Journal ArticleDOI
Monokine antagonism is reduced in patients with IDDM
Thomas Mandrup-Poulsen,Flemming Pociot,Jens Mølvig,Leland Shapiro,P. M. Nilsson,Torkil Emdal,Michael E Røder,Lisa L Kjems,Charles A. Dinarello,Jørn Nerup +9 more
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TLDR
Preliminary findings suggest that μ-cells in IDDM patients may be more sensitive to the cytotoxic effects of TNF-α and IL-1 because of less production of T NFsRp55 and, in a subset of ID DM patients, of IL-IRa during the inflammatory challenge of insulitis.Abstract:
Interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-alpha) have been implicated as immune effector molecules in the pathogenesis of insulin-dependent diabetes mellitus (IDDM). Recently, an increased frequency of the A1/A1 genotype of an IL-1 receptor antagonist (IL-1Ra) gene polymorphism was observed in patients with IDDM. Therefore, we investigated plasma IL-1Ra and soluble TNF p55 receptor (TNFsRp55) levels in 18 men with recent-onset IDDM, 10 men with long-standing IDDM, and 35 age-matched healthy men. No differences in plasma IL-1Ra were found among the three groups. However, when the plasma IL-1Ra levels in the subjects with IDDM and the control subjects were analyzed according to IL-1Ra genotypes, we found a 30% lower level of plasma IL-1Ra in subjects with IDDM carrying the A1/A1 genotype compared with the levels in those carrying the A1/A2 genotype (372 +/- 40 vs. 530 +/- 54 ng/l, respectively, P = 0.025). In contrast, no significant association was seen between plasma IL-1Ra and IL-1Ra genotype in the control subjects. The TNFsRp55 level in heparinized plasma was 17% lower in patients with IDDM than in control subjects (3.93 +/- 0.22 vs. 4.72 +/- 0.24 micrograms/l, respectively, P = 0.038). These findings could not be explained by metabolic derangement in the IDDM patients.(ABSTRACT TRUNCATED AT 250 WORDS)read more
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The role of interleukin-1 in the pathogenesis of IDDM.
TL;DR: "It is perhaps today, where a certain underevaluation well, even disrespect o f scientific research is growing useful again and again to refer to the fact how well suited the discovery of insulin is to demonstrate that unprejudiced scientific research sooner or later will be fruitful also to clinical practice".
Journal ArticleDOI
IL-1 receptor antagonist (IL-1Ra) plasma levels are co-ordinately regulated by both IL-1Ra and IL-1beta genes.
Mikko Hurme,Sari Santtila +1 more
TL;DR: The results indicate that theIL‐1β gene participates in the regulation of IL‐1Ra production in vivo and that the alleles of IL-1β and IL‐ 1Ra which demonstrate this cooperative effect are often associated.
Journal ArticleDOI
Sustained Effects of Interleukin-1 Receptor Antagonist Treatment in Type 2 Diabetes
Claus M. Larsen,Mirjam V. Faulenbach,Allan Vaag,Jan A. Ehses,Marc Y. Donath,Thomas Mandrup-Poulsen +5 more
TL;DR: IL-1 blockade with anakinra induces improvement of the PI/I ratio and markers of systemic inflammation lasting 39 weeks after treatment withdrawal, and a subgroup characterized by genetically determined low baseline IL-1Ra serum levels maintained the improved stimulated C-peptide obtained by 13 weeks of IL- 1Ra treatment.
Journal ArticleDOI
Genetics of type 1 diabetes mellitus
TL;DR: Elucidation of the function of particular genes (‘functional genomics’) in the pathogenesis of T1D will be a most important element in future studies in this field, in addition to more sophisticated methods of statistical analyses.
Journal ArticleDOI
Blockade of interleukin 1 in type 1 diabetes mellitus
TL;DR: The modulating effect of IL-1 on the interaction between the innate and adaptive immune systems and the effects ofIL- 1 on the β-cell point to this molecule being a potential interventional target in autoimmune diabetes mellitus.
References
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Journal ArticleDOI
Blocking IL-1: interleukin 1 receptor antagonist in vivo and in vitro.
TL;DR: IL-1ra reduces the severity of sepsis, colitis, arthritis and diabetes in animals and is presently being tested in humans with arthritis, shock and myelogenous leukemia.
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Increased plasma interleukin-1 activity in women after ovulation
TL;DR: Interleukin-1 appears to have a role in normal physiological conditions as well as in disease states.
Journal Article
Human tumor necrosis factor potentiates human interleukin 1-mediated rat pancreatic beta-cell cytotoxicity.
TL;DR: In this paper, the authors found that the cytokine interleukin 1 (IL-1) is selectively cytotoxic for isolated human and rat pancreatic beta-cells and that macrophages present in the intra-islet mononuclear cell infiltrate in insulin-dependent diabetes mellitus may secrete monokines that could be important effector molecules in beta-cell destruction.
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Does nitric oxide mediate autoimmune destruction of beta-cells? Possible therapeutic interventions in IDDM.
TL;DR: The role of nitric oxide in both cytokine-mediated β-cell dysfunction, and the antidiabetogenic effects of cytokines, as well as the potential therapeutic use of aminoguanidine, are evaluated in this study.
Journal ArticleDOI
Endotoxin‐Stimulated Human Monocyte Secretion of Interleukin 1, Tumour Necrosis Factor Alpha, and Prostaglandin E2 Shows Stable Interindividual Differences
Mølvig J,L. Baek,Poul Christensen,K. R. Manogue,H. Vlassara,P. Platz,L. S. Nielsen,A. Svejgaard,J. Nerup +8 more
TL;DR: Stable interindividual differences in in vitro monokine and PGE2 secretions of LPS‐stimulated Mø were demonstrated and it is suggested that HLA‐DR2‐positive individuals may be low responders.