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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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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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