Dose-Dependent Effects of Recombinant Human Interleukin-6 on Glucose Regulation
Abstract
Inflammatory cytokines have metabolic actions that probably contribute to the general adaptation of the organism during infectious or inflammatory stress. To examine the effects of interleukin 6 (IL-6), the main circulating cytokine, on glucose metabolism in man, we performed dose-response studies of recombinant human IL-6 in normal volunteers. Increasing single doses of IL-6 (0.1, 0.3, 1.0, 3.0, and 10.0 mg/Kg BW) were injected sc in 15 healthy male volunteers (3 in each dose) after a 12-h fast. All IL-6 doses were tolerated well and produced no significant adverse effects. We measured the circulating levels of glucose, insulin, C-peptide, and glucagon at baseline and half-hourly over 4 h after the IL-6 injection. Mean peak plasma levels of IL-6 were achieved between 120 and 240 min and were 8, 22, 65, 290, and 4050 pg/mL, respectively, for the 5 doses. After administration of the 2 smaller IL-6 doses, we observed no significant changes in plasma glucose levels, which, because of continued fasting, decreased slightly over time. By 60 min after the 3 higher IL-6 doses, however, the decline in fasting blood glucose was arrested, and glucose levels increased in a dose-dependent fashion. The concurrent levels of plasma insulin and C-peptide were not affected by any IL-6 dose. In contrast, IL-6 caused significant increases in plasma glucagon levels, which peaked between 120 and 150 min after the IL-6 injection. In conclusion, sc IL-6 administration induced dose-dependent increases in fasting blood glucose, probably by stimulating glucagon release and other counteregulatory hormones and/or by inducing peripheral resistance to insulin action.
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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 [60]
The Discussion reports that IL-6 increased blood glucose in human volunteers and proposes peripheral insulin resistance as a possible mechanism, not an established effect. It does not establish hepatic or muscle insulin resistance, and it reports no mouse experiments. (LLM, conf=0.88)
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“In addition, intravenous administration of IL-6 to human subjects results in an increase in blood glucose levels (Tsigos et al. 1997).”
BackgroundVarra, F., Varras, M. N., Varra, V., & Theodosis‐Nobelos, P. (2024) · Molecular Medicine Reports · doi:10.3892/mmr.2024.13219 · Cited by 194 · see citing works
Exercise Induced Adipokine Changes and the Metabolic Syndrome
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“Subcutaneous injections of recombinant human IL-6 also increase blood glucose and glucagon levels without changes in C-peptide levels, supporting the idea that IL-6 alters insulin sensitivity [131].”
BackgroundPathogenic perspectives for the role of inflammation in diabetic nephropathy
Rivero, A., Fernández, C. M., Muros, M., Garcı́a, J. G., Herrera, H., & Navarro‐González, J. F. (2009) · Clinical Science · doi:10.1042/cs20080394 · Cited by 190 · see citing works
β-Adrenergic Regulation of IL-6 Release from Adipose Tissue:In Vivoandin VitroStudies
Mohamed‐Ali, V., Flower, L., Sethi, J. K., Hotamışlıgil, G. S., Gray, R. P., Humphries, S. E., York, D. A., & Pinkney, J. H. (2001) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.86.12.8104 · Cited by 190 · see citing works
Production of Interleukin-6 by Skeletal Myotubes
Kosmidou, I., Vassilakopoulos, T., Xagorari, A., Zakynthinos, S. G., Papapetropoulos, A., & Roussos, C. (2002) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/ajrcmb.26.5.4598 · Cited by 182 · see citing works
Extracellular Adenosine Mediates a Systemic Metabolic Switch during Immune Response
Bajgar, A., Kučerová, K., Jonatova, L., Tomčala, A., Schneedorferová, I., Okrouhlík, J., & Doležal, T. (2015) · PLoS Biology · doi:10.1371/journal.pbio.1002135 · Cited by 170 · see citing works
“In mammalian systems, the inflammatory cytokines TNF-α, IFN-γ, IL-1, and IL-6 are released upon recognition of the pathogen and, besides modulating immune functions, they also stimulate energy release [2,13–16].”
BackgroundWong, S. C., Dobie, R., Altowati, M. A., Werther, G. A., Farquharson, C., & Ahmed, S. F. (2016) · Endocrine Reviews · doi:10.1210/er.2015-1026 · Cited by 163 · see citing works
Gregorio, G. B. D., Hensley, L. L., Lü, T., Ranganathan, G., & Kern, P. A. (2004) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00189.2003 · Cited by 160 · see citing works
“The injection of IL-6 into healthy human volunteers increased blood glucagon and increased fasting glucose (28).”
