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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 was reported to reduce insulin-dependent hepatic glycogen synthesis (3, 4) and glucose uptake”
BackgroundMediators of Impaired Adipogenesis in Obesity-Associated Insulin Resistance and T2DM
Al‐Sulaiti, H., Dömling, A. S. S., & Elrayess, M. A. (2019) · IntechOpen eBooks · doi:10.5772/intechopen.88746 · Cited by 12
“Furthermore, IL-6 was shown to reduce IS through decrease in adiponectin expression and secretion [72] and via impairment of insulin signaling in hepatocytes [73].”
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“Fasting levels of IL-6 and MCP-1, which decrease adiponectin expression and reduce insulin sensitivity in liver and skeletal muscle [35–38], were statistically indistinguishable in the four experimental groups under basal conditions but increased significantly in double-mutant males in response to the stress of separa…”
BackgroundClementi, A. H., Gaudy, A. M., Zimmers, T. A., Koniaris, L. G., & Mooney, R. A. (2011) · Metabolism · doi:10.1016/j.metabol.2011.04.004 · Cited by 14
“Our lab has demonstrated that chronic IL-6 impairs insulin receptor autophosphorylation, insulin receptor substrate-1 phosphorylation, and Akt activation in hepatocytes [3, 4].”
Self-citationPKCε induces interleukin-6 expression through the MAPK pathway in 3T3-L1 adipocytes
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Depot‐Specific Biology of Adipose Tissues: Links to Fat Distribution and Metabolic Risk
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“15 Sub-sequent chronic hyperglycemia triggers inflammatory response through increased oxidative stress, that further compromises insulin signaling.”
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Moderate increases in daily step count are associated with reduced IL6 and CRP in women with PCOS
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A Case of Euglycemic Diabetic Ketoacidosis in a Patient With Type 2 Diabetes Mellitus and COVID-19
Morrison, N. J., Barnett, K., Tantum, J., Morrison, H., & Whalen, M. (2020) · Cureus · doi:10.7759/cureus.12029 · Cited by 11
“IL-6 is a proposed dynamic cause of ketone production through the induction of cellular insulin resistance in hepatocytes [4,12-14].”
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“For example, IL-6 directly inhibits insulin sensitivity and upregulates the release of hormones that contribute to insulin resistance via induction by insulin receptor’s signal transduction in hepatocytes [44, 45].”
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“pro-inflammatory cytokines, such TNF-a and IL-6, have been shown to play a role in insulin resistance through the disruption of early insulin-stimulated tyrosine phosphorylation events, which is crucial to insulin transmembrane signalling, in cultured hepatocytes.(47,48) In our experimental conditions, choline depriva…”
BackgroundMyokines: Do they really exist?
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Role of interleukin-6 levels in cardiovascular autonomic dysfunction in type 2 diabetic patients
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“IL-6 is involved in the pathogenesis of insulin resistance [4, 5 ] and stimulates insulin secretion [6].”
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Exercise-modulated IL-6 in cancer cachexia: molecular mechanisms and therapeutic potential
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Cancer progression through the lens of age-induced metabolic reprogramming
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“A key aspect of inflammageing-mediated metabolic deregulation lies in the ability of these cytokines, particularly of TNF and IL-6, to promote the development of insulin resistance 125,126 .”
Ahmadi, A., Huda, M. N., Bennett, B. J., Gamboa, J. L., Zelnick, L. R., Smith, L., Chondronikola, M., Raftery, D., de Boer, I. H., & Roshanravan, B. (2022) · Journal of Renal Nutrition · doi:10.1053/j.jrn.2022.09.013 · Cited by 10
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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