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DOI: 10.1055/s-2004-830526
J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York
Differential Regulation of Human Blood Glucose Level by Interleukin-2 and -6
Publication History
Received: November 24, 2003
First decision: March 3, 2004
Accepted: June 28, 2004
Publication Date:
21 January 2005 (online)
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Abstract
While the acute phase reaction to infection is associated with hyperglycemia, during progressing infection hypoglycemia can develop. The cytokines regulating the dynamics of host defense may concurrently contribute to blood glucose regulation. To examine this hypothesis, changes in blood glucose concentrations in healthy men were compared following administration of interleukin-2 (IL-2) and IL-6 representing, respectively, major mediators of the adaptive and the early innate immune response to bacterial infection. Doses of 10 000 IU/kg IL-2 and 0.5 µg/kg IL-6 (vs. placebo) were administered subcutaneously in two groups of men (n = 18 and 16) at 1900 h before a period of nocturnal rest allowing an assessment of changes under basal conditions. Serum concentrations of glucose and of various hormones were assessed every 60 min. Despite generally lowered glucose concentration at night, IL-2 induced a transient but distinct decrease in blood glucose concentration most consistent 8 - 9 hours following injection (p < 0.01). The hypoglycemic response to IL-2 was not accompanied by changes in serum insulin, C-peptide or cortisol. In contrast to IL-2, IL-6 led to an increase in cortisol, followed by a pronounced increase in blood glucose again peaking about 8 hours after injection (p < 0.001). Results indicate a differential regulation of blood glucose concentration by cytokines. Contrasting with the hyperglycemic effects of the acute phase regulator IL-6, the T-cell cytokine IL-2 seems to support glucose uptake and utilization by immune cells.
Key words
Acute phase reaction - counter-regulatory hormones - cytokines - glucose regulation - inflammation - immune system
References
- 1 Barriere S L, Lowry S F. An overview of mortality risk prediction in sepsis. Crit Care Med. 1995; 23 376-393
- 2 Battelino T, Goto M, Krzisnik C, Zeller W P. Tumor necrosis factor-alpha alters glucose metabolism in suckling rats. J Lab Clin Med. 1999; 133 583-589
- 3 Besedovsky H O, del Rey A. Interleukin-1 and glucose homeostasis: An example of the biological relevance of immune-neuroendocrine interactions. Horm Res. 1989; 31 94-99
- 4 Bierwolf C, Struve K, Marshall L, Born J, Fehm H L. Slow wave sleep drives inhibition of pituitary-adrenal secretion in humans. J Neuroendocrinol. 1997; 9 479-484
- 5 Bindon C, Czerniecki M, Ruell P, Edwards A, McCarthy W H, Harris R, Hersey P. Clearance rates and systemic effects of intravenously administered interleukin 2 (IL-2) containing preparations in human subjects. Br J Cancer. 1983; 47 123-133
- 6 Casey L C. Role of cytokines in the pathogenesis of cardiopulmonary-induced multisystem organ failure. Ann Thorac Surg. 1993; 56 S92-S96
- 7 Chakrabarti R, Jung C Y, Lee T P, Liu H, Mookerjee B K. Changes in glucose transport and transporter isoforms during the activation of human peripheral blood lymphocytes by phytohemagglutinin. J Immunol. 1994; 152 2660-2668
- 8 Chambrier C, Mercatello A, Tognet E, Cottet-Emard J M, Cohen R, Blay J Y, Favrot M, Philip T, Beylot M. Hormonal and metabolic effects of chronic interleukin-2 infusion in cancer patients. J Biol Response Mod. 1990; 9 251-255
- 9 Crown J, Jakubowski A, Kemeny N, Gordon M, Gasparetto C, Wong G, Sheridan C, Toner G, Meisenberg B, Botet J. A phase I trial of recombinant human interleukin-1 beta alone and in combination with myelosuppressive doses of 5-fluorouracil in patients with gastrointestinal cancer. Blood. 1991; 78 1420-1427
- 10 del Rey A, Besedovsky H O. Interleukin-1 affects glucose homeostasis. Am J Physiol. 1987; 253 R794-798
- 11 del Rey A, Besedovsky H O. Antidiabetic effects of interleukin-1. Proc Natl Acad Sci USA. 1989; 86 5943-5947
- 12 del Rey A, Monge-Arditi G, Besedovsky H O. Central and peripheral mechanisms contribute to the hypoglycemia induced by interleukin-1. Ann N Y Acad Sci. 1998; 840 153-161
- 13 Ehrhart-Bornstein M, Hinson J P, Bornstein S R, Scherbaum W A, Vinson G P. Intra-adrenal interactions in the regulation of adrenocortical steroidogenesis. Endocr Rev. 1998; 19 101-143