BackgroundInterleukin-6 is a negative regulator of visfatin gene expression in 3T3-L1 adipocytes
Kralisch, S., Klein, J. C., Lössner, U., Blüher, M., Paschke, R., Stümvoll, M., & Faßhauer, M. (2005) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00090.2005 · Cited by 158 · see citing works
Metabolic effects of interleukin‐6 in human splanchnic and adipose tissue
Lyngsø, D., Simonsen, L., & Bülow, J. (2002) · The Journal of Physiology · doi:10.1113/jphysiol.2002.021022 · Cited by 155 · see citing works
“However, this is not likely since administration of IL-6 subcutaneously gave rise to a rapid increase in the circulating IL-6 concentration which began ~15 min after the injection (Tsigos et al. 1997a,b).”
BackgroundResultKim, J.-H., Kim, J. E., Liu, H.-Y., Cao, W., & Chen, J. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m708568200 · Cited by 154 · see citing works
Steensberg, A., Fischer, C. P., Sacchetti, M., Keller, C., Osada, T., Schjerling, P., van Hall, G., Febbraio, M. A., & Pedersen, B. K. (2003) · The Journal of Physiology · doi:10.1111/j.1469-7793.2003.00631.x · Cited by 152 · see citing works
“…exercise, prior to any release of IL-6 from the skeletal muscle (Steensberg et al. 2001), this hypothesis was supported by previous studies in which it was found that rhIL-6 infusion increased either circulating glucose (Tsigos et al. 1997) or isotopic tracer-determined EGP (Stouthard et al. 1995).”
BackgroundResultStenlöf, K., Asterholm, I. W., Fjällman, T., Wallenius, V., Wallenius, K., & Jansson, J. (2003) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2002-021733 · Cited by 150 · see citing works
Reduced exercise endurance in interleukin-6-deficient mice.
Fäldt, J., Wernstedt, I., Fitzgerald, S., Wallenius, K., Bergström, G., & Jansson, J. (2004) · Endocrinology · doi:10.1210/en.2003-1319 · Cited by 153 · see citing works
Interleukin-6 Delays Gastric Emptying in Humans with Direct Effects on Glycemic Control
Lang Lehrskov, L., Lyngbaek, M. P., Soederlund, L., Legaard, G. E., Ehses, J. A., Heywood, S. E., Wewer Albrechtsen, N. J., Holst, J. J., Karstoft, K., Pedersen, B. K., et al. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.04.008 · Cited by 135 · see citing works
Weigert, C., Hennige, A. M., Lehmann, R., Brodbeck, K., Baumgärtner, F., Schaüble, M., Häring, H. U., & Schleicher, E. D. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m509782200 · Cited by 140 · see citing works
Interleukin-6 and insulin sensitivity: friend or foe?
Carey, A. L., & Febbraio, M. A. (2004) · Diabetologia · doi:10.1007/s00125-004-1447-y · Cited by 140 · see citing works
“In contrast, others [ 80 ] demonstrated that an extremely high dose (10 µg/kg) of IL-6, resulting in a circulating plasma IL-6 concentration of >1000 pg/ml, caused modest hyperglycaemia.”
ResultNutritional interventions and the IL‐6 response to exercise
Hennigar, S. R., McClung, J. P., & Pasiakos, S. M. (2017) · The FASEB Journal · doi:10.1096/fj.201700080r · Cited by 140 · see citing works
“blood glucose concentrations (14) and increases in glucose disposal (15, 16), indicating that IL-6mayact as a signal for hepatic glucose release to maintain blood glucose levels during exercise.”
BackgroundInflammatory Concepts of Obesity
Rocha, V. Z., & Folco, E. J. E. (2011) · International Journal of Inflammation · doi:10.4061/2011/529061 · Cited by 134 · see citing works
“Whereas deficiency or inhibition of CD11c-positive cells [162], CD8 T cells [18], mast cells [20] and NKT cells [21] improves metabolic parameters, an increase in the pool of CD4+ Foxp3+ T cells following CD3-specific antibody treatment likely produce similar beneficial metabolic effects [27].”
BackgroundAdipose tissue as an endocrine organ: impact on insulin resistance.
