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Differential Effects of Interleukin-6 and -10 on Skeletal Muscle and Liver Insulin Action In Vivo
Open accessAbstract
The circulating level of the inflammatory cytokine interleukin (IL)-6 is elevated in various insulin-resistant states including type 2 diabetes, obesity, cancer, and HIV-associated lipodystrophy. To determine the role of IL-6 in the development of insulin resistance, we examined the effects of IL-6 treatment on whole-body insulin action and glucose metabolism in vivo during hyperinsulinemic-euglycemic clamps in awake mice. Pretreatment of IL-6 blunted insulin’s ability to suppress hepatic glucose production and insulin-stimulated insulin receptor substrate (IRS)-2–associated phosphatidylinositol (PI) 3-kinase activity in liver. Acute IL-6 treatment also reduced insulin-stimulated glucose uptake in skeletal muscle, and this was associated with defects in insulin-stimulated IRS-1–associated PI 3-kinase activity and increases in fatty acyl-CoA levels in skeletal muscle. In contrast, we found that co-treatment of IL-10, a predominantly anti-inflammatory cytokine, prevented IL-6–induced defects in hepatic insulin action and signaling activity. Additionally, IL-10 co-treatment protected skeletal muscle from IL-6 and lipid-induced defects in insulin action and signaling activity, and these effects were associated with decreases in intramuscular fatty acyl-CoA levels. This is the first study to demonstrate that inflammatory cytokines IL-6 and IL-10 alter hepatic and skeletal muscle insulin action in vivo, and the mechanism may involve cytokine-induced alteration in intracellular fat contents. These findings implicate an important role of inflammatory cytokines in the pathogenesis of insulin resistance.
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“In contexts of chronically increased IL6 such as obesity or rheumatoid arthritis, IL6 has been shown to induce insulin resistance (Castaneda et al., 2019; Kim et al., 2004; Perry et al., 2015).”
From Origin and function of stress-induced IL-6 in murine models (2020) · cites this paper as Kim et al., 2004
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“and causes hepatic and muscle insulin resistance in humans and in mice (39,55-60).”
From Expression of Mfn2, the Charcot-Marie-Tooth Neuropathy Type 2A Gene, in Human Skeletal Muscle (2005) · cites this paper as [57]
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“Recent studies in rodents have demonstrated that acute infusions of IL-6 caused insulin resistance in both liver and skeletal muscle (32).”
From Increased prevalence of insulin resistance and nonalcoholic fatty liver disease in Asian-Indian men (2006) · cites this paper as [32]
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“IL-6 infusion in mice has been reported to reduce the effect of insulin to suppress hepatic glucose output and reduce insulin-stimulated skeletal muscle glucose uptake (32), whereas others report no effect of IL-6 on whole-body glucose disposal (33).”
From Signaling Specificity of Interleukin-6 Action on Glucose and Lipid Metabolism in Skeletal Muscle (2006) · cites this paper as [32]
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“In vitro studies demonstrate that IL-6 can induce insulin resistance in isolated 3T3-L1 adipocytes [51, 52] and in mice [53].”
From Exercise as a Mean to Control Low‐Grade Systemic Inflammation (2008) · cites this paper as [53]
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Metadata
- Authors
- Kim, H.-J., Higashimori, T., Park, S.-Y., Choi, H., Dong, J., Kim, Y.-J., Noh, H.-L., Cho, Y.-R., Cline, G., Kim, Y.-B., & Kim, J. K.
- Affiliations
- Yale University (US)
- Department of Internal Medicine, Section of Endocrinology and Metabolism, Yale University School of Medicine, New Haven, Connecticut
- Beth Israel Deaconess Medical Center (US)
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2004-04-01
- Volume
- 53
- Issue
- 4
- Pages
- 1060-1067
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2097447032
- Cited by
- 534
- References
- 59
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 13 · 2023: 12 · 2022: 26 · 2021: 20 · 2020: 19 · 2019: 18 · 2018: 20 · 2017: 23 · 2016: 19 · 2015: 37 · 2014: 27 · 2013: 27 · 2012: 22
- FWCI
- 25.25
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Diabetes Association
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
- Keywords
- interleukin-6, IL-10, insulin resistance, hepatic glucose production, PI3K signaling, insulin receptor substrate 2, IRS-1, fatty acyl-CoA, inflammatory cytokines, hyperinsulinemic-euglycemic clamp, type 2 diabetes
- MeSH terms
- Animals, Blood Glucose, Hyperinsulinism, Infusions, Intravenous, Insulin, Lipids, Liver, Male, Mice, Inbred C57BL, Glucose Clamp Technique, Signal Transduction, Interleukin-6, Interleukin-10, Muscle, Skeletal, Mice
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