The role of interleukin-1 in the pathogenesis of IDDM

Mandrup‐Poulsen, Thomas

doi:10.1007/bf00400649

Cited by 477 publications

(178 citation statements)

References 284 publications

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“…Subsequently, an enormous amount of literature has described the toxic effects of the pro-inflammatory cytokines IL-1, IFNc and TNF on beta cells in vitro (reviewed in [78]). IL-1 on its own (in rat) or together with IFNc (in human and mouse) is potently toxic to isolated islets in vitro, killing the majority of cells in 3-4 days of culture.…”

Section: Pro-inflammatory Cytokinesmentioning

confidence: 99%

Beta cell apoptosis in diabetes

et al. 2009

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Apoptosis of beta cells is a feature of both type 1 and type 2 diabetes as well as loss of islets after transplantation. In type 1 diabetes, beta cells are destroyed by immunological mechanisms. In type 2 diabetes abnormal levels of metabolic factors contribute to beta cell failure and subsequent apoptosis. Loss of beta cells after islet transplantation is due to many factors including the stress associated with islet isolation, primary graft non-function and allogeneic graft rejection. Irrespective of the exact mediators, highly conserved intracellular pathways of apoptosis are triggered. This review will outline the molecular mediators of beta cell apoptosis and the intracellular pathways activated.

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Section: Pro-inflammatory Cytokinesmentioning

confidence: 99%

Beta cell apoptosis in diabetes

et al. 2009

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“…This is followed by overt diabetes, distinguished by insulin insufficiency due to the destruction of a majority of β-cells [2,3]. Cytokines produced by inflammatory leukocytes and resident and inflammatory macrophages are believed to contribute to the loss of β-cell function and viability during the development of autoimmune diabetes [4,5]. Interleukin (IL)-1 was identified as the active component of conditioned medium derived from activated human mononuclear cells that causes an inhibition of insulin secretion and the loss of islet cell viability, provided the initial evidence supporting a role for cytokines in the pathogenesis of autoimmune diabetes [6,7].…”

Section: Introductionmentioning

confidence: 99%

Interleukin-1 Stimulates β-Cell Necrosis and Release of the Immunological Adjuvant HMGB1

et al. 2005

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BackgroundThere are at least two phases of β-cell death during the development of autoimmune diabetes: an initiation event that results in the release of β-cell-specific antigens, and a second, antigen-driven event in which β-cell death is mediated by the actions of T lymphocytes. In this report, the mechanisms by which the macrophage-derived cytokine interleukin (IL)-1 induces β-cell death are examined. IL-1, known to inhibit glucose-induced insulin secretion by stimulating inducible nitric oxide synthase expression and increased production of nitric oxide by β-cells, also induces β-cell death.Methods and FindingsTo ascertain the mechanisms of cell death, the effects of IL-1 and known activators of apoptosis on β-cell viability were examined. While IL-1 stimulates β-cell DNA damage, this cytokine fails to activate caspase-3 or to induce phosphatidylserine (PS) externalization; however, apoptosis inducers activate caspase-3 and the externalization of PS on β-cells. In contrast, IL-1 stimulates the release of the immunological adjuvant high mobility group box 1 protein (HMGB1; a biochemical maker of necrosis) in a nitric oxide-dependent manner, while apoptosis inducers fail to stimulate HMGB1 release. The release of HMGB1 by β-cells treated with IL-1 is not sensitive to caspase-3 inhibition, while inhibition of this caspase attenuates β-cell death in response to known inducers of apoptosis.Patient SummaryBackgroundType 1 diabetes (also called autoimmune diabetes or juvenile diabetes) is an autoimmune disease. For unknown reasons, at some point in childhood or adolescence, the body's own immune system starts attacking and destroying the insulin-producing islet cells in the pancreas. Once the majority of islet cells are destroyed, patients can no longer produce insulin to regulate their blood sugar and must depend on strict diets and insulin injections. Scientists are trying to understand the early events during the development of the disease. There are two fundamentally different kinds of cell death in cells of higher animals and humans, called apoptosis and necrosis. Apoptosis (also called programmed cell death) is an organized, clean way in which cells die without spilling their contents and without causing an inflammatory immune response. They are simply gobbled up by other cells that serve as the body's garbage collectors. Necrosis, on the other hand, is a more messy process and one that does activate the immune system and cause local inflammation.Why Was This Study Done?The scientists who did this study are interested in the early stages of islet cell death. Specifically, they wanted to know whether islet cells during the early events of autoimmune diabetes die via apoptosis or necrosis. Earlier experiments to address this question had yielded no clear-cut results.What Did the Researchers Do and Find?All the experiments for this study were done in cultured cells in the laboratory. For the most part, the researchers used rodent islet cells, and then they confirmed the crucial finding in human islet cells. They ...

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“…Interleukin (IL)-1β has been proposed to mediate both impaired function and destruction of pancreatic β-cells during the development of autoimmune type 1 diabetes [38]. In a previous study, we showed that high concentrations of glucose induce β-cell production of IL-1β leading to impaired β-cell function and apoptosis.…”

Section: The Interplay Of Interleukin (Il)-1β and Il-1 Receptor Antagmentioning

confidence: 99%

β-Cells in Type 2 Diabetes: A Loss of Function and Mass

Maedler

Donath²

2004

Horm Res Paediatr

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Type 2 diabetes mellitus manifests itself in individuals who lose the ability to produce sufficient amounts of insulin to maintain normoglycaemia in the face of insulin resistance. The ability to secrete adequate amounts of insulin depends on β-cell function and mass. Chronic hyperglycaemia is detrimental to pancreatic β-cells, causing impaired insulin secretion and playing an essential role in the regulation of β-cell turnover. This paper will address the effect of chronically elevated glucose levels on β-cell turnover and function. In previous studies we have shown that elevated glucose concentrations induce apoptosis in human β-cells due to an interaction between constitutively expressed Fas ligand and upregulated Fas. Human β-cells produce interleukin (IL)-1β in response to high glucose concentrations, independently of an immune-mediated process. This was antagonized by the IL-1 receptor antagonist (IL-1Ra), a naturally occurring anti-inflammatory cytokine also found in the β-cell. Therefore the balance of IL-1β and IL-1Ra may play a crucial role in the pathogenesis of diabetes. Inhibition of glucotoxicity represents a promising therapeutic stratagem in diabetes therapy to preserve functional β-cell mass.

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The role of interleukin-1 in the pathogenesis of IDDM

Cited by 477 publications

References 284 publications

Beta cell apoptosis in diabetes

Beta cell apoptosis in diabetes

Interleukin-1 Stimulates β-Cell Necrosis and Release of the Immunological Adjuvant HMGB1

β-Cells in Type 2 Diabetes: A Loss of Function and Mass

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