Im, J., Pijl, H., & Ae, M. (2003) · PubMed · Cited by 137 · see citing works
Plasma interleukin-6 during strenuous exercise: role of epinephrine
Steensberg, A., Toft, A. D., Schjerling, P., Halkjær-Kristensen, J., & Pedersen, B. K. (2001) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.2001.281.3.c1001 · Cited by 137 · see citing works
“Thus it has been demonstrated that injection of recombinant human IL-6 to humans increases the fasting blood glucose concentration (23) and liver glucose output (22).”
BackgroundRole of adipocytokines in obesity-associated insulin resistance
Zou, C., & Shao, J. (2007) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2007.06.006 · Cited by 136 · see citing works
“Administration of recombinant IL-6 in rodent models and humans induces hepatic gluconeogenesis that, in turn, leads to hyperglycaemia and compensatory hyperinsulinaemia [101].”
BackgroundRole of interleukin‐6 signalling in glucose and lipid metabolism
Glund, S., & Krook, A. (2007) · Acta Physiologica · doi:10.1111/j.1748-1716.2007.01779.x · Cited by 126 · see citing works
“An acute in vivo increase in systemic IL-6 levels in healthy human subjects has been reported to either not affect (Petersen et al. 2005) or increase (Stouthard et al. 1995, Tsigos et al. 1997) plasma glucose levels (Table.”
BackgroundSun, Z., Klein, A. S., Radaeva, S., Hong, F., El-Assal, O. N., Pan, H.-N., Jaruga, B., Bátkai, S., Hoshino, S., Tian, Z., et al. (2003) · Gastroenterology · doi:10.1016/s0016-5085(03)00696-6 · Cited by 126 · see citing works
Lonardo, A., Ballestri, S., Guaraldi, G., Nascimbeni, F., Romagnoli, D., Zona, S., & Targher, G. (2016) · World Journal of Gastroenterology · doi:10.3748/wjg.v22.i44.9674 · Cited by 123 · see citing works
Margeli, A., Skenderi, K., Tsironi, M., Hantzi, E., Matalas, A., Vrettou, C., Kanavakis, E., Chrousos, G. P., & Papassotiriou, I. (2005) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2004-2346 · Cited by 118 · see citing works
“The earlier normalization of IL-6, which has a relatively short plasma half-life of 20–30 min, than those of SAA and CRP (10 and 20 h, respectively), in the presence of sustained tissue damage markers, indicates that the secretion of this cytokine may develop tolerance to inflammatory stimuli (22, 28, 30).”
BackgroundSelf-citationMartínez, C., Abad, C., Delgado, M., Arranz, A., Juarranz, M. G., Rodríguez‐Henche, N., Brabet, P., Leceta, J., & Gomariz, R. P. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.012367999 · Cited by 118 · see citing works
Chia, S., Qadan, M., Newton, R., Ludlam, C. A., Fox, K. A. A., & Newby, D. E. (2003) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.0000065195.22904.fa · Cited by 116 · see citing works
The effect of exercise on IL-6-induced cachexia in the ApcMin/+ mouse
Puppa, M. J., White, J. P., Velázquez, K. T., Baltgalvis, K. A., Sato, S., Baynes, J., & Carson, J. (2011) · Journal of Cachexia, Sarcopenia and Muscle · doi:10.1007/s13539-011-0047-1 · Cited by 122 · see citing works
“It has also been shown to increase fasting glucose levels in a dose-dependent manner in healthy human subjects [37].”
BackgroundRashid, K., Chowdhury, S., Ghosh, S., & Sil, P. C. (2017) · Biochemical Pharmacology · doi:10.1016/j.bcp.2017.07.009 · Cited by 115 · see citing works
Inflammatory Mediators in Gestational Diabetes Mellitus
Richardson, A. C., & Carpenter, M. W. (2007) · Obstetrics and Gynecology Clinics of North America · doi:10.1016/j.ogc.2007.04.001 · Cited by 116 · see citing works
Dose-Dependent Effects of Recombinant Human Interleukin-6 on the Pituitary-Testicular Axis
Tsigos, C., Papanicolaou, D. A., Kyrou, I., Raptis, S. A., & Chrousos, G. P. (1999) · Journal of Interferon & Cytokine Research · doi:10.1089/107999099312948 · Cited by 111 · see citing works
Self-citationIncrease in interstitial interleukin-6 of human skeletal muscle with repetitive low-force exercise
Rosendal, L., Søgaard, K., Kjær, M., Sjøgaard, G., Langberg, H., & Kristiansen, J. (2004) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00130.2004 · Cited by 110 · see citing works
“glucose release and to induce lipolysis in adipose tissue, thereby increasing the total substrate availability (6, 21, 28, 29).”
