IL-6 increases muscle insulin sensitivity only at superphysiological levels
Abstract
Exercise induces an increase in glucose transport in muscle. As the acute increase in glucose transport reverses, it is replaced by an increase in insulin sensitivity. Interleukin-6 (IL-6) increases with exercise and has been reported to activate AMP-activated protein kinase (AMPK). Based on this information, we hypothesized that IL-6 would result in an increase in muscle insulin sensitivity. Rat epitrochlearis and soleus muscles were incubated with 120 ng/ml IL-6. Exposure to IL-6 induced a modest acute increase in glucose transport and was followed 3.5 h later by an increase in insulin sensitivity in epitrochlearis but not soleus muscles. IL-6 also brought about an increase in AMPK phosphorylation in epitrochlearis muscles. We conclude that exposure of fast-twitch muscle to 120 ng/ml IL-6 increases insulin sensitivity by activating AMPK. However, exposure of epitrochlearis muscles to 10 ng/ml IL-6, a concentration >100-fold higher than that attained in plasma during exercise, had no effect on glucose transport or insulin sensitivity. These findings provide evidence that the increases in glucose transport and insulin sensitivity induced by IL-6 are pharmacological rather than physiological effects. We interpret our results as evidence that the increase in IL-6 during exercise does not play a role in the exercise-induced increases in muscle glucose uptake and insulin sensitivity.
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Only higher concentrations of IL-6 increased AMPK phosphorylation in whole muscle.
“In contrast, Geiger et al. [164] showed that in whole muscle, which is more biologically relevant, that only higher concentrations of IL-6 increased AMPK phosphorylation; suggesting that under physiological conditions, such as during exercise, IL-6 may play a less significant role in positively regulating metabolic processes.”
From AMPK and Exercise: Glucose Uptake and Insulin Sensitivity (2013) · cites this paper as [164]
IL-6 is additive to insulin in stimulating glucose uptake, but this was not observed by all studies.
“Their study and Geiger et al. [164] also suggested that IL-6 is additive to insulin in stimulating glucose uptake; however, this was not observed by all studies [165] who found that IL-6 regulated glucose uptake and glycogen synthesis via a PI3-dependent pathway and not AMPK; given human myotubes targeted for AMPK depletion by siRNA did not have impaired insulin sensitivity.”
From AMPK and Exercise: Glucose Uptake and Insulin Sensitivity (2013) · cites this paper as [164]
Cites
PROTEIN MEASUREMENT WITH THE FOLIN PHENOL REAGENT
Lowry, O. H., Rosebrough, N., Farr, A. L., & Randall, R. (1951) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)52451-6 · Cited by 315,771 · see citing works
C-Reactive Protein, Interleukin 6, and Risk of Developing Type 2 Diabetes Mellitus
Pradhan, A. D. (2001) · JAMA · doi:10.1001/jama.286.3.327 · Cited by 4,433 · see citing works
Physical Activity, All-Cause Mortality, and Longevity of College Alumni
Paffenbarger, R. S., Hyde, R., Wing, A. L., & Hsieh, C.-C. (1986) · New England Journal of Medicine · doi:10.1056/nejm198603063141003 · Cited by 2,742 · see citing works
Physical Fitness and All-Cause Mortality: A Prospective Study of Healthy Men and Women
Blair, S. N. (1989) · JAMA · doi:10.1001/jama.1989.03430170057028 · Cited by 2,658 · see citing works
Ridker, P. M., Rifai, N., Stampfer, M. J., & Hennekens, C. H. (2000) · Circulation · doi:10.1161/01.cir.101.15.1767 · Cited by 2,429 · see citing works
Blair, S. N. (1996) · JAMA: The Journal of the American Medical Association · doi:10.1001/jama.1996.03540030039029 · Cited by 1,819 · see citing works
Pickup, J. C., Mattock, M. B., Chusney, G. D., & Burt, D. J. (1997) · Diabetologia · doi:10.1007/s001250050822 · Cited by 1,241 · see citing works
Rotter, V., Nagaev, I., & Smith, U. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m301977200 · Cited by 1,062 · see citing works
Merrill, G. F., Kurth, E. J., Hardie, D. G., & Winder, W. W. (1997) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1997.273.6.e1107 · Cited by 1,027 · see citing works
Carey, A. L., Steinberg, G. R., Macaulay, S. L., Thomas, W. G., Holmes, A. G., Ramm, G., Prelovsek, O., Hohnen-Behrens, C., Watt, M. J., James, D. E., et al. (2006) · Diabetes · doi:10.2337/db05-1404 · Cited by 898 · see citing works
Interleukin-6 induces cellular insulin resistance in hepatocytes.
