vu.edu.au erichter@nexs.ku.dk.|College of Health and Biomedicine, Victoria University, Melbourne, Victoria, Australia.
authors.forename: Glenn K
authors.initials: GK
authors.lastname: McConell
mesh_terms: D000328:Adult; D003287:Contrast Media; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015444:Exercise / Q000502:physiology*; D005263:Femoral Artery; D020690:GTPase-Activating Proteins / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D015309:Glucose Clamp Technique; D006006:Glycogen Synthase / Q000378:metabolism; D064368:Healthy Volunteers; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance; D007866:Leg; D008297:Male; D055806:Microvessels / Q000187:drug effects / Q000502:physiology*; D018482:Muscle, Skeletal / Q000098:blood supply / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010766:Phosphorylation; D015398:Signal Transduction; D014463:Ultrasonography; D055815:Young Adult; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D003287:Contrast Media; D004791:Enzyme Inhibitors; D020690:GTPase-Activating Proteins; D007004:Hypoglycemic Agents; D007328:Insulin; C518767:TBC1D4 protein, human; D019323:omega-N-Methylarginine; D019001:Nitric Oxide Synthase; D006006:Glycogen Synthase; D005947:Glucose