Home LiteratureArticle Details
PMID: 18239070 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

The antiinflammatory cytokine interleukin-1 receptor antagonist protects from high-fat diet-induced hyperglycemia.

Endocrinology ·Vol. 149 ·No. 5 ·2008-05-00 ·Pages 2208-18

Sauter NS, Schulthess FT, Galasso R, Castellani LW, Maedler K

Abstract

Subclinical inflammation is a recently discovered phenomenon in type 2 diabetes. Elevated cytokines impair beta-cell function and survival. A recent clinical trial shows that blocking IL-1beta signaling by IL-1 receptor antagonist (IL-1Ra) improves beta-cell secretory function in patients with type 2 diabetes. In the present study, we provide further mechanisms of the protective role of IL-1Ra on the beta-cell. IL-1Ra prevented diabetes in vivo in C57BL/6J mice fed a high-fat/high-sucrose diet (HFD) for 12 wk; it improved glucose tolerance and insulin secretion. High-fat diet treatment increased serum levels of free fatty acids and of the adipokines resistin and leptin, which were reduced by IL-1Ra treatment. In addition, IL-1Ra counteracted adiponectin levels, which were decreased by high-fat feeding. Studies on isolated islets revealed that IL-1Ra specifically acted on the beta-cell. IL-1Ra protected islets from HFD treated animals from beta-cell apoptosis, induced beta-cell proliferation, and improved glucose-stimulated insulin secretion. Insulin mRNA was reduced in islets from mice fed a HFD but normalized in the IL-1Ra group. Our results show that IL-1Ra improves beta-cell survival and function, and support the potential role for IL-1Ra in the treatment of diabetes.

