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Cited by 164Metabolism, Diabetes, and CancerCardiovascular and exercise physiologyDiabetes, Cardiovascular Risks, and Lipoproteins

Exercise Increases Human Skeletal Muscle Insulin Sensitivity via Coordinated Increases in Microvascular Perfusion and Molecular Signaling

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Sjøberg, Kim A., Frøsig, Christian, Kjøbsted, Rasmus, Sylow, Lykke, Kleinert, Maximilian, Betik, Andrew C., Shaw, Christopher S., Kiens, Bente +4 more·2017·Diabetes
DOI 10.2337/db16-1327
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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 Ser318 and Ser704 and 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.

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  • Following a single exercise bout, improved insulin action involves coordinated effects on vasodilation, capillary perfusion, and GLUT4 translocation to the muscle surface membrane.

    “Following a single exercise bout, the mechanisms underlying improved insulin action involve a coordinated effect of insulin action on vasodilation, augmented capillary perfusion, and increased glucose transporter 4 (GLUT4) translocation to the muscle surface membrane 55, 56.”

    From Effect of exercise training on insulin-stimulated glucose disposal: A systematic review and meta-analysis of randomized controlled trials (2023) · cites this paper as [55]

    The Discussion (p. 6) reports that acute exercise augments insulin-stimulated microvascular perfusion and coordinates greater glucose delivery with muscle-cell signaling; the paper also describes insulin as a vasodilator (p. 2). But the Discussion (p. 6) says the cellular response is *likely* at the level of GLUT4 translocation. It does not establish increased GLUT4 translocation as a measured effect. (LLM, conf=0.84)

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  1. [20]20. Baron AD, Clark MG. Role of blood fl ow in the regulation of muscle glucose uptake. Annu Rev Nutr 1997;17:487 -499

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Authors
Sjøberg, K. A., Frøsig, C., Kjøbsted, R., Sylow, L., Kleinert, M., Betik, A. C., Shaw, C. S., Kiens, B., Wojtaszewski, J. F. P., Rattigan, S., Richter, E. A., & McConell, G. K.
Affiliations
  • University of Copenhagen (DK)
  • Victoria University (AU)
  • Deakin University (AU)
  • University of Tasmania (AU)
Corresponding author
  • Richter, Erik A.
  • McConell, Glenn K.
ORCID
Venue
Diabetes
Publisher
American Diabetes Association
Published
2017-03-14
Volume
66
Issue
6
Pages
1501-1510
ISSN
  • 0012-1797 (ISSN-L)
  • 1939-327X
DOI
10.2337/db16-1327
OpenAlex
W2596171931
Semantic Scholar
2ed1ea584eedfb788916e4eadf19e75df50a4fbb
Cited by
164
References
37
Citations by year
2026: 13 · 2025: 13 · 2024: 11 · 2023: 14 · 2022: 12 · 2021: 26 · 2020: 31 · 2019: 26 · 2018: 12 · 2017: 5
FWCI
8.27
Type
journal article
Language
en
Open access
Licence
www.diabetesjournals.org/content/license (vor, 69 d)
Locations
  • Diabetes (publishedVersion)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion)
  • Deakin Research Online (Deakin University) (submittedVersion)
  • eCite Digital Repository (University of Tasmania) (submittedVersion)
  • UTAS Research Repository (submittedVersion)
  • Victoria University Research Repository (Victoria University) (submittedVersion)
  • Figshare (submittedVersion, cc-by)
Funders
  • Council for Independent Research/Medicine (4092-00309, 4004-0045)
  • National Health and Medical Research Council of Australia (1012181)
  • Lundbeck Foundation (R204-2016-137)
  • Fabrikant Vilhelm Pedersen og Hustrus Legat by recommendation from the Novo Nordisk Foundation
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Health Sciences › Medicine › Complementary and alternative medicine › Cardiovascular and exercise physiology
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
Keywords
acute exercise, skeletal muscle insulin sensitivity, insulin resistance, microvascular blood flow, glucose uptake, nitric oxide synthase, TBC1D4, glycogen synthase, insulin signaling, glucose delivery, contrast-enhanced ultrasound
MeSH terms
Adult, Contrast Media, Enzyme Inhibitors, Femoral Artery, Glucose, Glycogen Synthase, Humans, Hypoglycemic Agents, Insulin, Insulin Resistance, Leg, Male, Phosphorylation, Ultrasonography, Glucose Clamp Technique, Signal Transduction, Exercise, Muscle, Skeletal, Nitric Oxide Synthase, omega-N-Methylarginine, GTPase-Activating Proteins, Microvessels, Young Adult, Healthy Volunteers

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