Associations between insulin resistance and TNF-α in plasma, skeletal muscle and adipose tissue in humans with and without type 2 diabetes
Open accessAbstract
Aims/hypothesis Clear evidence exists that TNF-alpha inhibits insulin signalling and thereby glucose uptake in myocytes and adipocytes. However, conflicting results exist with regard to the role of TNF-alpha in type 2 diabetes.Methods We obtained blood and biopsy samples from skeletal muscle and subcutaneous adipose tissue in patients with type 2 diabetes (n = 96) and healthy controls matched for age, sex and BMI (n = 103).Results Patients with type 2 diabetes had higher plasma levels of fasting insulin (p < 0.0001) and glucose (p < 0.0001) compared with controls, but there was no difference between groups with regard to fat mass. Plasma levels of TNF-alpha (p = 0.0009) and soluble TNF receptor 2 (sTNFR2; p = 0.002) were elevated in diabetic patients. Insulin sensitivity was correlated with quartiles of plasma TNF-alpha after adjustment for age, sex, obesity, WHR, neutrophils, IL-6 and maximum O(2) uptake (VO2/kg) in the diabetes group (p < 0.05). The TNF mRNA content of adipose or muscle tissue did not differ between the groups, whereas muscle TNF-alpha protein content, evaluated by western blotting, was higher in type 2 diabetic patients. Immunohistochemistry revealed more TNF-alpha protein in type 2 than in type 1 muscle fibres.Conclusions/interpretation After adjustment for multiple confounders, plasma TNF-alpha is associated with insulin resistance. This supports the idea that TNF-alpha plays a significant role in the pathogenesis of chronic insulin resistance in humans. However, findings on the TNF-alpha protein levels in plasma and skeletal muscle indicate that measurement of TNF mRNA content in adipose or muscle tissue provides no information with regard to the degree of insulin resistance.
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After adjustment for multiple confounders including IL-6, high plasma TNF concentrations are associated with insulin resistance.
“After adjustment for multiple confounders, including IL-6, high plasma TNF concentrations are associated with insulin resistance [40].”
From Exercise as a Mean to Control Low‐Grade Systemic Inflammation (2008) · cites this paper as [40]
Elevated TNF-α is not secondary to the pathological conditions associated with insulin resistance, but plays a direct pathogenic role in glucose metabolism.
“Thus, a number of studies indicate that elevated TNF-α is not secondary to the pathological conditions associated with insulin resistance, but that TNF-α plays a direct pathogenic role in glucose metabolism [29, 40].”
From Exercise as a Mean to Control Low‐Grade Systemic Inflammation (2008) · cites this paper as [40]
Both TNF-α and IL-6 induce lipolysis, but only IL-6 appears to induce fat oxidation.
“Of note, whereas it is known that both TNF-α and IL-6 induce lipolysis [40, 49], only IL-6 appears to induce fat oxidation [19, 59].”
From Exercise as a Mean to Control Low‐Grade Systemic Inflammation (2008) · cites this paper as [40]
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Cites
Obesity is associated with macrophage accumulation in adipose tissue
Weisberg, S. P., McCann, D., Desai, M., Rosenbaum, M., Leibel, R. L., & Ferrante, A. W. (2003) · Journal of Clinical Investigation · doi:10.1172/jci200319246 · Cited by 10,041 · see citing works
Use and Abuse of HOMA Modeling
Wallace, T. M., Levy, J. C., & Matthews, D. R. (2004) · Diabetes Care · doi:10.2337/diacare.27.6.1487 · Cited by 5,114 · see citing works
Hotamisligil, G. S., Arner, P., Caro, J. F., Atkinson, R. L., & Spiegelman, B. M. (1995) · Journal of Clinical Investigation · doi:10.1172/jci117936 · Cited by 3,543 · see citing works
Hotamisligil, G. S., Peraldi, P., Budavari, A., Ellis, R., White, M. F., & Spiegelman, B. M. (1996) · Science · doi:10.1126/science.271.5249.665 · Cited by 2,630 · see citing works
Subcutaneous Adipose Tissue Releases Interleukin-6, But Not Tumor Necrosis Factor-α,in Vivo1
Mohamed‐Ali, V., Goodrick, S., Rawesh, A., Katz, D. R., Miles, J. M., Yudkin, J. S., Klein, S., & Coppack, S. W. (1997) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.82.12.4450 · Cited by 2,030 · see citing works
Boulé, N. G., Haddad, E., Kenny, G. P., Wells, G. A., & Sigal, R. J. (2001) · JAMA · doi:10.1001/jama.286.10.1218 · Cited by 1,889 · see citing works
Kern, P. A., Ranganathan, S., Li, C., Wood, L., & Ranganathan, G. (2001) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.2001.280.5.e745 · Cited by 1,883 · see citing works
Inflammation and Activated Innate Immunity in the Pathogenesis of Type 2 Diabetes
Pickup, J. C. (2004) · Diabetes Care · doi:10.2337/diacare.27.3.813 · Cited by 1,414 · see citing works
Percutaneous Needle Biopsy of Skeletal Muscle in Physiological and Clinical Research
Bergström, J. P. (1975) · Scandinavian Journal of Clinical and Laboratory Investigation · doi:10.3109/00365517509095787 · Cited by 1,173 · see citing works
DeFronzo, R. A., Gunnarsson, R., Björkman, O., Olsson, M., & Wahren, J. (1985) · Journal of Clinical Investigation · doi:10.1172/jci111938 · Cited by 1,167 · see citing works
Is Type II diabetes mellitus a disease of the innate immune system?