Senn, J. J., Klover, P. J., Nowak, I. A., & Mooney, R. A. (2002) · Diabetes · doi:10.2337/diabetes.51.12.3391 · Cited by 883 · see citing works
Hayashi, T., Hirshman, M. F., Kurth, E. J., Winder, W. W., & Goodyear, L. J. (1998) · Diabetes · doi:10.2337/diab.47.8.1369 · Cited by 774 · see citing works
5' AMP-activated protein kinase activation causes GLUT4 translocation in skeletal muscle.
Kurth-Kraczek, E. J., Hirshman, M. F., Goodyear, L. J., & Winder, W. W. (1999) · Diabetes · doi:10.2337/diabetes.48.8.1667 · Cited by 715 · see citing works
Activation of AMP-activated protein kinase increases mitochondrial enzymes in skeletal muscle
Winder, W. W., Holmes, B. F., Rubink, D. S., Jensen, E. B., Chen, M., & Holloszy, J. O. (2000) · Journal of Applied Physiology · doi:10.1152/jappl.2000.88.6.2219 · Cited by 709 · see citing works
Self-citationEvidence that interleukin-6 is produced in human skeletal muscle during prolonged running
Ostrowski, K., Rohde, T., Zacho, M., Asp, S., & Pedersen, B. K. (1998) · The Journal of Physiology · doi:10.1111/j.1469-7793.1998.949bp.x · Cited by 673 · see citing works
Physical Activity in the Prevention of Type 2 Diabetes
Laaksonen, D. E., Lindström, J., Lakka, T. A., Eriksson, J. G., Niskanen, L., Wikström, K., Aunola, S., Keinänen-Kiukaanniemi, S., Laakso, M., Valle, T. T., et al. (2005) · Diabetes · doi:10.2337/diabetes.54.1.158 · Cited by 614 · see citing works
Daily activity energy expenditure and mortality among older adults
Manini, T. M., Everhart, J. E., Patel, K. V., Schoeller, D. A., Colbert, L. H., Visser, M., Tylavsky, F., Bauer, D. C., Goodpaster, B. H., & Harris, T. B. (2006) · JAMA · doi:10.1001/jama.296.2.171 · Cited by 598 · see citing works
Fernandez-Real, J.-M., Vayreda, M., Richart, C., Gutierrez, C., Broch, M., Vendrell, J., & Ricart, W. (2001) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.86.3.7305 · Cited by 567 · see citing works
Effects of exercise and diet on chronic disease
Roberts, C. K., & Barnard, R. J. (2005) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00852.2004 · Cited by 556 · see citing works
Cardiorespiratory Fitness Is Inversely Associated With the Incidence of Metabolic Syndrome
LaMonte, M. J., Barlow, C. E., Jurča, R., Kampert, J. B., Church, T. S., & Blair, S. N. (2005) · Circulation · doi:10.1161/circulationaha.104.503805 · Cited by 506 · see citing works
Exercise-induced increase in muscle insulin sensitivity
Holloszy, J. O. (2005) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00123.2005 · Cited by 494 · see citing works
Self-citationVlachopoulos, C., Dima, I., Aznaouridis, K., Vasiliadou, C., Ioakeimidis, N., Aggeli, C., Toutouza, M., & Stefanadis, C. (2005) · Circulation · doi:10.1161/circulationaha.105.535435 · Cited by 492 · see citing works
The Association of Plasma IL-6 Levels With Functional Disability in Community-Dwelling Elderly
Cohen, H. J., Pieper, C. F., Harris, T., Rao, K. M. K., & Currie, M. S. (1997) · The Journals of Gerontology Series A: Biological Sciences and Medical Sciences · doi:10.1093/gerona/52a.4.m201 · Cited by 476 · see citing works
Glucose transporter protein content and glucose transport capacity in rat skeletal muscles
Henriksen, E. J., Bourey, R. E., Rodnick, K. J., Koranyi, L. I., Permutt, M. A., & Holloszy, J. O. (1990) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1990.259.4.e593 · Cited by 435 · see citing works
Self-citationContraction-Induced Myokine Production and Release: Is Skeletal Muscle an Endocrine Organ?
