Cited by 883Adipokines, Inflammation, and Metabolic DiseasesCytokine Signaling Pathways and InteractionsMetabolism, Diabetes, and Cancer

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Interleukin-6 induces cellular insulin resistance in hepatocytes.

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Senn, Joseph J., Klover, Peter J., Nowak, Irena A., Mooney, Robert A.·2002·Diabetes

DOI 10.2337/diabetes.51.12.3391

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Abstract

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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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
DOI: 10.2337/diabetes.51.12.3391
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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Interleukin-6 induces cellular insulin resistance in hepatocytes.

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