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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Adipocyte-specific deletion of IL-6 does not attenuate obesity-induced weight gain or glucose intolerance in mice
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“Furthermore, preclinical studies have demonstrated that IL-6 causes insulin resistance, particularly in the liver, by activating suppressor of cytokine signaling 3 (SOCS3), leading to defective tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1) (17, 18).”
Background
Hepatomegaly Associated with Non-Obstructive Sinusoidal Dilation in Experimental Visceral Leishmaniasis
Maeda, K., Sadoughi, S., Morimoto, A., Uchida, K., CHAMBERS, J. K., Sanjoba, C., Yamagishi, J., & Goto, Y. (2021) · Pathogens · doi:10.3390/pathogens10111356 · Cited by 26
“Since IL-6 affects hepatocytes and causes insulin resistance [38], it is possible that infection-induced inflammation results in insulin resistance.”
Background
Lactiplantibacillus plantarum FRT4 protects against fatty liver hemorrhage syndrome: regulating gut microbiota and FoxO/TLR-4/NF-κB signaling pathway in laying hens
Li, D., Meng, K., Liu, G., Wen, Z., Han, Y., Liu, W., Xu, X. J., Song, L., Cai, H., & Yang, P. (2025) · Microbiome · doi:10.1186/s40168-025-02083-0 · Cited by 27
“Generally, IL-1β is a pro-inflammatory factor, whereas IL-10 has anti-inflammatory effects [53, 54].”
Review article: The role of adipose tissue in uraemia‐related insulin resistance
Manolescu, B. N., Stoian, I. A.-M., Atanasiu, V., Buşu, C., & Lupescu, O. (2008) · Nephrology · doi:10.1111/j.1440-1797.2008.01022.x · Cited by 26
“It was found that IL-6 can also inhibit the insulin signalling pathway, probably at the level of insulin receptor – IRS-1 interaction, being a supplementary factor for insulin resistance.(71) The strength and duration of the cellular response to different cytokines is regulated, at least in part, by a group of protein…”
Background
High pulse pressure is related to risk of type 2 diabetes mellitus in Chinese middle-aged females
Zhang, L., Wang, B., Wang, C., Li, L., Ren, Y., Zhang, H., Yang, X., Zhao, Y., Han, C., Zhou, J., et al. (2016) · International Journal of Cardiology · doi:10.1016/j.ijcard.2016.06.233 · Cited by 26
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Toddler With New Onset Diabetes and Atypical Hemolytic-Uremic Syndrome in the Setting of COVID-19
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Protein kinase C-δ is involved in the inflammatory effect of IL-6 in mouse adipose cells
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“Chronically elevated IL-6 levels have been shown to negatively affect insulin signalling and action in liver [5], adipose cells [6–8] and skeletal muscles [9].”
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Antimicrobial-Sensing Proteins in Obesity and Type 2 Diabetes
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Sterculic Oil, a Natural SCD1 Inhibitor, Improves Glucose Tolerance in Obese ob/ob Mice
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“While IL-6 is traditionally considered a pro-inflammatory cytokine involved in the reduction of insulin sensitivity [52–54], there is separate evidence that disputes this dogma and suggests IL-6 may improve insulin sensitivity/glucose uptake [55– 57].”
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Adiposity, joint and systemic inflammation: the additional risk of having a metabolic syndrome in rheumatoid arthritis
Ferraccioli, G., & Gremese, E. (2011) · Swiss Medical Weekly · doi:10.4414/smw.2011.13211 · Cited by 26
Health Effects of Alternate Day Fasting Versus Pair-Fed Caloric Restriction in Diet-Induced Obese C57Bl/6J Male Mice
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Valdecoxib improves lipid-induced skeletal muscle insulin resistance via simultaneous suppression of inflammation and endoplasmic reticulum stress
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Loss of interleukin‐10 exacerbates early Type‐1 diabetes‐induced bone loss
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Administration of progranulin (PGRN) triggers ER stress and impairs insulin sensitivity via PERK-eIF2α-dependent manner
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“Additionally, PGRN ablation resulted in decreased levels of IL-6 in serum and adipose tissue,(7) and IL-6 itself is a key player of insulin resistance.(48) Thus, a state of inflammation could be the part of reason for our observations.”
Telmisartan, an Angiotensin II Type 1 Receptor Blocker, Inhibits Advanced Glycation End-product (AGE)-elicited Hepatic Insulin Resistance via Peroxisome Proliferator-activated Receptor-γ Activation
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Torenia concolorLindley var.formosanaYamazaki extracts improve inflammatory response and lipid accumulationviaPPARs activation
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“…the liver to cause triglyceride secretion (Nonogaki et al., 1995), affect insulin signal transduction, and influence insulin-induced glycogen production in hepatocytes (Senn et al., 2002), the latter of which thereby reduces insulin sensitivity and leads to hyperglycemia (Tsigos et al., 1997).”
Background
Modulatory effect of berberine on adipose tissue PPARγ, adipocytokines and oxidative stress in high fat diet/ streptozotocin-induced diabetic rats
Mahmoud, A. M., Abdel-Rahman, M. M., Bastawy, N., & Eissa, H. (2017) · Journal of Applied Pharmaceutical Science · doi:10.7324/japs.2017.70401 · Cited by 25
“…pro-inflammatory cytokines including IL-6 lead to reduction in IRS-1 tyrosine phosphorylation and association with phosphatidylinositol (PI)-3 kinase, inhibition of Akt activation (Bastard et al., 2000; Senn et al., 2002) and suppressed lipoprotein lipase (LPL) activity (Greenberg et al., 1992).”
