Type 1 Diabetes: Etiology, Immunology, and Therapeutic Strategies

Center for Type 1 Diabetes Research, La Jolla Institute for Allergy and Immunology, La Jolla, California 92037, USA.
Physiological Reviews (Impact Factor: 27.32). 01/2011; 91(1):79-118. DOI: 10.1152/physrev.00003.2010
Source: PubMed

ABSTRACT Type 1 diabetes (T1D) is a chronic autoimmune disease in which destruction or damaging of the beta-cells in the islets of Langerhans results in insulin deficiency and hyperglycemia. We only know for sure that autoimmunity is the predominant effector mechanism of T1D, but may not be its primary cause. T1D precipitates in genetically susceptible individuals, very likely as a result of an environmental trigger. Current genetic data point towards the following genes as susceptibility genes: HLA, insulin, PTPN22, IL2Ra, and CTLA4. Epidemiological and other studies suggest a triggering role for enteroviruses, while other microorganisms might provide protection. Efficacious prevention of T1D will require detection of the earliest events in the process. So far, autoantibodies are most widely used as serum biomarker, but T-cell readouts and metabolome studies might strengthen and bring forward diagnosis. Current preventive clinical trials mostly focus on environmental triggers. Therapeutic trials test the efficacy of antigen-specific and antigen-nonspecific immune interventions, but also include restoration of the affected beta-cell mass by islet transplantation, neogenesis and regeneration, and combinations thereof. In this comprehensive review, we explain the genetic, environmental, and immunological data underlying the prevention and intervention strategies to constrain T1D.

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    • "Over time, pancreatic b-cells fail to compensate for the increased insulin demand due to loss of key b-cell functions such as glucose-stimulated insulin secretion (GSIS), in concert with a gradual depletion of b-cell mass [2]. In contrast, T1D, which often manifests during childhood, is a result of selective autoimmune destruction of the pancreatic b-cells, leading to insulin deficiency [3]. The mechanisms linking glucose metabolism and insulin secretion in the b-cell are still incompletely understood, as are the mechanisms of b-cell dysfunction and death. "
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    ABSTRACT: Metabolomics, the characterization of the set of small molecules in a biological system, is advancing research in multiple areas of islet biology. Measuring a breadth of metabolites simultaneously provides a broad perspective on metabolic changes as the islets respond dynamically to glucose or environmental stressors. As a result, metabolomics has the potential to provide new mechanistic insights into islet physiology and pathophysiology. Here we summarize advances in our understanding of islet physiology and the etiologies of type-1 and type-2 diabetes derived from metabolomics studies. Copyright © 2015. Published by Elsevier Inc.
    Archives of Biochemistry and Biophysics 06/2015; DOI:10.1016/ · 3.02 Impact Factor
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    • "Activation and subsequent proliferation of resting CD4 + T cells are essential processes that are associated with increased release of IL- 2 [4]. On the other hand, cytokines such as IL-4, IL-10 and TGF-␤ are inhibitory and may mediate the suppressive effect of Treg [2] [5]. "
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    ABSTRACT: We have recently shown that carbon monoxide releasing molecule (CORM)-A1 prevents type 1 diabetes induced in C57BL/6 mice with multiple low doses of streptozotocin (MLDS) by shifting the Th1/Th17/M1 balance towards a Th2/M2 response. In the present work we tested the hypothesis that CORM-A1 might influence regulatory arm of the immune response, as well as beta cell regeneration. CORM-A1 (2mg/kg/day) was administered for 10 days to mice induced with MLDS and/or depleted of low dose cyclophosphamide (CY)-sensitive FoxP3(+) T regulatory (Treg) cells. Besides monitoring hyperglycaemia, ex vivo analysis of spleen, pancreatic lymph nodes (PLN) and pancreas was performed at the end of treatment. In CORM-A1-treated MLDS-induced mice the improvement of hyperglycaemia was observed only without depletion of CY-sensitive FoxP3(+) Treg cells. This was accompanied by decreased levels of interleukin (IL)-12, IL-2 and early activation marker CD25 in the spleen and PLN and increased transforming growth factor (TGF)-β, resulting in reduced lymphocyte proliferation in both organs. In parallel, decreased transcript levels of IL-2, but increased mRNA expression of TGF-β, accompanied with up-regulation of Ki-67 protein expression was observed within pancreas. Together, the data suggested that besides the immunomodulatory potential, CORM-A1 probably induces beta cell regeneration. Copyright © 2015. Published by Elsevier B.V.
    Immunology letters 03/2015; 165(1). DOI:10.1016/j.imlet.2015.03.009 · 2.51 Impact Factor
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    • "In recent years, prevalence has not only risen, but T1D became increasingly diagnosed at younger ages [2]. In type 1 or insulin-dependent diabetes mellitus (IDDM), the pancreatic islets and, specifically, the islet beta-cells become the target of an autoimmune response which destroys their insulin-producing capacity [3]. Human enterovirus (HEV) infections have long been suspected as environmental triggers of human T1D [4]. "
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    ABSTRACT: Inflammatory mechanisms play a key role in the pathogenesis of type 1 and type 2 diabetes. IL6, a pleiotropic cytokine with impact on immune and non-immune cell types, has been proposed to be involved in the events causing both forms of diabetes and to play a key role in experimental insulin-dependent diabetes development. The aim of this study was to investigate how beta-cell specific overexpression of IL-6 influences diabetes development. We developed two lines of rat insulin promoter (RIP)-lymphocytic choriomeningitis virus (LCMV) mice that also co-express IL6 in their beta-cells. Expression of the viral nucleoprotein (NP), which has a predominantly intracellular localization, together with IL6 led to hyperglycemia, which was associated with a loss of GLUT-2 expression in the pancreatic beta-cells and infiltration of CD11b+ cells, but not T cells, in the pancreas. In contrast, overexpression of the LCMV glycoprotein (GP), which can localize to the surface, with IL-6 did not lead to spontaneous diabetes, but accelerated virus-induced diabetes by increasing autoantigen-specific CD8+ T cell responses and reducing the regulatory T cell fraction, leading to increased pancreatic infiltration by CD4+ and CD8+ T cells as well as CD11b+ and CD11c+ cells. The production of IL-6 in beta-cells acts prodiabetic, underscoring the potential benefit of targeting IL6 in diabetes.
    Journal of Autoimmunity 12/2014; 55(1). DOI:10.1016/j.jaut.2014.02.002 · 8.41 Impact Factor
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