MeSH Terms
Adipokines/blood Animals Anti-Inflammatory Agents/pharmacology,therapeutic use Apoptosis/drug effects Cell Count Cell Proliferation/drug effects Cells, Cultured Diabetes Mellitus, Type 2/complications,drug therapy,prevention & control Diet, Atherogenic Disease Progression Drug Evaluation, Preclinical Eating/drug effects Glucose Intolerance/drug therapy Hyperglycemia/etiology,prevention & control Insulin-Secreting Cells/cytology,drug effects,physiology Interleukin 1 Receptor Antagonist Protein/pharmacology,therapeutic use Mice Mice, Inbred C57BL Weight Gain/drug effects
Chemicals
Adipokines Anti-Inflammatory Agents Interleukin 1 Receptor Antagonist Protein
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Sauter Nadine S
Larry L. Hillblom Islet Research Center, University of California Los Angeles, Los Angeles, California 90095-7345, USA.
Schulthess Fabienne T
Galasso Ryan
Castellani Lawrence W
Maedler Kathrin
References (56)
56 references, click to expand
  1. Human tumor necrosis factor potentiates human interleukin 1-mediated rat pancreatic beta-cell cytotoxicity.
    J Immunol. 1987 Dec 15;139(12):4077-82 PMID: 3320203
  2. Distinct effects of saturated and monounsaturated fatty acids on beta-cell turnover and function.
    Diabetes. 2001 Jan;50(1):69-76 PMID: 11147797
  3. Glucose induces beta-cell apoptosis via upregulation of the Fas receptor in human islets.
    Diabetes. 2001 Aug;50(8):1683-90 PMID: 11473025
  4. Diet-induced type II diabetes in C57BL/6J mice.
    Diabetes. 1988 Sep;37(9):1163-7 PMID: 3044882
  5. Islet beta cell failure in type 2 diabetes.
    J Clin Invest. 2006 Jul;116(7):1802-12 PMID: 16823478
  6. The role of the interleukin-1-receptor antagonist in blocking inflammation mediated by interleukin-1.
    N Engl J Med. 2000 Sep 7;343(10):732-4 PMID: 10974140
  7. An interleukin-1 receptor antagonist protein protects insulin-producing beta cells against suppressive effects of interleukin-1 beta.
    Diabetologia. 1991 Jun;34(6):445-8 PMID: 1832112
  8. FLIP switches Fas-mediated glucose signaling in human pancreatic beta cells from apoptosis to cell replication.
    Proc Natl Acad Sci U S A. 2002 Jun 11;99(12):8236-41 PMID: 12060768
  9. Protection from experimental autoimmune diabetes in the non-obese diabetic mouse with soluble interleukin-1 receptor.
    Eur J Immunol. 1994 Aug;24(8):1843-7 PMID: 8056041
  10. Free radicals, antioxidants, and human disease: curiosity, cause, or consequence?
    Lancet. 1994 Sep 10;344(8924):721-4 PMID: 7915779
  11. Cytokine-mediated modulation of leptin and adiponectin secretion during in vitro adipogenesis: evidence that tumor necrosis factor-alpha- and interleukin-1beta-treated human preadipocytes are potent leptin producers.
    Cytokine. 2005 Oct 21;32(2):94-103 PMID: 16213747
  12. A urine inhibitor of interleukin 1 activity affects both interleukin 1 alpha and 1 beta but not tumor necrosis factor alpha.
    J Immunol. 1987 Sep 1;139(5):1541-5 PMID: 3040855
  13. The adipocyte-myocyte axis in insulin resistance.
    Trends Endocrinol Metab. 2006 Dec;17(10):416-22 PMID: 17084639
  14. Monolayer culture of adult rat pancreatic islets on extracellular matrix: modulation of B-cell function by chronic exposure to high glucose.
    Endocrinology. 1991 Oct;129(4):2067-76 PMID: 1717241
  15. Dietary-fat-induced obesity in mice results in beta cell hyperplasia but not increased insulin release: evidence for specificity of impaired beta cell adaptation.
    Diabetologia. 2005 Jul;48(7):1350-8 PMID: 15937671
  16. Functions of interleukin 1 receptor antagonist in gene knockout and overproducing mice.
    Proc Natl Acad Sci U S A. 1996 Oct 1;93(20):11008-13 PMID: 8855299
  17. Interleukin-1 receptor antagonist is upregulated during diet-induced obesity and regulates insulin sensitivity in rodents.
    Diabetologia. 2006 Feb;49(2):387-93 PMID: 16385385
  18. Leptin modulates beta cell expression of IL-1 receptor antagonist and release of IL-1beta in human islets.
    Proc Natl Acad Sci U S A. 2004 May 25;101(21):8138-43 PMID: 15141093
  19. Biological role of interleukin 1 receptor antagonist isoforms.
    Ann Rheum Dis. 2000 Nov;59 Suppl 1:i60-4 PMID: 11053091
  20. Adipocytokines: leptin--the classical, resistin--the controversical, adiponectin--the promising, and more to come.
    Best Pract Res Clin Endocrinol Metab. 2005 Dec;19(4):525-46 PMID: 16311215
  21. Reduced beta-cell mass and expression of oxidative stress-related DNA damage in the islet of Japanese Type II diabetic patients.
    Diabetologia. 2002 Jan;45(1):85-96 PMID: 11845227
  22. Nuclear factor-kappaB regulates beta-cell death: a critical role for A20 in beta-cell protection.
    Diabetes. 2006 Sep;55(9):2491-501 PMID: 16936197
  23. Adipocytokines - novel link between inflammation and vascular function?
    J Physiol Pharmacol. 2006 Dec;57(4):505-28 PMID: 17229978
  24. Pancreatic beta cell senescence contributes to the pathogenesis of type 2 diabetes in high-fat diet-induced diabetic mice.
    Diabetologia. 2005 Jan;48(1):58-67 PMID: 15624098
  25. Diabetes due to a progressive defect in beta-cell mass in rats transgenic for human islet amyloid polypeptide (HIP Rat): a new model for type 2 diabetes.
