Interleukin-6 Is a Novel Factor Mediating Glucose Homeostasis During Skeletal Muscle Contraction
Open accessAbstract
The mechanisms that mediate the tightly controlled production and clearance of glucose during muscular work are unclear, and it has been suggested that an unidentified “work factor” exists that influences the contraction-induced increase in endogenous glucose production (EGP). The cytokine interleukin (IL)-6 is released from skeletal muscle during contraction. Here we show that IL-6 contributes to the contraction-induced increase in EGP. Six men performed 2 h of bicycle exercise on three separate occasions, at a relatively high intensity (HI) or at a low intensity with (LO + IL-6) or without (LO) an infusion of recombinant human IL-6 that matched the circulating concentration of IL-6 seen in HI exercise. The stable isotope 6,6 2H2 glucose was infused to calculate EGP (rate of glucose appearance [Ra]), whole-body glucose disposal (rate of glucose disappearance [Rd]), and metabolic clearance rate (MCR) of glucose. Glucose Ra, Rd, and MCR were higher (P < 0.05) at HI than at LO. Throughout exercise at LO + IL-6, glucose Ra and Rd were higher (P < 0.05) than LO, even though the exercise intensity was identical. In addition, MCR was higher (P < 0.05) at LO + IL-6 than at LO at 90 min. Insulin, glucagon, epinephrine, norepinephrine, cortisol, and growth hormone were identical when comparing LO + IL-6 with LO. These data suggest that IL-6 influences glucose homeostasis during exercise. Our results provide potential new insights into factors that mediate glucose production and disposal and implicates IL-6 in the so-called “work factor.”
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Interleukin-6 contributes to the contraction-induced increase in hepatic glucose production.
“In this connection, it has been shown that interleukin-6 contributes to the contractioninduced increase in hepatic glucose production (64).”
From Expression of <i>Mfn2</i>, the Charcot-Marie-Tooth Neuropathy Type 2A Gene, in Human Skeletal Muscle (2005) · cites this paper as [64]
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Knudsen, J. G., Gudiksen, A., Bertholdt, L., Overby, P., Villesen, I., Schwartz, C. L., & Pilegaard, H. (2017) · PLOS ONE · doi:10.1371/journal.pone.0189301 · Cited by 42 · see citing works
Banzet, S., Koulmann, N., Simler, N., Sanchez, H., Chapot, R., Serrurier, B., Peinnequin, A., & Bigard, X. (2009) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00739.2009 · Cited by 42 · see citing works
Who would have thought—Myokines two decades on
Febbraio, M. A., & Pedersen, B. K. (2020) · Nature Reviews Endocrinology · doi:10.1038/s41574-020-00408-7 · Cited by 34 · see citing works
Self-citationNutrient Timing: The Means to Improved Exercise Performance, Recovery, and Training Adaptation
Ivy, J. L., & Ferguson-Stegall, L. M. (2014) · American Journal of Lifestyle Medicine · doi:10.1177/1559827613502444 · Cited by 22 · see citing works
Glucose ingestion during endurance training in men attenuates expression of myokine receptor
Akerstrom, T. C. A., Krogh‐Madsen, R., Petersen, A. M. W., & Pedersen, B. K. (2009) · Experimental Physiology · doi:10.1113/expphysiol.2009.048983 · Cited by 21 · see citing works
Self-citationClark, J. E. (2012) · Journal of Diabetes & Metabolic Disorders · doi:10.1186/2251-6581-11-19 · Cited by 19 · see citing works
IL-6 Activity is Required for Maximal Catecholamine Release During High-Intensity Exercise in Men
Ziegler, A. K., Schauer, T., Myrup, S. F., van Hall, G., Pedersen, B. K., Christensen, J. F., & Ellingsgaard, H. (2026) · Molecular Metabolism · doi:10.1016/j.molmet.2026.102395 · Cited by 1 · see citing works
Self-citation
- Authors
- Febbraio, M. A., Hiscock, N., Sacchetti, M., Fischer, C. P., & Pedersen, B. K.
- Affiliations
- University of Copenhagen (DK)
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2004-07-01
- Volume
- 53
- Issue
- 7
- Pages
- 1643-1648
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2098882931
- Cited by
- 455
- References
- 29
- Citations by year
- 2026: 20 · 2025: 18 · 2024: 27 · 2023: 27 · 2022: 24 · 2021: 28 · 2020: 28 · 2019: 19 · 2018: 24 · 2017: 25 · 2016: 14 · 2015: 12 · 2014: 26 · 2013: 19 · 2012: 21
- FWCI
- 19.47
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- RMIT Research Repository (RMIT University Library) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion, other-oa)
- Funders
- Sundhed og Sygdom, Det Frie Forskningsråd (22-01-009)
- National Research Foundation
- Danmarks Grundforskningsfond (22-01-009, 504–14)
- Lundbeckfonden
- Novo Nordisk
- Augustinus Fonden
- Rigshospitalet
- Novo Nordisk Fonden
- Medical Research Council
- National Health and Medical Research Council (251558)
- Topics
- Health Sciences › Medicine › Rehabilitation › Exercise and Physiological Responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- interleukin-6, glucose homeostasis, skeletal muscle contraction, physical activity, endogenous glucose production, glucose disposal, metabolic clearance rate, work factors, cytokines, glucose appearance, glucose disappearance, insulin, glucagon, epinephrine, norepinephrine, cortisol, growth hormone
- MeSH terms
- Adult, Bicycling, Fatty Acids, Nonesterified, Glucose, Homeostasis, Hormones, Humans, Male, Metabolic Clearance Rate, Muscle Contraction, Recombinant Proteins, Exercise, Interleukin-6, Muscle, Skeletal, Lactic Acid
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