185 research outputs found

    Inflammatory mediators and islet β-cell failure: a link between type 1 and type 2 diabetes

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    Pancreatic islet β-cell death occurs in type 1 and 2 diabetes mellitus, leading to absolute or relative insulin deficiency. β-cell death in type 1 diabetes is due predominantly to autoimmunity. In type 2 diabetes β-cell death occurs as the combined consequence of increased circulating glucose and saturated fatty acids together with adipocyte secreted factors and chronic activation of the innate immune system. In both diabetes types intra-islet inflammatory mediators seem to trigger a final common pathway leading to β-cell apoptosis. Therefore anti-inflammatory therapeutic approaches designed to block β-cell apoptosis could be a significant new development in type 1 and 2 diabete

    Autoimmune-Mediated Beta-Cell Death & Dysfunction: Potential Role of Signaling through the Fas Receptor

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    Type 1 diabetes mellitus (T1DM) is an endocrine disorder that continues to afflict a growing proportion of the U.S. population. Characterized by an autoimmune attack on the pancreatic [beta] cells that leads to their destruction, T1DM develops from absolute insulin deficiency resulting in chronic hyperglycemia. Although the disease requires lifelong insulin therapy and confers enhanced risk for long-term complications, the mechanism of [beta] cell death remains unclear. Fas receptor signaling is critical among cells of hematopoietic origin for its role in immune homeostasis and mediation of target cell death. Fas receptor-ligand interactions might also have a role in [beta] cell death leading to the development of T1DM; pro-inflammatory cytokines released from islet leukocytes can induce Fas receptor to the [beta] cell surface, and systemic loss-of-function mutations in Fas receptor and Fas ligand (FasL) abrogate disease in spontaneous diabetes-prone mice. However, systemic deficiency in Fas and FasL causes an alteration in the T cell repertoire that prevents diabetes, and thus cannot be attributed to absence of Fas [beta] cell signaling. Moreover, the use of distinct Fas mutations and transgenic models that produce dissimilar mechanisms of [beta] cell death leads to conflicting results reported in the scientific literature. Recent evidence using transgenic mouse models of diabetes has indicated a role for Fas in the insulitic phase but not the effector phase of [beta] cell death, while other studies have suggested that alteration of the T cell repertoire by Fas signaling is a causal factor in the autoimmune [beta] cell attack. Furthermore, ectopically-expressed FasL is a potential therapeutic tool for protection of islet transplants by its known ability to provide immune privilege in some tissues. This literature review collectively presents the diverse roles for Fas signaling in [beta] cell death and provides insight into why conflicting conclusions regarding Fas signaling currently exist. Thus, the goal of this literature review is to enable investigators interested in Fas-mediated signaling in the pancreatic [beta] cell to choose an appropriate model system for study design that ideally will translate to therapeutic interventions for T1DM

    The role of mig6 in pancreas development and diabetes

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    Indiana University-Purdue University Indianapolis (IUPUI)Diabetes occurs as a result of the failure of pancreatic insulin-producing β cells. The preservation or renewal of β cells is a strategy that can prevent diabetes by targeted manipulation of mechanisms associated with autoimmune β cell destruction or β cell regeneration. ErbB signaling, specifically epidermal growth factor receptor (EGFR) signaling, is associated with cell survival, growth, and proliferation. Thus, we investigated the role of the ErbB inhibitor, mitogen-inducible gene 6 (mig6), in pancreas development and in the progression to diabetes. Using morpholino knockdown in a zebrafish model of development, we discovered that mig6 is required for the generation of α and β cells as well as the formation of the exocrine pancreas. We suspect that the loss of mig6 function causes premature differentiation of ductal progenitor cells, and acts as a switch between progenitor differentiation and endocrine transdifferentiation. Furthermore, we established a pancreas-specific mig6 knockout mouse that maintained glucose tolerance and had a higher β cell mass after chemically-induced β cell injury by way of increased β cell proliferation. Our data suggests that mig6 is required during pancreas development and may be employed as a switch to direct the production of new β cells, but that during adulthood, it is detrimental to the recovery of β cell mass, making it a therapeutic target for β cell preservation after the onset of diabetes

    Fatal Attraction: Interactions between antigen-presenting cells and islets of Langerhans in the pathogenesis of autoimmune diabetes

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    The onset of diabetes mellitus is characterized by various symptoms, all the result of a disturbed glucose metabolism. The main symptoms are thirst and an excessive production of urine. The disturbed glucose metabolism underlying these symptoms is due to an absolute deficiency of insulin secretion (type 1 diabetes mellitus), a reduction in its biological effectiveness (type 2 diabetes mellitus) or a combination of these factors. Type 1 diabetes mellitus is predominantly manifesting in children, and needs to be treated by life-long exogenous insulin administration to prevent high blood glucose levels. Type 2 diabetes mellitus occurs classically in adults, and is relatively milder in its appearance; usually, exogenous insulin administration is not required. This thesis concerns type 1 (ins
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