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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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“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 [60]
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“Administration of IL-6 to healthy volunteers induced dose-dependent increases in fasting blood glucose (17).”
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“Substantial experimental evidence and cross-sectional data suggest that IL-6 is associated with hyperglycemia, insulin resistance, and overt type 2 diabetes [33,34].”
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“This cytokine has been described in vivo to determine whether it activates (40, 41) or inhibits HGP (7, 21).”
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“Nevertheless, IL-6 has been shown previously to stimulate glucagon secretion,(44) and administration of rhIL-6 into healthy humans also increased glucagon levels.(21,45,46) Our data support the theory that IL-6 may play a physiological role in regulating glucagon in the context of exercise and that this might only bec…”
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“IL-6 induces hyperglycemia by increasing insulin resistance in the liver (Tsigos et al. 1997).”
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“Moreover, infusion of IL-6 in humans suggested that IL-6 could enhance endogenous glucose production during prolonged exercise [17] or increase hepatic glucose output [14].”
Lutz, S. Z., Hennige, A. M., Feil, S. C., Peter, A., Gerling, A., Machann, J., Kröber, S. M., Rath, M., Schürmann, A., Weigert, C., et al. (2011) · Diabetes · doi:10.2337/db10-0760 · Cited by 41
“Moreover, administration of IL-6 to human volunteers induced higher energy expenditure (49) and elevated fasting blood glucose levels (50).”
Sopasakis, V. R., Larsson, B.-M., Johansson, A., Holm�ng, A., & Smith, U. (2004) · Diabetologia · doi:10.1007/s00125-004-1544-y · Cited by 40
“Previous studies of the effects of IL-6 on glucose metabolism in man have also produced contradictory results [ 27 , 28], possibly a consequence of such non-steady-state experimental conditions.”
ResultPendharkar, S. A., Singh, R. G., Chand, S. K., Cervantes, A., & Petrov, M. S. (2017) · Inflammation Research · doi:10.1007/s00011-017-1125-4 · Cited by 38
Effect of a High-Fat Meal on the Growth Hormone Response to Exercise in Children
Galassetti, P. R., Larson, J., Iwanaga, K., Salsberg, S., Eliakim, A., & Pontello, A. M. (2006) · Journal of Pediatric Endocrinology and Metabolism · doi:10.1515/jpem.2006.19.6.777 · Cited by 35
Gestational diabetes and subclinical inflammation: Evaluation of first year postpartum outcomes
Özuğuz, U., Işık, S., Berker, D. S., Arduç, A., Tütüncü, Y., Akbaba, G., Gökay, F., & Güler, S. (2011) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2011.08.024 · Cited by 34
“[8] Tsigos C, Papanicolaou DA, Kyrou I, Defensor R, Mitsiadis CS, Chrousos GP.”
BackgroundChielle, E. O., de Souza, W. M., da Silva, T. P., Moresco, R. N., & Moretto, M. B. (2016) · Clinical Biochemistry · doi:10.1016/j.clinbiochem.2016.01.003 · Cited by 34
Endocrine and neurological adverse effects of the therapeutic interferons
Vial, T., Choquet‐Kastylevsky, G., Liautard, C., & Descotes, J. (2000) · Toxicology · doi:10.1016/s0300-483x(99)00141-9 · Cited by 33
Adipocyte metabolism and the metabolic syndrome
Stears, A. J., & Byrne, C. D. (2001) · Diabetes Obesity and Metabolism · doi:10.1046/j.1463-1326.2001.00151.x · Cited by 33
Yang, C., Shiau, M., Lai, Y.-R., Ho, K.-T., Hsiao, C., Chen, C., Lo, Y., & Chang, Y.-H. (2018) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2018/6923187 · Cited by 32
“In hepatocytes, IL-6 inhibits insulin signaling and GS activities [19, 44], as well as promotes glucose output, glycogen phosphorylase activity, lipolysis, and triglyceride production [16, 45, 46].”