BackgroundSteensberg, A., Fischer, C. P., Sacchetti, M., Keller, C., Osada, T., Schjerling, P., van Hall, G., Febbraio, M. A., & Pedersen, B. K. (2003) · The Journal of Physiology · doi:10.1113/jphysiol.2002.032938 · Cited by 152 · see citing works
Adiposity signals, genetic and body weight regulation in humans
Cancello, R., Tounian, A., Poitou, C., & Clément, K. (2004) · Diabetes & Metabolism · doi:10.1016/s1262-3636(07)70112-x · Cited by 107 · see citing works
“IL6 injections also decrease body weight in non-human primates [48, 49] and in humans it enhances energy expenditure and lipid oxidation [50-53].”
BackgroundPostburn trauma insulin resistance and fat metabolism
Cree‐Green, M., & Wolfe, R. R. (2007) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00562.2007 · Cited by 106 · see citing works
“NF- B also induces the production of IL-6, and this can cause increased hepatic glucose release and hepatic insulin resistance (54, 102).”
BackgroundThe metabolic syndrome: The crossroads between rheumatoid arthritis and cardiovascular risk
Gremese, E., & Ferraccioli, G. (2011) · Autoimmunity Reviews · doi:10.1016/j.autrev.2011.04.018 · Cited by 105 · see citing works
“However, the role of IL-6 in insulin resistance has been controversial, because IL-6 has been shown to impair insulinmediated glycogenesis [60], and to stimulate hepatic gluconeogenesis [61], but, in contrast, IL-6 deficiency exacerbates hepatic insulin resistance and inflammation in mice on a high-fat diet [62].”
BackgroundThe role of interleukin-6 in glucose homeostasis and lipid metabolism
Lehrskov, L. L., & Christensen, R. H. (2019) · Seminars in Immunopathology · doi:10.1007/s00281-019-00747-2 · Cited by 114 · see citing works
Hormones and cytokines in childhood obesity
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“Administration of IL6 in healthy volunteers induces dose dependent increases in blood glucose(64).”
BackgroundCirculating interleukin-6 concentrations during and after gestational diabetes mellitus
Morisset, A., Dubé, M., Côté, J. A., Robitaille, J., Weisnagel, S. J., & Tchernof, A. (2011) · Acta Obstetricia Et Gynecologica Scandinavica · doi:10.1111/j.1600-0412.2011.01094.x · Cited by 94 · see citing works
“demonstrated that IL-6 infusion in healthy individuals was associated with an increase in blood glucose (26).”
BackgroundRelationship between obesity and serum markers of oxidative stress and inflammation in Japanese.
Suzuki, K. A. O., Ito, Y., Ochiai, J., Kusuhara, Y., Hashimoto, S., Tokudome, S., Kojima, M., Wakai, K., Toyoshima, H., Tamakoshi, K., et al. (2003) · PubMed · Cited by 94 · see citing works
- Authors
- Tsigos, C., Papanicolaou, D. A., Kyrou, I., Defensor, R., Mitsiadis, C. S., & Chrousos, G. P.
- Affiliations
- National Institutes of Health (US)
- Hellenic National Center for Research, Prevention and Treatment of Diabetes Mellitus and its Complications (C.T., I.K.), Athens 106 75, Greece
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 1997-12-01
- Volume
- 82
- Issue
- 12
- Pages
- 4167-4170
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2086682722
- Cited by
- 324
- References
- 23
- Citations by year
- 2026: 2 · 2025: 8 · 2024: 5 · 2023: 5 · 2022: 6 · 2021: 5 · 2020: 8 · 2019: 5 · 2018: 17 · 2017: 10 · 2016: 11 · 2015: 8 · 2014: 21 · 2013: 9 · 2012: 16
- FWCI
- 3.12
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Keywords
- interleukin-6, glucose regulation, glucagon, insulin, C-peptide, dose-response relationship, inflammatory cytokines, insulin resistance, fasting blood glucose
- MeSH terms
- Adult, Blood Glucose, C-Peptide, Dose-Response Relationship, Drug, Glucagon, Humans, Injections, Subcutaneous, Insulin, Male, Recombinant Proteins, Interleukin-6
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