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Interleukin-6 induces cellular insulin resistance in hepatocytes.
Open accessAbstract
Interleukin (IL)-6 is one of several proinflammatory cytokines that have been associated with insulin resistance and type 2 diabetes. A two- to threefold elevation of circulating IL-6 has been observed in these conditions. Nonetheless, little evidence supports a direct role for IL-6 in mediating insulin resistance. Here, we present data that IL-6 can inhibit insulin receptor (IR) signal transduction and insulin action in both primary mouse hepatocytes and the human hepatocarcinoma cell line, HepG2. This inhibition depends on duration of IL-6 exposure, with a maximum effect at 1-1.5 h of pretreatment with IL-6 in both HepG2 cells and primary hepatocytes. The IL-6 effect is characterized by a decreased tyrosine phosphorylation of IR substrate (IRS)-1 and decreased association of the p85 subunit of phosphatidylinositol 3-kinase with IRS-1 in response to physiologic insulin levels. In addition, insulin-dependent activation of Akt, important in mediating insulin's downstream metabolic actions, is markedly inhibited by IL-6 treatment. Finally, a 1.5-h preincubation of primary hepatocytes with IL-6 inhibits insulin-induced glycogen synthesis by 75%. These data suggest that IL-6 plays a direct role in insulin resistance at the cellular level in both primary hepatocytes and HepG2 cell lines and may contribute to insulin resistance and type 2 diabetes.
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“consistent with previous studies that indicate IL-6 promotes hepatic insulin resistance through IL-6/STAT3induced inhibition of insulin receptor signaling 18,45,46”
From Amphiregulin from regulatory T cells promotes liver fibrosis and insulin resistance in non-alcoholic steatohepatitis (2024) · cites this paper as [45]
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“genes reported to be involved in hepatic insulin resistance, including Il6 45-48 , Spp1 49,50 and Igfbp1 51”
From Amphiregulin from regulatory T cells promotes liver fibrosis and insulin resistance in non-alcoholic steatohepatitis (2024) · cites this paper as [45]
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“In cultured hepatocytes (25)(26)(27)(28), preadipocytes, and mature adipocytes (29), IL-6 directly impairs insulin action.”
From Signaling Specificity of Interleukin-6 Action on Glucose and Lipid Metabolism in Skeletal Muscle (2006) · cites this paper as [27]
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“IL-6 contributed to insulin resistance in hepatocytes by disrupting key steps in the insulin signal transduction (52).”
BackgroundMetabolic syndrome: the danger signal in atherosclerosis
Mathieu, P., Pîbarot, P., & Després, J. (2006) · Vascular Health and Risk Management · doi:10.2147/vhrm.2006.2.3.285 · Cited by 117
“Indeed, it was recently demonstrated that IL-6 impaired insulin signaling in hepatocytes (Senn et al 2002).”
BackgroundInterleukin-6 serum levels and genotypes influence the risk for myocardial infarction
Bennet, A. (2003) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2003.08.029 · Cited by 113
“It is possible that the proposed insulin receptor inhibiting effects from IL-6 [23] could provide a possible mechanism behind the potential interaction between insulin and IL-6, which was indicated among both men and women.”
BackgroundFatty acids and the metabolic syndrome
Roche, H. M. (2005) · Proceedings of The Nutrition Society · doi:10.1079/pns2004405 · Cited by 113
“More recently, it has been shown that IL-6 inhibits insulin transduction in hepatocytes (Senn et al. 2002).”
BackgroundGarcía-Galiano, D., Sanchez-Garrido, M. A., Espejo, I., Montero, J. L., Costán, G., Marchal, T., Membrives, A., Gallardo-Valverde, J. M., Muñoz-Castañeda, J. R., Arévalo, E., et al. (2007) · Obesity Surgery · doi:10.1007/s11695-007-9087-1 · Cited by 113
Lipolytic and thermogenic depletion of adipose tissue in cancer cachexia
Tsoli, M., Swarbrick, M. M., & Robertson, G. R. (2015) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2015.10.039 · Cited by 113
Insulin resistance in patients with rheumatoid arthritis: effect of anti‐TNFα therapy
Rosenvinge, A., Krogh‐Madsen, R., Baslund, B., & Pedersen, B. K. (2007) · Scandinavian Journal of Rheumatology · doi:10.1080/03009740601179605 · Cited by 112
The dual function of hepatic SOCS3 in insulin resistance in vivo
Torisu, T., Sato, N., Yoshiga, D., Kobayashi, T., Yoshioka, T., Mori, H., Iida, M., & Yoshimura, A. (2007) · Genes to Cells · doi:10.1111/j.1365-2443.2007.01044.x · Cited by 118
“Elevated TNFα (Hotamisligil et al. 1996) and IL-6 (Senn et al. 2002) from the liver could be a possible mechanism for insulin resistance.”
