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Exp Clin Endocrinol Diabetes 2005; 113(1): 43-48
DOI: 10.1055/s-2004-830526
Article

J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York

Differential Regulation of Human Blood Glucose Level by Interleukin-2 and -6

M. J. Harnish1 , T. Lange2 , S. Dimitrov1 , J. Born1 , H. L. Fehm2
  • 1Department of Neuroendocrinology, University of Lübeck, Germany
  • 2Department of Internal Medicine, University of Lübeck, Germany
Weitere Informationen

Publikationsverlauf

Received: November 24, 2003 First decision: March 3, 2004

Accepted: June 28, 2004

Publikationsdatum:
21. Januar 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
    PubMedSuche in Google Scholar
  • 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
    CrossrefPubMedSuche in Google Scholar
  • 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
    PubMedSuche in Google Scholar
  • 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
    CrossrefPubMedSuche in Google Scholar
  • 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
    PubMedSuche in Google Scholar
  • 6 Casey L C. Role of cytokines in the pathogenesis of cardiopulmonary-induced multisystem organ failure.  Ann Thorac Surg. 1993;  56 S92-S96
    PubMedSuche in Google Scholar
  • 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
    PubMedSuche in Google Scholar
  • 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
    PubMedSuche in Google Scholar
  • 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
    PubMedSuche in Google Scholar
  • 10 del Rey A, Besedovsky H O. Interleukin-1 affects glucose homeostasis.  Am J Physiol. 1987;  253 R794-798
    PubMedSuche in Google Scholar
  • 11 del Rey A, Besedovsky H O. Antidiabetic effects of interleukin-1.  Proc Natl Acad Sci USA. 1989;  86 5943-5947
    PubMedSuche in Google Scholar
  • 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
    PubMedSuche in Google Scholar
  • 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
    CrossrefPubMedSuche in Google Scholar
  • 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
    CrossrefPubMedSuche in Google Scholar
  • 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
    CrossrefPubMedSuche in Google Scholar
  • 16 Hanisch U K, Quirion R. Interleukin-2 as a neuroregulatory cytokine.  Brain Res Brain Res Rev. 1995;  21 246-284
    CrossrefPubMedSuche in Google Scholar
  • 17 Lager I. The insulin-antagonistic effect of the counterregulatory hormones.  J Intern Med Suppl. 1991;  735 41-47
    PubMedSuche in Google Scholar
  • 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
    CrossrefPubMedSuche in Google Scholar
  • 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
    CrossrefPubMedSuche in Google Scholar
  • 20 McCowen K C, Malhotra A, Bistrian B R. Stress-induced hyperglycemia.  Crit Care Clin. 2001;  17 107-124
    CrossrefPubMedSuche in Google Scholar
  • 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
    CrossrefPubMedSuche in Google Scholar
  • 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
    PubMedSuche in Google Scholar
  • 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
    CrossrefPubMedSuche in Google Scholar
  • 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
    CrossrefPubMedSuche in Google Scholar
  • 25 Ritchie D G. Interleukin 6 stimulates hepatic glucose release from prelabeled glycogen pools.  Am J Physiol. 1990;  258 E57-E64
    PubMedSuche in Google Scholar
  • 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
    CrossrefPubMedSuche in Google Scholar
  • 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
    PubMedSuche in Google Scholar
  • 28 Smith K A. Lowest dose interleukin-2 immunotherapy.  Blood. 1993;  6 1414-1424
    PubMedSuche in Google Scholar
  • 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
    CrossrefPubMedSuche in Google Scholar
  • 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
    CrossrefPubMedSuche in Google Scholar
  • 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
    CrossrefPubMedSuche in Google Scholar
  • 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
    PubMedSuche in Google Scholar
  • 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
    CrossrefPubMedSuche in Google Scholar
  • 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
    CrossrefPubMedSuche in Google Scholar
  • 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
    CrossrefPubMedSuche in Google Scholar
  • 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
    PubMedSuche in Google Scholar

Dr. med. Tanja Lange

Medizinische Klinik I
Universität zu Lübeck

Ratzeburger Allee 160

23538 Lübeck

Germany

Telefon: + 494515003639

Fax: + 49 45 15 00 35 40

eMail: lange@kfg.mu-luebeck.de