    Diabetes. 2004 Jun;53(6):1509-16 PMID: 15161755
  26. Beta cell apoptosis in T cell-mediated autoimmune diabetes.
    Proc Natl Acad Sci U S A. 1997 Jan 7;94(1):213-8 PMID: 8990188
  27. TLR4 links innate immunity and fatty acid-induced insulin resistance.
    J Clin Invest. 2006 Nov;116(11):3015-25 PMID: 17053832
  28. Mechanisms of beta-cell death in type 2 diabetes.
    Diabetes. 2005 Dec;54 Suppl 2:S108-13 PMID: 16306327
  29. A choice of death--the signal-transduction of immune-mediated beta-cell apoptosis.
    Diabetologia. 2001 Dec;44(12):2115-33 PMID: 11793013
  30. Biologic basis for interleukin-1 in disease.
    Blood. 1996 Mar 15;87(6):2095-147 PMID: 8630372
  31. Glucose-induced beta cell production of IL-1beta contributes to glucotoxicity in human pancreatic islets.
    J Clin Invest. 2002 Sep;110(6):851-60 PMID: 12235117
  32. Insulin-secreting beta-cell dysfunction induced by human lipoproteins.
    J Biol Chem. 2003 May 16;278(20):18368-75 PMID: 12594227
  33. Selective beta-cell loss and alpha-cell expansion in patients with type 2 diabetes mellitus in Korea.
    J Clin Endocrinol Metab. 2003 May;88(5):2300-8 PMID: 12727989
  34. Oxygen free radical scavengers protect rat islet cells from damage by cytokines.
    Diabetologia. 1989 Nov;32(11):792-6 PMID: 2480259
  35. The role of interleukin-1 in the pathogenesis of IDDM.
    Diabetologia. 1996 Sep;39(9):1005-29 PMID: 8877284
  36. Differential effects of fat and sucrose on the development of obesity and diabetes in C57BL/6J and A/J mice.
    Metabolism. 1995 May;44(5):645-51 PMID: 7752914
  37. Inflammatory mediators and islet beta-cell failure: a link between type 1 and type 2 diabetes.
    J Mol Med (Berl). 2003 Aug;81(8):455-70 PMID: 12879149
  38. Diverse effect of inflammatory markers on insulin resistance and insulin-resistance syndrome in the elderly.
    J Am Geriatr Soc. 2004 Mar;52(3):399-404 PMID: 14962155
  39. Combination therapy with an antioxidant and a corticosteroid prevents autoimmune diabetes in NOD mice.
    Life Sci. 1992;51(25):1937-43 PMID: 1453877
  40. Interleukin-1-receptor antagonist in type 2 diabetes mellitus.
    N Engl J Med. 2007 Apr 12;356(15):1517-26 PMID: 17429083
  41. Sustained beta cell apoptosis in patients with long-standing type 1 diabetes: indirect evidence for islet regeneration?
    Diabetologia. 2005 Nov;48(11):2221-8 PMID: 16205882
  42. Interleukin-1 receptor antagonist prevents low dose streptozotocin induced diabetes in mice.
    Biochem Biophys Res Commun. 1994 Jul 15;202(1):543-8 PMID: 8037760
  43. beta-cell apoptosis: stimuli and signaling.
    Diabetes. 2001 Feb;50 Suppl 1:S58-63 PMID: 11272204
  44. Enzymatic methods for quantification of lipoprotein lipids.
    Methods Enzymol. 1986;129:101-23 PMID: 3724535
  45. Low concentration of interleukin-1beta induces FLICE-inhibitory protein-mediated beta-cell proliferation in human pancreatic islets.
    Diabetes. 2006 Oct;55(10):2713-22 PMID: 17003335
  46. A urine inhibitor of interleukin 1 activity that blocks ligand binding.
    J Immunol. 1987 Sep 1;139(5):1546-9 PMID: 2957429
  47. Insulin resistance is not necessarily an essential component of type 2 diabetes.
    J Clin Endocrinol Metab. 2000 Jun;85(6):2113-5 PMID: 10852436
  48. Insulin resistance or insulin deficiency. Which is the primary cause of NIDDM?
    Diabetes. 1994 Jun;43(6):735-40 PMID: 8194657
  49. Altered beta-cell distribution of pdx-1 and GLUT-2 after a short-term challenge with a high-fat diet in C57BL/6J mice.
    Diabetes. 2002 Feb;51 Suppl 1:S138-43 PMID: 11815473
  50. Insulin response to glucose infusion in diabetic and non-diabetic monozygotic twin pairs. Genetic control of insulin response?
    Acta Endocrinol (Copenh). 1967 Jun;55(2):330-45 PMID: 5338208
  51. Adenoviral gene transfer of the interleukin-1 receptor antagonist protein to human islets prevents IL-1beta-induced beta-cell impairment and activation of islet cell apoptosis in vitro.
    Diabetes. 1999 Sep;48(9):1730-6 PMID: 10480601
  52. IL-1 receptor antagonist inhibits recurrence of disease after syngeneic pancreatic islet transplantation to spontaneously diabetic non-obese diabetic (NOD) mice.
    Clin Exp Immunol. 1997 May;108(2):314-7 PMID: 9158104
  53. An immune origin of type 2 diabetes?
    Diabetologia. 2005 Jun;48(6):1038-50 PMID: 15864529
  54. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes.
    Diabetes. 2003 Jan;52(1):102-10 PMID: 12502499
  55. Islet growth and development in the adult.
    J Mol Endocrinol. 2000 Jun;24(3):297-302 PMID: 10828822
  56. Inflammatory cytokines and the risk to develop type 2 diabetes: results of the prospective population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study.
    Diabetes. 2003 Mar;52(3):812-7 PMID: 12606524
Article Info
Journal
Endocrinology
Abbr.
Endocrinology
ISSN
0013-7227
DOI
10.1210/en.2007-1059
Published
2008-05-00
Epub
2008-00-31
Pages
2208-18
Language
English
Region
United States
NLM ID
0375040
PMCID
PMC2734491
Subset
IM
External Links
PubMed source DOI: 10.1210/en.2007-1059 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2