BackgroundAdipose tissue, inflammation and cardiovascular disease
Ikeoka, D., Mader, J. K., & Pieber, T. R. (2010) · Revista da Associação Médica Brasileira · doi:10.1590/s0104-42302010000100026 · Cited by 110
AICAR stimulates adiponectin and inhibits cytokines in adipose tissue
Lihn, A. S., Jessen, N., Pedersen, S. B., Lund, S. A., & Richelsen, B. (2004) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2004.02.139 · Cited by 111
Andreozzi, F., Laratta, E., Procopio, M. C., Hribal, M. L., Sciacqua, A., Perticone, M., Miele, C., Perticone, F., & Sesti, G. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.01340-06 · Cited by 116
“By contrast, according to the results obtained with HUVECs, SOCS-3 expression was not induced by IL-6 during the time frame of its maximal effect on STAT-3 activation (data not shown).”
BackgroundInfluentialResident and migratory adipose immune cells control systemic metabolism and thermogenesis
Man, K., Kallies, A., & Vasanthakumar, A. (2021) · Cellular and Molecular Immunology · doi:10.1038/s41423-021-00804-7 · Cited by 115
“Analogous to TNF, IL-6 can also inhibit insulin signaling by promoting serine phosphorylation of IRS proteins [72].”
BackgroundBartolo, B. A. D., Chan, J., Bennett, M. R., Cartland, S. P., Bao, S., Tuch, B. E., & Kavurma, M. M. (2011) · Diabetologia · doi:10.1007/s00125-011-2308-0 · Cited by 109
“Increased circulating IL-6 and MCP-1 are associated with type 2 diabetes [18–20].”
de Rooij, S. R., Nijpels, G., Nilsson, P. M., Nolan, J. J., Gabriel, R., Bobbioni-Harsch, E., Mingrone, G., Dekker, J. M., & for the Relationship Between Insulin Sensitivity and Cardiovascular Disease (RISC) Investigators (2009) · Diabetes Care · doi:10.2337/dc08-1795 · Cited by 109
“IL-6 has been shown to inhibit insulin signaling in hepatocytes (16).”
BackgroundMenopause, obesity and inflammation: interactive risk factors for Alzheimer’s disease
Christensen, A., & Pike, C. J. (2015) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2015.00130 · Cited by 112
“For example, in mouse hepatocytes and a human hepatocarcinoma model, IL-6 disrupts insulin signaling by decreasing insulin’s ability to activate Akt, a critical part of insulin’s modulation of downstream metabolic effects (Senn et al., 2002).”
BackgroundRegulation of glucose/lipid metabolism and insulin sensitivity by interleukin-4
Chang, Y.-H., Ho, K.-T., Lu, S.-H., Huang, C.-N., & Shiau, M.-Y. (2011) · International Journal of Obesity · doi:10.1038/ijo.2011.168 · Cited by 107
Role of Cytokines in the Pathogenesis of Non-Alcoholic Fatty Liver Disease
Das, S. K., & Balakrishnan, V. (2011) · Indian Journal of Clinical Biochemistry · doi:10.1007/s12291-011-0121-7 · Cited by 114
Dang, S., Leng, Y., Wang, Z., Xiao, X., Zhang, X., Wen, T., Gong, H.-Z., Hong, A., & Ma, Y. (2019) · International Journal of Biological Sciences · doi:10.7150/ijbs.28522 · Cited by 112
Collino, M., Aragno, M., Castiglia, S., Miglio, G., Tomasinelli, C. E., Boccuzzi, G., Thiemermann, C., & Fantozzi, R. (2010) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2010.00671.x · Cited by 107
“In vitro studies have clearly shown that incubation of both primary mouse hepatocytes and human hepatocarcinoma cell lines with IL-6 or TNF-a cause a near complete inhibition of insulin-induced Akt activation and the subsequent glycogen synthesis (Cheung et al., 2000; Senn et al., 2002).”