Pickup, J. C., & Crook, M. A. (1998) · Diabetologia · doi:10.1007/s001250051058 · Cited by 1,040 · see citing works
The expression of TNF alpha by human muscle. Relationship to insulin resistance.
Saghizadeh, M., Ong, J. M., Garvey, W. T., Henry, R. R., & Kern, P. A. (1996) · Journal of Clinical Investigation · doi:10.1172/jci118504 · Cited by 717 · see citing works
Plomgaard, P., Bouzakri, K., Krogh-Madsen, R., Mittendorfer, B., Zierath, J. R., & Pedersen, B. K. (2005) · Diabetes · doi:10.2337/diabetes.54.10.2939 · Cited by 627 · see citing works
Self-citationOfei, F., Hurel, S. J., Newkirk, J., Sopwith, M., & Taylor, R. (1996) · Diabetes · doi:10.2337/diab.45.7.881 · Cited by 510 · see citing works
Resistance exercise decreases skeletal muscle tumor necrosis factor α in frail elderly humans
GREIWE, J. S., CHENG, B., RUBIN, D. C., YARASHESKI, K. E., & SEMENKOVICH, C. F. (2001) · The FASEB Journal · doi:10.1096/fj.00-0274com · Cited by 454 · cited 1× · see citing works
“Regular exercise improves insulin sensitivity [15] and the amount of TNF-α protein is reduced by resistance exercise in frail elderly patients [16].”
BackgroundProduction of soluble tumor necrosis factor receptors by human subcutaneous adipose tissue in vivo
Mohamed‐Ali, V., Goodrick, S., Bulmer, K., Holly, J. M. P., Yudkin, J. S., & Coppack, S. W. (1999) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1999.277.6.e971 · Cited by 396 · see citing works
Role of Cytokines in Inducing Hyperlipidemia
Feingold, K. R., & Grünfeld, C. (1992) · Diabetes · doi:10.2337/diab.41.2.s97 · Cited by 380 · see citing works
Muscle Fiber Composition and Capillary Density in Women and Men With NIDDM
Mårin, P., Andersson, B., Krotkiewski, M., & Björntorp, P. A. (1994) · Diabetes Care · doi:10.2337/diacare.17.5.382 · Cited by 342 · see citing works
Katsuki, A., Sumida, Y., Murashima, S., Murata, K., Takarada, Y., Ito, K., Fujii, M., Tsuchihashi, K., Goto, H., Nakatani, K., et al. (1998) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.83.3.4618 · Cited by 321 · see citing works
McKeigue, P., Pierpoint, T., Ferrie, J. E., & Marmot, M. G. (1992) · Diabetologia · doi:10.1007/bf00429101 · Cited by 281 · see citing works
Paquot, N., Castillo, M. J., Lefèbvre, P. J., & Scheen, A. J. (2000) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.85.3.6417 · Cited by 213 · see citing works
Xu, H., Uysal, K. T., Becherer, J. D., Arner, P., & Hotamışlıgil, G. S. (2002) · Diabetes · doi:10.2337/diabetes.51.6.1876 · Cited by 189 · see citing works
TNF-α-Induced Insulin Resistance In Vivo and Its Prevention by Troglitazone
Miles, P. D. G., Romeo, O. M., Higo, K., Cohen, A., Rafaat, K., & Olefsky, J. M. (1997) · Diabetes · doi:10.2337/diab.46.11.1678 · Cited by 182 · see citing works
TNF induces internalization of the p60 receptor and shedding of the p80 receptor.
