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Cited by 488Adipokines, Inflammation, and Metabolic DiseasesCytokine Signaling Pathways and InteractionsMetabolism, Diabetes, and Cancer

Chronic Exposure to Interleukin-6 Causes Hepatic Insulin Resistance in Mice

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Klover, Peter J., Zimmers, Teresa A., Koniaris, Leonidas G., Mooney, Robert A.·2003·Diabetes
DOI 10.2337/diabetes.52.11.2784
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Abstract

Interleukin (IL)-6 is one of several proinflammatory cytokines associated with the insulin resistance of obesity and type 2 diabetes. There is, however, little direct evidence in vivo for a causative role of IL-6 in insulin resistance. Here, a 5-day constant subcutaneous infusion of hIL-6 before portal vein insulin challenge resulted in impairment of early insulin receptor signaling in the liver of mice. Importantly, the sixfold elevation of IL-6 attained with constant infusion was similar to levels reached in obesity. Consistent with an hepatic response to IL-6, STAT3 phosphorylation was increased in livers of IL-6-treated mice at 5 days. Chronic infusion of IL-6 also reduced hepatic insulin receptor autophosphorylation by 60% and tyrosine phosphorylation of insulin receptor substrates-1 and -2 by 60 and 40%, respectively. IL-6 had no effect on the mass of these proteins. IL-6 also decreased refeeding-dependent glucokinase mRNA induction by ∼40%. Insulin tolerance tests revealed reduced insulin sensitivity. In contrast to hepatic insulin receptor signal transduction, 5-day IL-6 exposure failed to suppress skeletal muscle insulin receptor signal transduction. These data suggest that chronic IL-6 treatment selectively impairs hepatic insulin signaling in vivo, further supporting a role for IL-6 in hepatic insulin resistance of obesity.

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  • Interleukin-6 causes hepatic and muscle insulin resistance in humans and in mice.

    “and causes hepatic and muscle insulin resistance in humans and in mice (39,55-60).”

    From Expression of <i>Mfn2</i>, the Charcot-Marie-Tooth Neuropathy Type 2A Gene, in Human Skeletal Muscle (2005) · cites this paper as [55]

    The Results section, “Effect of IL-6 on liver versus skeletal muscle” (page not supplied), reports impaired hepatic insulin signaling in mice but no effect on skeletal-muscle insulin receptor signaling. The Discussion likewise says the findings suggest IL-6 may not mediate skeletal-muscle insulin resistance. The paper discusses insulin resistance in humans as a hypothesis, not a demonstrated causal finding. (LLM, conf=0.90)

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  • Interleukin-6 interferes with insulin signaling in muscle and hepatic cells.

    “Several reports indicate that interleukin-6 interferes with insulin signaling in muscle and hepatic cells (39,55)”

    From Expression of <i>Mfn2</i>, the Charcot-Marie-Tooth Neuropathy Type 2A Gene, in Human Skeletal Muscle (2005) · cites this paper as [55]

    The ‘Effect of IL-6 on liver versus skeletal muscle’ section reports impaired insulin signaling in mouse liver, but explicitly says that chronic IL-6 treatment did not affect insulin receptor signaling in skeletal muscle. The Discussion likewise describes the effect as hepatic rather than muscular, contrary to the claim’s muscle component. (LLM, conf=0.88)

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Authors
Klover, P. J., Zimmers, T. A., Koniaris, L. G., & Mooney, R. A.
Affiliations
University of Rochester Medicine (US)
ORCID
Venue
Diabetes
Publisher
American Diabetes Association
Published
2003-11-01
Volume
52
Issue
11
Pages
2784-2789
ISSN
  • 0012-1797 (ISSN-L)
  • 1939-327X
DOI
10.2337/diabetes.52.11.2784
OpenAlex
W2155824086
Cited by
488
References
47
Citations by year
2026: 8 · 2025: 14 · 2024: 13 · 2023: 16 · 2022: 14 · 2021: 12 · 2020: 18 · 2019: 14 · 2018: 22 · 2017: 13 · 2016: 24 · 2015: 24 · 2014: 25 · 2013: 33 · 2012: 29
FWCI
14.27
Type
journal article
Language
en
Open access
Locations
  • Diabetes (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • U.S. Public Health Service
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK060732, R01DK038138, R01-DK38138, R01-DK60732)
Topics
  • Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords
interleukin-6, hepatic insulin resistance, insulin receptor signaling, STAT3 phosphorylation, insulin receptor autophosphorylation, IRS-1, insulin receptor substrate 2, glucokinase, insulin tolerance, obesity, type 2 diabetes, inflammatory cytokines, skeletal muscle insulin signaling
MeSH terms
Animals, Glucokinase, Infusions, Parenteral, Insulin Antagonists, Insulin Resistance, Liver, Phosphoproteins, Phosphorylation, Receptor, Insulin, RNA, Messenger, Transcription, Genetic, Signal Transduction, Interleukin-6, Muscle, Skeletal, Intracellular Signaling Peptides and Proteins, Mice, Insulin Receptor Substrate Proteins

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