Febbraio, M. A., & Pedersen, B. K. (2005) · Exercise and Sport Sciences Reviews · doi:10.1097/00003677-200507000-00003 · Cited by 402 · see citing works
Ca2+ and AMPK Both Mediate Stimulation of Glucose Transport by Muscle Contractions
Wright, D. C., Hucker, K. A., Holloszy, J. O., & Han, D. H. (2004) · Diabetes · doi:10.2337/diabetes.53.2.330 · Cited by 398 · see citing works
Self-citationMüller, S., Martin, S., Koenig, W., Hanifi-Moghaddam, P., Rathmann, W., Haastert, B., Giani, G., Illig, T., Thorand, B., & Kolb, H. (2002) · Diabetologia · doi:10.1007/s00125-002-0829-2 · Cited by 311 · see citing works
Activation of p38 MAP kinase enhances sensitivity of muscle glucose transport to insulin
Geiger, P. C., Wright, D. C., Han, D., & Holloszy, J. O. (2004) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00477.2004 · Cited by 306 · see citing works
Self-citationHu, G., Tuomilehto, J., Silventoinen, K., Barengo, N. C., Peltonen, M., & Jousilahti, P. (2005) · International Journal of Obesity · doi:10.1038/sj.ijo.0802870 · Cited by 294 · see citing works
AMPK activity is diminished in tissues of IL-6 knockout mice: the effect of exercise.
Kelly, M., Keller, C., Avilucea, P. R., Keller, P., Luo, Z., Xiang, X., Giralt, M., Hidalgo, J., Saha, A. K., Pedersen, B. K., et al. (2004) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2004.05.188 · Cited by 289 · see citing works
Acharya, P., Beckel, J. M., Ruiz, W. G., Wang, E., Rojas, R., Birder, L. A., & Apodaca, G. L. (2004) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00341.2003 · Cited by 252 · see citing works
Activation of AMP kinase enhances sensitivity of muscle glucose transport to insulin
Fisher, J. S., Gao, J., Han, D.-H., Holloszy, J. O., & Nolte, L. A. (2002) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.2002.282.1.e18 · Cited by 244 · see citing works
Self-citationSopasakis, V. R., Sandqvist, M., Gustafson, B., Hammarstedt, A., Schmelz, M., Yang, X., Jansson, P., & Smith, U. (2004) · Obesity Research · doi:10.1038/oby.2004.51 · Cited by 243 · see citing works
Hansen, P. A., Gulve, E. A., & Holloszy, J. O. (1994) · Journal of Applied Physiology · doi:10.1152/jappl.1994.76.2.979 · Cited by 234 · see citing works
Self-citationAMP-activated protein kinase activity and glucose uptake in rat skeletal muscle
Musi, N., Hayashi, T., FUJII, N. L., Hirshman, M. F., Witters, L. A., & Goodyear, L. J. (2001) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.2001.280.5.e677 · Cited by 219 · see citing works
Sinha, S., Perdomo, G., Brown, N. F., & O'Doherty, R. M. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m406514200 · Cited by 215 · see citing works
The effect of graded exercise on IL‐6 release and glucose uptake in human skeletal muscle
Helge, J. W., Stallknecht, B., Pedersen, B. K., Galbo, H., Kiens, B., & Richter, E. A. (2003) · The Journal of Physiology · doi:10.1113/jphysiol.2002.030437 · Cited by 212 · see citing works
Regulation of GLUT4 biogenesis in muscle: evidence for involvement of AMPK and Ca2+
Ojuka, E. O., Jones, T. E., Nolte, L. A., Chen, M. W., Wamhoff, B. R., Sturek, M. S., & Holloszy, J. O. (2002) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00512.2001 · Cited by 208 · see citing works
Self-citationLangberg, H., Olesen, J. L., Gemmer, C., & Kjær, M. (2002) · The Journal of Physiology · doi:10.1113/jphysiol.2002.019141 · Cited by 186 · see citing works
Kado, S., Nagase, T., & Nagata, N. (1999) · Acta Diabetologica · doi:10.1007/s005920050147 · Cited by 158 · see citing works
Young, D. A., Uhl, J. J., Cartee, G. D., & Holloszy, J. O. (1986) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)66674-8 · Cited by 153 · see citing works
Self-citationRegulation of glucose transport into skeletal muscle
Holloszy, J. O., & Hansen, P. A. (1996) · Reviews of physiology, biochemistry and pharmacology · doi:10.1007/3-540-61343-9_8 · Cited by 151 · see citing works