Higuchi, M., & Aggarwal, B. B. (1994) · The Journal of Immunology · doi:10.4049/jimmunol.152.7.3550 · Cited by 173 · see citing works
You, T., Yang, R., Lyles, M. F., Gong, D., & Nicklas, B. J. (2005) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00419.2004 · Cited by 173 · see citing works
Carey, A. L., Bruce, C. R., Sacchetti, M., Anderson, M. J., Olsen, D. B., Saltin, B., Hawley, J. A., & Febbraio, M. A. (2004) · Diabetologia · doi:10.1007/s00125-004-1403-x · Cited by 170 · see citing works
Inflammation and nitric oxide production in skeletal muscle of type 2 diabetic patients
Sh, T., Sanctis, J. B. D., Briceño, L., Hernandez, N., & Finol, H. (2004) · Journal of Endocrinology · doi:10.1677/joe.0.1810419 · Cited by 163 · see citing works
Mishima, Y., Kuyama, A., Tada, A., Takahashi, K., Ishioka, T., & Kibata, M. (2001) · Diabetes Research and Clinical Practice · doi:10.1016/s0168-8227(00)00247-3 · Cited by 161 · see citing works
Bouzakri, K., & Zierath, J. R. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m608602200 · Cited by 154 · see citing works
Interrelationships between muscle morphology, insulin action, and adiposity
Kriketos, A. D., Pan, D. A., Lillioja, S., Cooney, G. J., Baur, L. A., Milner, M. R., Sutton, J. R., Jenkins, A. B., BOGARDUS, C., & Storlien, L. H. (1996) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.1996.270.6.r1332 · Cited by 134 · see citing works
Fischer, C. P., Perstrup, L. B., Berntsen, A., Eskildsen, P. C., & Pedersen, B. K. (2005) · Clinical Immunology · doi:10.1016/j.clim.2005.07.008 · Cited by 134 · see citing works
Self-citationSkeletal Muscle Inflammation and Nitric Oxide in Patients with COPD
Montes de Oca, M., Torres, S. H., De Sanctis, J., Mata, A., Hernández, N., & Tálamo, C. (2005) · European Respiratory Journal · doi:10.1183/09031936.05.00107404 · Cited by 123 · see citing works
Yang, Y., Jemioło, B., & Trappe, S. W. (2006) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00438.2006 · Cited by 122 · see citing works
Hube, Birgel, Lee, & Hauner (1999) · European Journal of Clinical Investigation · doi:10.1046/j.1365-2362.1999.00520.x · Cited by 112 · see citing works
Bertin, É., Nguyên, P., Guenounou, M., Durlach, V., Potron, G., & Leuténegger, M. (2000) · PubMed · Cited by 109 · see citing works
Shedding of TNF-α receptors, blood pressure, and insulin sensitivity in type 2 diabetes mellitus
Fernández‐Real, J. M., Lainez, B., Vendrell, J. J., Rigla, M., Castro, A., Peñarroja, G., Broch, M., Pérez, A., Richart, C., Engel, P., et al. (2002) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00444.2001 · Cited by 77 · see citing works
Winkler, G., Salamon, F., Harmos, G., Salamon, D., Speer, G., Szekeres, O., Hajós, P., Kovács, M., Simon, K. A., & Cseh, K. (1998) · Diabetes Research and Clinical Practice · doi:10.1016/s0168-8227(98)00109-0 · Cited by 64 · see citing works
Lechleitner, M., Herold, M., Dzien‐Bischinger, C., Hoppichler, F., & Dzien, A. (2002) · Diabetic Medicine · doi:10.1046/j.1464-5491.2002.00846.x · Cited by 59 · see citing works
Good, M., Newell, F., Haupt, L. M., Whitehead, J. P., Hutley, L. J., & Prins, J. B. (2006) · Diabetes and Vascular Disease Research · doi:10.3132/dvdr.2006.003 · Cited by 57 · see citing works
Gordon, P., Vannier, E. G., Hamada, K., Layne, J. E., Hurley, B. F., Roubenoff, R., & Castaneda‐Sceppa, C. (2006) · International Journal of Immunopathology and Pharmacology · doi:10.1177/039463200601900404 · Cited by 52 · see citing works
Monocyte Chemoattractant Protein‐1 in Obesity and Type 2 Diabetes. Insulin Sensitivity Study
Chacón, M. R., Fernández‐Real, J. M., Richart, C., Megía, A., Gómez, J. M., Miranda, M., Caubet, E., Pastor, R., Noguera, C. M., Vilarrasa, N., et al. (2007) · Obesity · doi:10.1038/oby.2007.578 · Cited by 50 · see citing works