BackgroundRetractedNerstedt, A., Johansson, A., Andersson, C. X., Cansby, E., Smith, U., & Mahlapuu, M. (2010) · Diabetologia · doi:10.1007/s00125-010-1856-z · Cited by 106
Deletion of SOCS7 leads to enhanced insulin action and enlarged islets of Langerhans
Banks, A. S., Li, J., McKeag, L., Hribal, M. L., Kashiwada, M., Accili, D., & Rothman, P. B. (2005) · Journal of Clinical Investigation · doi:10.1172/jci23853 · Cited by 104
The metabolic syndrome: The crossroads between rheumatoid arthritis and cardiovascular risk
Gremese, E., & Ferraccioli, G. (2011) · Autoimmunity Reviews · doi:10.1016/j.autrev.2011.04.018 · Cited by 105
“However, the role of IL-6 in insulin resistance has been controversial, because IL-6 has been shown to impair insulinmediated glycogenesis [60], and to stimulate hepatic gluconeogenesis [61], but, in contrast, IL-6 deficiency exacerbates hepatic insulin resistance and inflammation in mice on a high-fat diet [62].”
BackgroundEpicardial Fat: Physiological, Pathological, and Therapeutic Implications
Salazar, J. J., Luzardo, E., Mejías, J. C., Rojas, J., Ferreira, A. M., Rivas-Ríos, J. R., & Bermúdez, V. (2016) · Cardiology Research and Practice · doi:10.1155/2016/1291537 · Cited by 115
“The study showed a statistically significant decrease in the concentration of total cholesterol, TAG, LDL, and epicardial fat storage with the continued use of these drugs.”
BackgroundBerberine Inhibits Inflammatory Response and Ameliorates Insulin Resistance in Hepatocytes
Lou, T., Zhang, Z., Xi, Z., Liu, K., Li, L., Liu, B., & Huang, F. (2010) · Inflammation · doi:10.1007/s10753-010-9276-2 · Cited by 104
“Some proinflammatory cytokines, including IL-6 and TNF-α have been well reported to be associated with the initiation of insulin resistance by disturbing insulinmediated tyrosine phosphorylation of IRS-1 [3, 38].”
BackgroundNie, J., Chang, Y., Li, Y., Zhou, Y., Qin, J., Sun, Z., & Li, H. (2017) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.7b02880 · Cited by 104
Anti-Obesity Effect of the CB2 Receptor Agonist JWH-015 in Diet-Induced Obese Mice
Verty, A. N. A., Stefanidis, A., McAinch, A. J., Hryciw, D. H., & Oldfield, B. J. (2015) · PLoS ONE · doi:10.1371/journal.pone.0140592 · Cited by 103
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Cimini, F. A., Barchetta, I., Carotti, S., Bertoccini, L., Baroni, M. G., Vespasiani-Gentilucci, U., Cavallo, M.-G., & Morini, S. (2017) · World Journal of Gastroenterology · doi:10.3748/wjg.v23.i19.3407 · Cited by 101
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“IL-6 was reported to reduce insulin-dependent hepatic glycogen synthesis (19, 28) and glucose uptake in adipocytes (27).”
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Inflammation and wasting in chronic kidney disease: Partners in crime
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Autophagy and oxidative stress in non-communicable diseases: A matter of the inflammatory state?
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The implication of proinflammatory cytokines in type 2 diabetes
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“IL-6 also reduces insulin signalling through downregulation of insulin receptor substrate-1 and Akt [96-99], an effect that can be suppressed by TZD treatment [100].”
Background
Metadata
- Authors
- Senn, J. J., Klover, P. J., Nowak, I. A., & Mooney, R. A.
- Affiliations
- University of Rochester Medicine (US)
- ORCID
- Mooney, Robert A.
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2002-12-01
- Volume
- 51
- Issue
- 12
- Pages
- 3391-3399
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2130078845
- Cited by
- 883
- References
- 51
- Citations by year
- 2026: 27 · 2025: 19 · 2024: 22 · 2023: 29 · 2022: 28 · 2021: 41 · 2020: 42 · 2019: 31 · 2018: 31 · 2017: 36 · 2016: 49 · 2015: 46 · 2014: 46 · 2013: 34 · 2012: 39
- FWCI
- 23.00
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Centers for Disease Control and Prevention (PHS R01 38138)
- U.S. Public Health Service
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- interleukin-6, insulin resistance, hepatocytes, insulin receptor signaling, IRS-1 tyrosine phosphorylation, phosphatidylinositol 3-kinase, p85 regulatory subunit, Akt activation, glycogen synthesis, type 2 diabetes, inflammatory cytokines
- MeSH terms
- Animals, Cell Line, Dose-Response Relationship, Drug, Humans, Insulin, Insulin Resistance, Phosphoproteins, Phosphorylation, Proto-Oncogene Proteins, Receptor, Insulin, Time Factors, Tyrosine, Signal Transduction, Interleukin-6, Protein Serine-Threonine Kinases, Phosphatidylinositol 3-Kinases, Hepatocytes, Proto-Oncogene Proteins c-akt, Mice, Insulin Receptor Substrate Proteins
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