- 14 Gesbert F, Delespine-Carmagnat M, Bertoglio J. Recent advances in the understanding of interleukin-2 signal transduction. J Clin Immunol. 1998; 18 307-320
- 15 Goodman S, Sprung C L. The Int. Sepsis Forum's controversies in sepsis: corticosteroids should be used to treat septic shock. Crit Care. 2002; 6 381-383
- 16 Hanisch U K, Quirion R. Interleukin-2 as a neuroregulatory cytokine. Brain Res Brain Res Rev. 1995; 21 246-284
- 17 Lager I. The insulin-antagonistic effect of the counterregulatory hormones. J Intern Med Suppl. 1991; 735 41-47
- 18 Lange T, Marshall L, Späth-Schwalbe E, Fehm H L, Born J. Systemic immune parameters and sleep after ultra-low dose administration of IL-2 in healthy men. Brain Behav Immun. 2002; 16 663-674
- 19 Mastorakos G, Weber J S, Magiakou M A, Gunn H, Chrousos G P. Hypothalamic-pituitary-adrenal axis activation and stimulation of systemic vasopressin secretion by recombinant interleukin-6 in humans: potential implications for the syndrome of inappropriate vasopressin secretion. J Clin Endocrinol Metab. 1994; 79 934-939
- 20 McCowen K C, Malhotra A, Bistrian B R. Stress-induced hyperglycemia. Crit Care Clin. 2001; 17 107-124
- 21 Miller S L, Wallace R J, Musher D M, Septimus E J, Kohl S, Baughn R E. Hypoglycemia as a manifestation of sepsis. Am J Med. 1980; 68 649-653
- 22 Oguri S, Motegi K, Iwakura Y, Endo Y. Primary role of interleukin-1α and interleukin-1β in lipopolysaccharide-induced hypoglycemia in mice. Clin Diag Lab Immunol. 2002; 9 1307-1312
- 23 Plat L, Leproult R, L'Hermite-Baleriaux M, Fery F, Mockel J, Polonsky K S, Van Cauter E. Metabolic effects of short-term elevations of plasma cortisol are more pronounced in the evening than in the morning. J Clin Endocrinol Metab. 1999; 84 3082-3092
- 24 Petitto J M, Huang Z. Molecular cloning of the coding sequence of an interleukin-2 receptor alpha subunit cDNA in murine brain. J Neuroimmunol. 1995; 59 135-141
- 25 Ritchie D G. Interleukin 6 stimulates hepatic glucose release from prelabeled glycogen pools. Am J Physiol. 1990; 258 E57-E64
- 26 Ruetten H, Thiemermann C. Effects of tyrphostins and genistein on the circulatory failure and organ dysfunction caused by endotoxin in the rat: a possible role for protein tyrosine kinase. Br J Pharmacol. 1997; 122 59-70
- 27 Sievers E L, Lange B J, Sondel P M, Krailo M D, Gan J, Liu-Mares W, Feig S A. Feasibility, toxicity, and biologic response of interleukin-2 after consolidation chemotherapy for acute myelogenous leukemia: A report from the Children's Cancer Group. J Clin Oncol. 1998; 16 914-919
- 28 Smith K A. Lowest dose interleukin-2 immunotherapy. Blood. 1993; 6 1414-1424
- 29 Späth-Schwalbe E, Born J, Schrezenmeier H, Bornstein S R, Stromeyer P, Drechsler S, Fehm H L, Porzsolt F. Interleukin-6 stimulates the hypothalamus-pituitary-adrenocortical axis in man. J Clin Endocrinol Metab. 1994; 79 1212-1214
- 30 Späth-Schwalbe E, Hansen K, Schmidt F, Schrezenmeier H, Marshall L, Burger K, Fehm H L, Born J. Acute effects of recombinant human interleukin-6 on endocrine and central nervous sleep functions in healthy men. J Clin Endocrinol Metab. 1998; 83 1573-1579
- 31 Steensberg A, Fischer C P, Sacchetti M, Keller C, Osada T, Schjerling P, van Hall G, Febbraio M A, Pedersen B K. Acute interleukin-6 administration does not impair muscle glucose uptake or whole-body glucose disposal in healthy humans. J Physiol. 2003; 548 631-638
- 32 Stouthard J M, Romijn J A, Van der Poll T, Endert E, Klein S, Bakker P J, Veenhof C H, Sauerwein H P. Endocrinologic and metabolic effects of interleukin-6 in humans. Am J Physiol. 1995; 268 E813-E819
- 33 Tsigos C, Papanicolaou D A, Kyrou I, Defensor R, Mitsiadis C S, Chrousos G P. Dose-dependent effects of recombinant human interleukin-6 on glucose regulation. J Clin Endocrinol Metab. 1997 a; 82 4167-4170
- 34 Tsigos C, Papanicolaou D A, Defensor R, Mitsiadis C S, Kyrou I, Chrousos G P. Dose effects of recombinant human interleukin-6 on pituitary hormone secretion and energy expenditure. Neuroendocrinology. 1997 b; 66 54-62
- 35 Van Cauter E, Polonsky K S, Scheen A J. Roles of circadian rhythmicity and sleep in human glucose regulation. Endocr Rev. 1997; 18 716-738
- 36 Witek-Janusek L, Yelich M R. Role of the adrenal cortex and medulla in the young rats' glucoregulatory response to endotoxin. Shock. 1995; 3 434-439
Dr. med. Tanja Lange
Medizinische Klinik I
Universität zu Lübeck
Ratzeburger Allee 160
23538 Lübeck
Germany
Phone: + 494515003639
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Email: lange@kfg.mu-luebeck.de