Background
The anti‐inflammatory effect of metformin: The molecular targets
Sakata, N. (2024) · Genes to Cells · doi:10.1111/gtc.13098 · Cited by 28
“In this several decades, many studies revealed that the inflammation is critical in the progression of diabetes (Borst, 2004; Forrester et al., 2020; J. C. Jha et al., 2022; Karam et al., 2017; Senn et al., 2002; Sharif et al., 2021; Winiarska et al., 2021).”
Background
Tumour necrosis factor‐α attenuates insulin action on phosphoenolpyruvate carboxykinase gene expression and gluconeogenesis by altering the cellular localization of Foxa2 in HepG2 cells
Pandey, A. K., Bhardwaj, V., & Datta, M. (2009) · FEBS Journal · doi:10.1111/j.1742-4658.2009.07091.x · Cited by 24
The Effects of an Arabinogalactan-Protein from the White-Skinned Sweet Potato (Ipomoea batatas L.) on Blood Glucose in Spontaneous Diabetic Mice
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Total and Differential Leukocyte Counts in Relation to Incidence of Diabetes Mellitus: A Prospective Population-Based Cohort Study
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Coated sodium butyrate ameliorates high-energy and low-protein diet induced hepatic dysfunction via modulating mitochondrial dynamics, autophagy and apoptosis in laying hens
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“Additionally, elevated levels of IL-1β have been proved to promote insulin resistance and liver inflammation [51], whereas IL-10 has the opposite effect [52].”
Background
Anti- and non-tumor necrosis factor-α-targeted therapies effects on insulin resistance in rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis
Wang, C., & Tsai, H. (2021) · World Journal of Diabetes · doi:10.4239/wjd.v12.i3.238 · Cited by 25
Diabetes mellitus and apoptosis: inflammatory cells
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“Increases in these cytokines can directly promote insulin resistance [7–9].”
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Exercise protects against insulin-dependent diabetes-induced osteoarthritis in rats: A scanning electron microscopy study
Al-Hashem, F. H., Karib, A. O. E., Bin‐Jaliah, I., Dallak, M. A., Sakr, H. F., Eid, R. A., Zaki, M. S. A., Shamsi, M. A., Haidara, M. A., & Al‐Ani, B. (2017) · Ultrastructural Pathology · doi:10.1080/01913123.2017.1313346 · Cited by 23
“In addition, proinflammatory cytokines are known to be involved in the pathology of diabetes [14,15] and OA [16,17].”
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Metabolic Perturbations and Severe COVID-19 Disease: Implication of Molecular Pathways
Nigro, E., Perrotta, F., Polito, R., D’Agnano, V., Scialò, F., Bianco, A., & Daniele, A. (2020) · International Journal of Endocrinology · doi:10.1155/2020/8896536 · Cited by 24
“A further IL-6 increase in COVID-19 diabetic patients can exacerbate insulin resistance by inhibiting the autophosphorylation of the insulin receptor and the activation of PI3K and AKTpathway [107, 108].”
Background
Markers of insulin sensitivity in placentas and cord serum of intrauterine growth‐restricted newborns
Street, M. E., Volta, C., Ziveri, M. A., Viani, I., & Bernasconi, S. (2009) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2009.03533.x · Cited by 23
Activation of opioid μ-receptors by loperamide to improve interleukin-6-induced inhibition of insulin signals in myoblast C2C12 cells
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BackgroundMethodInfluential
IGFBP5 suppresses oleate‐induced intramyocellular lipids deposition and enhances insulin signaling
Xiang, A., Chu, G., Zhu, Y., Ma, G., Yang, G., & Sun, S. (2019) · Journal of Cellular Physiology · doi:10.1002/jcp.28174 · Cited by 21
Is the serum delta neutrophil index level different in gestational diabetic women?
Uysal, N. Ş., Eroğlu, H., Özcan, Ç., Şahın, D., & Yücel, A. (2020) · The Journal of Maternal-Fetal & Neonatal Medicine · doi:10.1080/14767058.2020.1760833 · Cited by 22
Daidzein improves insulin resistance in ovariectomized rats
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Effect of cytokine antibodies in the immunomodulation of inflammatory response and metabolic disorders induced by scorpion venom
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Associations of Innate and Adaptive Immune Cell Subsets With Incident Type 2 Diabetes Risk: The MESA Study
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Emerging Treatment Options for Sarcopenia in Chronic Liver Disease
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Partial hepatic resistance to IL-6-induced inflammation develops in type 2 diabetic mice, while the anti-inflammatory effect of AMPK is maintained
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FOXO1 Content Is Reduced in Cystic Fibrosis and Increases with IGF-I Treatment
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High-Sensitivity CRP Reflects Insulin Resistance in Smokers
Hanyu, O., Yoshida, J., Abe, E., Hirayama, S., Miyake, K., Aizawa, Y., & Miida, T. (2009) · Journal of Atherosclerosis and Thrombosis · doi:10.5551/jat.869 · Cited by 22

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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