BackgroundFenkçi, S. M., Rota, S., Sabir, N., Sermez, Y., Güçlü, A., & Akdağ, B. (2006) · Journal of Investigative Medicine · doi:10.2310/6650.2006.06010 · Cited by 31
“Both of these cytokines induce insulin resistance.(1,8,9,12,13) The abdominal fat layers comprise subcutaneous, preperitoneal, and visceral fat compartments.”
BackgroundJiao, K., Liu, H., Chen, J., Tian, D., Hou, J., & Kaye, A. D. (2008) · Cytokine · doi:10.1016/j.cyto.2007.12.002 · Cited by 29
“Elevation of plasma insulin and glucose levels has also been observed in healthy controls receiving injection of IL-6 [14].”
Gavito, A., Bautista, D., Suárez, J., Badran, S., Arco, R., Pavón, F. J., Serrano, A., Rivera, P., Decara, J. M., Cuesta, A. L., et al. (2016) · PLoS ONE · doi:10.1371/journal.pone.0157956 · Cited by 28
“In addition, we observed in DIO mice that the IL-6 treatment elevated peripheral glucose levels (Table 2), which is in agreement with other studies in humans showing a correlation between increased levels of IL-6 and increased blood glucose [27].”
ResultInterleukin-4 Promotes Myogenesis and Boosts Myocyte Insulin Efficacy
Chang, Y.-H., Tsai, J., Chen, T.-L., Ho, K.-T., Cheng, H. K., Hsiao, C., & Shiau, M. (2019) · Mediators of Inflammation · doi:10.1155/2019/4182015 · Cited by 28
“The incompetency of long-term IL-4 injection to ameliorate insulin resistance is probably due to physical adaptation and/or compensation under consistent IL-4 exposure for meeting the in vivo energy requirements to maintain homeostasis [37, 38].”
BackgroundAdipocyte biology and adipocytokines
Haque, W. A., & Garg, A. (2004) · Clinics in Laboratory Medicine · doi:10.1016/j.cll.2004.01.007 · Cited by 27
Gump, B. S., McMullan, D. R., Cauthon, D. J., Whitt, J. A., Mundo, J. D. D., Letham, T., Kim, P. J., Friedlander, G. N., Pingel, J., Langberg, H., et al. (2013) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00219.2013 · Cited by 26
Wang, N., Xu, T.-Y., Zhang, X., Li, J.-Y., Wang, Y.-X., Guo, X.-C., Li, S.-M., Wang, W.-F., & Li, D.-S. (2018) · International Immunopharmacology · doi:10.1016/j.intimp.2018.01.048 · Cited by 23
Fighting obesity: When muscle meets fat
Yang, X., Bi, P., & Kuang, S. (2014) · Adipocyte · doi:10.4161/21623945.2014.964075 · Cited by 25
Liang, Y.-C., Hu, J.-C., Li, P., Huang, G., Kuo, Y., & Chao, C. (2017) · Biomedicine · doi:10.1051/bmdcn/2017070318 · Cited by 24
“…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).”
BackgroundCirculating glucagon is associated with inflammatory mediators in metabolically compromised subjects
Ortega, F. J., Moreno‐Navarrete, J. M., Sabater, M., Ricart, W., Frühbeck, G., & Fernández‐Real, J. M. (2011) · European Journal of Endocrinology · doi:10.1530/eje-11-0384 · Cited by 24
“Otherwise, the deregulation of glucagon levels (i.e. hyperglucagonemia) could lead to hyperglycemia and aggravate their negative effects in individuals with glucose intolerance (impaired glucose tolerance (IGT)) and type 2 diabetes (T2D).”