Self-citationPlasma interleukin-6 during strenuous exercise: role of epinephrine
Steensberg, A., Toft, A. D., Schjerling, P., Halkjær-Kristensen, J., & Pedersen, B. K. (2001) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.2001.281.3.c1001 · Cited by 137 · see citing works
Sweeney, G., Keen, J., Somwar, R., Konrad, D., Garg, R. R., & Klip, A. (2001) · Endocrinology · doi:10.1210/endo.142.11.8496 · Cited by 106 · see citing works
Effect of diffusion distance on measurement of rat skeletal muscle glucose transport in vitro
Henriksen, E. J., & Holloszy, J. O. (1991) · Acta Physiologica Scandinavica · doi:10.1111/j.1748-1716.1991.tb09249.x · Cited by 79 · see citing works
Self-citationMcCarthy, A. M., Spisak, K. O., Brozinick, J. T., & Elmendorf, J. S. (2006) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00107.2006 · Cited by 75 · see citing works
Cytokines in Heart Failure: Pathogenetic Mechanisms and Potential Treatment
Dibbs, Z. I., Kurrelmeyer, K. M., Kalra, D. K., Seta, Y., Wang, F., Bozkurt, B., Baumgarten, G., Sivasubramanian, N., & Mann, D. L. (1999) · Proceedings of the Association of American Physicians · doi:10.1111/paa.1999.111.5.423 · Cited by 62 · see citing works
PPARδ activator GW-501516 has no acute effect on glucose transport in skeletal muscle
Terada, S., Wicke, S., Holloszy, J. O., & Han, D. (2005) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00430.2005 · Cited by 32 · see citing works
Self-citationPhorbol esters affect skeletal muscle glucose transport in a fiber type-specific manner
Wright, D. C., Geiger, P. C., Rheinheimer, M. J., Han, D. H., & Holloszy, J. O. (2004) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00082.2004 · Cited by 13 · see citing works
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Fève, B., & Bastard, J.-P. (2009) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2009.62 · Cited by 343 · see citing works
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O'Neill, H. M. (2013) · Diabetes & Metabolism Journal · doi:10.4093/dmj.2013.37.1.1 · Cited by 295 · see citing works
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Zaha, V. G., & Young, L. H. (2012) · Circulation Research · doi:10.1161/circresaha.111.255505 · Cited by 279 · see citing works
- Authors
- Geiger, P. C., Hancock, C., Wright, D. C., Han, D.-H., & Holloszy, J. O.
- Affiliations
- Washington University in St. Louis (US)
- Venue
- American Journal of Physiology-Endocrinology and Metabolism
- Publisher
- American Physiological Society
- Published
- 2007-06
- Volume
- 292
- Issue
- 6
- Pages
- E1842-E1846
- ISSN
- 0193-1849 (ISSN-L)
- 1522-1555
- OpenAlex
- W2146913744
- Cited by
- 36
- References
- 49
- Citations by year
- 2026: 2 · 2025: 1 · 2021: 1 · 2020: 3 · 2019: 1 · 2018: 1 · 2016: 1 · 2014: 2 · 2013: 4 · 2012: 1
- FWCI
- 2.12
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Physiology-Endocrinology and Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (AG 00078)
- National Institute of Diabetes and Digestive and Kidney Diseases (F32DK076410, DK-018986, R01DK018986, P30DK056341)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Rehabilitation › Exercise and Physiological Responses
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- interleukin-6, skeletal muscle insulin sensitivity, AMPK, glucose transport, physical activity, epitrochlearis muscle, soleus muscle, fast-twitch muscle, AMPK phosphorylation, muscle glucose uptake, dose-dependent effects
- MeSH terms
- Animals, Biological Transport, Dose-Response Relationship, Drug, Enzyme Activation, Forelimb, Glucose, Hindlimb, Insulin, Male, Multienzyme Complexes, Time Factors, Interleukin-6, Rats, Wistar, Protein Serine-Threonine Kinases, Muscle, Skeletal, Rats, AMP-Activated Protein Kinases
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