Home LiteratureArticle Details
PMID: 19666548 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

IL-1 antagonism reduces hyperglycemia and tissue inflammation in the type 2 diabetic GK rat.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 106 ·No. 33 ·2009-08-18 ·Pages 13998-4003

Ehses JA, Lacraz G, Giroix MH, Schmidlin F, Coulaud J, Kassis N, Irminger JC, Kergoat M, Portha B, Homo-Delarche F, Donath MY

Abstract

Recent studies suggest an inflammatory process, characterized by local cytokine/chemokine production and immune cell infiltration, regulates islet dysfunction and insulin resistance in type 2 diabetes. However, the factor initiating this inflammatory response is not known. Here, we characterized tissue inflammation in the type 2 diabetic GK rat with a focus on the pancreatic islet and investigated a role for IL-1. GK rat islets, previously characterized by increased macrophage infiltration, displayed increased expression of several inflammatory markers including IL-1beta. In the periphery, increased expression of IL-1beta was observed primarily in the liver. Specific blockade of IL-1 activity by the IL-1 receptor antagonist (IL-1Ra) reduced the release of inflammatory cytokines/chemokines from GK islets in vitro and from mouse islets exposed to metabolic stress. Islets from mice deficient in IL-1beta or MyD88 challenged with glucose and palmitate in vitro also produced significantly less IL-6 and chemokines. In vivo, treatment of GK rats with IL-1Ra decreased hyperglycemia, reduced the proinsulin/insulin ratio, and improved insulin sensitivity. In addition, islet-derived proinflammatory cytokines/chemokines (IL-1beta, IL-6, TNFalpha, KC, MCP-1, and MIP-1alpha) and islet CD68(+), MHC II(+), and CD53(+) immune cell infiltration were reduced by IL-1Ra treatment. Treated GK rats also exhibited fewer markers of inflammation in the liver. We conclude that elevated islet IL-1beta activity in the GK rat promotes cytokine and chemokine expression, leading to the recruitment of innate immune cells. Rather than being directly cytotoxic, IL-1beta may drive tissue inflammation that impacts on both beta cell functional mass and insulin sensitivity in type 2 diabetes.