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Pedersen, B. K., & Febbraio, M. A. (2008) · Physiological Reviews · doi:10.1152/physrev.90100.2007 · Cited by 2,388 · see citing works
Self-citationAnti-inflammatory effects of exercise: role in diabetes and cardiovascular disease
Pedersen, B. K. (2017) · European Journal of Clinical Investigation · doi:10.1111/eci.12781 · Cited by 617 · see citing works
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Mathur, N., & Pedersen, B. K. (2008) · Mediators of Inflammation · doi:10.1155/2008/109502 · Cited by 514 · see citing works
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Zhou, L., Zhao, S. Z., Koh, S. K., Chen, L., Vaz, C., Tanavde, V., Li, X. R., & Beuerman, R. W. (2012) · Journal of Proteomics · doi:10.1016/j.jprot.2012.04.053 · Cited by 379 · see citing works
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Tiganis, T. (2011) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2010.11.006 · Cited by 256 · see citing works
Hansen, J., Brandt, C., Nielsen, A. R., Hojman, P., Whitham, M., Febbraio, M. A., Pedersen, B. K., & Plomgaard, P. (2011) · Endocrinology · doi:10.1210/en.2010-0868 · Cited by 200 · see citing works
Self-citationExercise and regulation of adipokine and myokine production
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Pedersen, B. K. (2019) · Annual Review of Physiology · doi:10.1146/annurev-physiol-020518-114339 · Cited by 163 · see citing works
Self-citationAbrigo, J., Rivera, J. C., Aravena, J., Cabrera, D., Simon, F., Ezquer, F., Ezquer, M., & Cabello-Verrugio, C. (2016) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2016/9047821 · Cited by 109 · see citing works
Hansen, J., Rinnov, A., Krogh‐Madsen, R., Fischer, C. P., Andreasen, A. S., Berg, R. M. G., Møller, K., Pedersen, B. K., & Plomgaard, P. (2013) · Diabetes/Metabolism Research and Reviews · doi:10.1002/dmrr.2415 · Cited by 71 · see citing works
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- Authors
- Plomgaard, P., Nielsen, A. R., Fischer, C. P., Mortensen, O. H., Broholm, C., Penkowa, M., Krogh-Madsen, R., Erikstrup, C., Lindegaard, B., Petersen, A. M. W., Taudorf, S., & Pedersen, B. K.
- Affiliations
- University of Copenhagen (DK)
- Corresponding author
- Plomgaard, P.
- ORCID
- Venue
- Diabetologia
- Published
- 2007-10-10
- Volume
- 50
- Issue
- 12
- Pages
- 2562-2571
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- OpenAlex
- W1989605721
- Cited by
- 152
- References
- 41
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 4 · 2023: 11 · 2022: 7 · 2021: 3 · 2020: 5 · 2019: 8 · 2018: 9 · 2017: 5 · 2016: 7 · 2015: 11 · 2014: 10 · 2013: 12 · 2012: 12
- FWCI
- 8.02
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Diabetologia (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Scopus (Elsevier) (submittedVersion)
- Funders
- Sundhed og Sygdom, Det Frie Forskningsråd (LSHM-CT-2004-005272 EXGENESIS, LSHM-CT-2004-005272)
- National Research Foundation
- Danmarks Grundforskningsfond (02-512-555, DG 02–512‐555, LSHM-CT-2004-005272, LSHM-CT-2004-005272 EXGENESIS)
- Novo Nordisk
- Novo Nordisk Fonden
- Diabetesforeningen
- Medical Research Council
- Topics
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- type 2 diabetes, insulin resistance, TNF-α, soluble TNF receptor 2, skeletal muscle, subcutaneous adipose tissue, insulin sensitivity, TNF-alpha mRNA, muscle fiber type, insulin signaling, glucose uptake
- MeSH terms
- Adipose Tissue, Body Composition, C-Reactive Protein, Cross-Sectional Studies, Diabetes Mellitus, Type 2, Female, Humans, Insulin Resistance, Leukocyte Count, Male, Middle Aged, Neutrophils, Tumor Necrosis Factor-alpha, Interleukin-6, Case-Control Studies, Muscle, Skeletal, Receptors, Tumor Necrosis Factor, Type II
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