ResultInfluentialKahles, F., Meyer, C., Diebold, S., Foldenauer, A. C., Stöhr, R., Möllmann, J., Lebherz, C., Findeisen, H. M., Marx, N., & Lehrke, M. (2016) · Diabetes Obesity and Metabolism · doi:10.1111/dom.12711 · Cited by 24
Hypoxic damage to pancreatic beta cells – The hidden link between sleep apnea and diabetes
Pallayová, M., Lazúrová, I., & Donič, V. (2011) · Medical Hypotheses · doi:10.1016/j.mehy.2011.08.016 · Cited by 23
Nitric Oxide Stimulates Interleukin-6 Production in Skeletal Myotubes
Makris, A. C., Sotzios, Y., Zhou, Z., Makropoulou, M., Papapetropoulos, N., Zacharatos, P., Pyriochou, A., Roussos, C., Papapetropoulos, A., & Vassilakopoulos, T. (2009) · Journal of Interferon & Cytokine Research · doi:10.1089/jir.2009.0022 · Cited by 23
Li, T., Wu, C.-L., Gleeson, M., & Williams, C. (2004) · International Journal of Sport Nutrition and Exercise Metabolism · doi:10.1123/ijsnem.14.6.647 · Cited by 22
Katagiri, S., Nagasawa, T., Kobayashi, H., Takamatsu, H., Bharti, P., Izumiyama, H., UCHIMURA, I., TAGAMI, T., Suzuki, T., Nanbara, H., et al. (2012) · Journal of Diabetes Investigation · doi:10.1111/j.2040-1124.2012.00209.x · Cited by 26
Adipokine gene transcription level in adipose tissue of runt piglets
Ramsay, T. G., Stoll, M. J., & Caperna, T. J. (2009) · Comparative Biochemistry and Physiology Part B Biochemistry and Molecular Biology · doi:10.1016/j.cbpb.2009.09.006 · Cited by 21
“If peripheral IL6 concentrations were affected by an increase in IL6 expression in the neonatal adipose tissue as suggested in the present study, liver glycogen storage (Tsigos et al., 1997) and thus glucose homeostasis would also be impaired during the critical first days postnatal.”
BackgroundInflammatory Markers and Outcomes in Kidney Transplant Recipients
Molnar, M. Z., Nagy, K., Remport, Á., Tapolyai, M. B., Fülöp, T., Kamal, F., Kovesdy, C. P., Mucsi, I., & Máthé, Z. (2016) · Transplantation · doi:10.1097/tp.0000000000001548 · Cited by 22
“Copyright © 2017 Wolters Kluwer adipocytes.(38,39) Unfortunately, we do not have data regarding insulin resistance or new onset diabetes mellitus to test this hypothesis in our cohort.”
Drugs acting on the immune system
Vial, T., Descotes, J., Screaton, G. R., Behrend, M., & Ludwig, C. (2003) · Side effects of drugs annual · doi:10.1016/s0378-6080(03)80044-2 · Cited by 21
SGLT2 inhibitors as metabolic modulators: beyond glycemic control in type 2 diabetes
Wu, Q., Zhang, J., Zhang, F., & Li, D. (2025) · Frontiers in Endocrinology · doi:10.3389/fendo.2025.1601633 · Cited by 20
Sarkar, J., Dwivedi, G., Chen, Q., Sheu, I. E., Paich, M., Chelini, C. M., D'Alessandro, P. M., & Burns, S. P. (2018) · PLoS ONE · doi:10.1371/journal.pone.0192472 · Cited by 21
Hypothalamic-Pituitary-Adrenal Axis
Kyrou, I., & Tsigos, C. (2005) · Springer eBooks · doi:10.1007/3-540-26861-8_3 · Cited by 20
Self-citationStress, Endocrine Manifestations, and Diseases
Chrousos, G. P., Tsigos, C., & Kyrou, I. (2004) · CRC Press eBooks · doi:10.1201/9781420039702.ch6 · Cited by 19
Self-citationBirjmohun, R. S., Bisoendial, R. J., van Leuven, S. I., Ackermans, M. T., Zwinderman, A. H., Kastelein, J. J. P., Stroes, E. S. G., & Sauerwein, H. P. (2007) · Metabolism · doi:10.1016/j.metabol.2007.06.026 · Cited by 19
“Most likely, the increases in plasma cortisol and norepinephrine concentrations are secondary to increased IL-6 release peaking at 4 hours [13-15].”
BackgroundThe effect of insulin-induced hypoglycemia on inflammatory markers: A systematic review
Drummond, J., Barbosa, I. G., Dantzer, R., & Teixeira, A. L. (2018) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2018.05.003 · Cited by 18
Metadata
- 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 › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › 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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