MeSH Terms
Animals Antigens, CD/biosynthesis Antigens, Differentiation, Myelomonocytic/biosynthesis Antigens, Differentiation, T-Lymphocyte/biosynthesis Diabetes Mellitus, Experimental/metabolism Diabetes Mellitus, Type 2/metabolism Hyperglycemia/pathology Inflammation/pathology Interleukin 1 Receptor Antagonist Protein/metabolism Interleukin-1/antagonists & inhibitors,metabolism Interleukin-1beta/metabolism Interleukin-6/metabolism Islets of Langerhans/metabolism Macrophages/metabolism Mice Myeloid Differentiation Factor 88/metabolism Rats Rats, Wistar Tetraspanin 25
Chemicals
Antigens, CD Antigens, Differentiation, Myelomonocytic Antigens, Differentiation, T-Lymphocyte CD53 protein, human CD68 antigen, human Cd53 protein, mouse Cd53 protein, rat Interleukin 1 Receptor Antagonist Protein Interleukin-1 Interleukin-1beta Interleukin-6 Myd88 protein, mouse Myeloid Differentiation Factor 88 Tetraspanin 25
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Ehses J A
Division of Endocrinology, Diabetes, and Nutrition and Center for Integrated Human Physiology, University Hospital of Zurich, 8045 Zurich, Switzerland. [email protected]
Lacraz G
Giroix M-H
Schmidlin F
Coulaud J
Kassis N
Irminger J-C
Kergoat M
Portha B
Homo-Delarche F
Donath M Y
References (42)
42 references, click to expand
  1. Increased interleukin (IL)-1beta messenger ribonucleic acid expression in beta -cells of individuals with type 2 diabetes and regulation of IL-1beta in human islets by glucose and autostimulation.
    J Clin Endocrinol Metab. 2008 Oct;93(10):4065-74 PMID: 18664535
  2. Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB.
    Nat Med. 2005 Feb;11(2):183-90 PMID: 15685173
  3. Mature-onset obesity in interleukin-1 receptor I knockout mice.
    Diabetes. 2006 May;55(5):1205-13 PMID: 16644674
  4. Toll-like receptors: critical proteins linking innate and acquired immunity.
    Nat Immunol. 2001 Aug;2(8):675-80 PMID: 11477402
  5. Impaired insulin secretion and excessive hepatic glucose production are both early events in the diabetic GK rat.
    Am J Physiol. 1996 Oct;271(4 Pt 1):E755-62 PMID: 8897865
  6. Differential effects of hyperlipidemia on insulin secretion in islets of langerhans from hyperglycemic versus normoglycemic rats.
    Diabetes. 2002 Mar;51(3):662-8 PMID: 11872664
  7. Increased fat:carbohydrate oxidation ratio in Il1ra (-/-) mice on a high-fat diet is associated with increased sympathetic tone.
    Diabetologia. 2008 Sep;51(9):1698-706 PMID: 18594791
  8. Programmed disorders of beta-cell development and function as one cause for type 2 diabetes? The GK rat paradigm.
    Diabetes Metab Res Rev. 2005 Nov-Dec;21(6):495-504 PMID: 15926190
  9. Interleukin-1-receptor antagonist in type 2 diabetes mellitus.
    N Engl J Med. 2007 Apr 12;356(15):1517-26 PMID: 17429083
  10. Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function.
    Immunity. 1998 Jul;9(1):143-50 PMID: 9697844
  11. Inflammation, stress, and diabetes.
    J Clin Invest. 2005 May;115(5):1111-9 PMID: 15864338
  12. Functional and metabolic perturbations in isolated pancreatic islets from the GK rat, a genetic model of noninsulin-dependent diabetes.
    Endocrinology. 1993 Feb;132(2):815-22 PMID: 8425496
  13. Cytokines and beta-cell biology: from concept to clinical translation.
    Endocr Rev. 2008 May;29(3):334-50 PMID: 18048762
  14. Altered proinsulin conversion in rat pancreatic islets exposed long-term to various glucose concentrations or interleukin-1beta.
    J Endocrinol. 2007 Feb;192(2):381-7 PMID: 17283238
  15. Islet inflammation in type 2 diabetes: from metabolic stress to therapy.
    Diabetes Care. 2008 Feb;31 Suppl 2:S161-4 PMID: 18227479
  16. beta-cell function and viability in the spontaneously diabetic GK rat: information from the GK/Par colony.
    Diabetes. 2001 Feb;50 Suppl 1:S89-93 PMID: 11272210
  17. A choice of death--the signal-transduction of immune-mediated beta-cell apoptosis.
    Diabetologia. 2001 Dec;44(12):2115-33 PMID: 11793013
  18. Biologic basis for interleukin-1 in disease.
    Blood. 1996 Mar 15;87(6):2095-147 PMID: 8630372
  19. 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
  20. Follow-up of GK rats during prediabetes highlights increased insulin action and fat deposition despite low insulin secretion.
    Am J Physiol Endocrinol Metab. 2008 Jan;294(1):E168-75 PMID: 17986628
  21. A natural interleukin 1 (IL-1) inhibitor counteracts the inhibitory effect of IL-1 on insulin production in cultured rat pancreatic islets.
    J Autoimmun. 1989 Apr;2(2):163-71 PMID: 2527507
  22. Decreased fat mass in interleukin-1 receptor antagonist-deficient mice: impact on adipogenesis, food intake, and energy expenditure.
    Diabetes. 2005 Dec;54(12):3503-9 PMID: 16306368
  23. Persistent improvement of type 2 diabetes in the Goto-Kakizaki rat model by expansion of the beta-cell mass during the prediabetic period with glucagon-like peptide-1 or exendin-4.
    Diabetes. 2002 May;51(5):1443-52 PMID: 11978641
  24. Exposure of human islets to cytokines can result in disproportionately elevated proinsulin release.
    J Clin Invest. 1999 Jul;104(1):67-72 PMID: 10393700
  25. Cytokines affect PDX-1 expression, insulin and proinsulin secretion from iNOS deficient murine islets.
    Mol Cell Endocrinol. 2005 Aug 30;240(1-2):50-7 PMID: 16023781
  26. Cytotoxicity of human pI 7 interleukin-1 for pancreatic islets of Langerhans.
    Science. 1986 Jun 20;232(4757):1545-7 PMID: 3086977
  27. The antiinflammatory cytokine interleukin-1 receptor antagonist protects from high-fat diet-induced hyperglycemia.
    Endocrinology. 2008 May;149(5):2208-18 PMID: 18239070
  28. 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
  29. A urine inhibitor of interleukin 1 activity that blocks ligand binding.
    J Immunol. 1987 Sep 1;139(5):1546-9 PMID: 2957429
  30. Islet inflammation and fibrosis in a spontaneous model of type 2 diabetes, the GK rat.
    Diabetes. 2006 Jun;55(6):1625-33 PMID: 16731824
  31. Abnormal expression of pancreatic islet exocytotic soluble N-ethylmaleimide-sensitive factor attachment protein receptors in Goto-Kakizaki rats is partially restored by phlorizin treatment and accentuated by high glucose treatment.
    Endocrinology. 2002 Nov;143(11):4218-26 PMID: 12399415
  32. TLR signaling pathways.
    Semin Immunol. 2004 Feb;16(1):3-9 PMID: 14751757
  33. Interleukins and tumor necrosis factor as inhibitors of food intake.
    Neuropeptides. 1999 Oct;33(5):415-24 PMID: 10657519
  34. Increased number of islet-associated macrophages in type 2 diabetes.
    Diabetes. 2007 Sep;56(9):2356-70 PMID: 17579207
  35. The interleukin-1 family: 10 years of discovery.
    FASEB J. 1994 Dec;8(15):1314-25 PMID: 8001745
  36. Effect of gliclazide treatment on insulin secretion and beta-cell mass in non-insulin dependent diabetic Goto-Kakisaki rats.
    Eur J Pharmacol. 1998 Nov 20;361(2-3):243-51 PMID: 9865514
  37. The GK rat beta-cell: a prototype for the diseased human beta-cell in type 2 diabetes?
    Mol Cell Endocrinol. 2009 Jan 15;297(1-2):73-85 PMID: 18640239
  38. 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
  39. Insulin resistance in the GK rat: decreased receptor number but normal kinase activity in liver.
    Am J Physiol. 1993 Nov;265(5 Pt 1):E807-13 PMID: 8238507
  40. Immunological and inflammatory functions of the interleukin-1 family.
    Annu Rev Immunol. 2009;27:519-50 PMID: 19302047
  41. An immune origin of type 2 diabetes?
    Diabetologia. 2005 Jun;48(6):1038-50 PMID: 15864529
  42. Ciliary neurotrophic factor potentiates the beta-cell inhibitory effect of IL-1beta in rat pancreatic islets associated with increased nitric oxide synthesis and increased expression of inducible nitric oxide synthase.
    Diabetes. 1998 Oct;47(10):1602-8 PMID: 9753298
Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
1091-6490
DOI
10.1073/pnas.0810087106
Email
[email protected]
Published
2009-08-18
Epub
2009-00-30
Pages
13998-4003
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC2729009
Subset
IM
External Links
PubMed source DOI: 10.1073/pnas.0810087106 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