Insulin as a key autoantigen in the development of type 1 diabetes
ABSTRACT Type 1 diabetes is a T-cell-mediated autoimmune disease against pancreatic beta cells. T cells target various antigens such as insulin, chromogranin A, glutamic acid decarboxylase and islet-specific glucose-6-phosphatase catalytic subunit-related protein. Elimination of insulin dramatically prevents diabetes in the non-obese diabetic (NOD) mouse model and response to insulin occurs prior to that to other antigens. These findings suggest that insulin is a target antigen at the early stage of the disease and is likely to be essential to cause anti-islet autoimmunity in NOD mice. In this review, we discuss whether insulin is truly essential and is only the single essential autoantigen for NOD mice and potentially for man. Although the ultimate principle is still being addressed, it is certain that T-cell response to insulin is a major check point to develop type 1 diabetes in NOD mice. Given multiple similarities between diabetes of NOD mice and man, targeting insulin and insulin-reactive T cells may provide opportunities to develop robust immunotherapies.
SourceAvailable from: Maria Dalamaga[Show abstract] [Hide abstract]
ABSTRACT: Leptin is an adipocyte-secreted hormone that has been proposed to regulate energy homeostasis as well as metabolic, reproductive, neuroendocrine, and immune functions. In the context of open-label uncontrolled studies, leptin administration has demonstrated insulin-sensitizing effects in patients with congenital lipodystrophy associated with relative leptin deficiency. Leptin administration has also been shown to decrease central fat mass and improve insulin sensitivity and fasting insulin and glucose levels in HIV-infected patients with highly active antiretroviral therapy (HAART)-induced lipodystrophy, insulin resistance, and leptin deficiency. On the contrary, the effects of leptin treatment in leptin-replete or hyperleptinemic obese individuals with glucose intolerance and diabetes mellitus have been minimal or null, presumably due to leptin tolerance or resistance that impairs leptin action. Similarly, experimental evidence suggests a null or a possibly adverse role of leptin treatment in nonlipodystrophic patients with nonalcoholic fatty liver disease. In this review, we present a description of leptin biology and signaling; we summarize leptin's contribution to glucose metabolism in animals and humans in vitro, ex vivo, and in vivo; and we provide insights into the emerging clinical applications and therapeutic uses of leptin in humans with lipodystrophy and/or diabetes.Endocrine reviews 03/2013; 34(3). DOI:10.1210/er.2012-1053 · 19.36 Impact Factor
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ABSTRACT: The earliest events leading to autoimmune type 1 diabetes (T1D) are not known in any species. A T-cell receptor variable region, TCR-Vβ13, is required for susceptibility to autoimmune diabetes in rats, and selective depletion of Vβ13(+) T-cells with an allele-specific monoclonal antibody prevents disease in multiple rat strains. To investigate the role of Vβ13 early in diabetes, we examined islet T-cell transcripts in susceptible (LEW.1WR1) and resistant (LEW.1W and WF) strains induced with polyinosinic:polycytidylic acid (poly I:C). Vβ13(+) T-cells displayed antigenic focusing in LEW.1WR1 islets five days post-induction and were characterized by a substantial decrease in CDR3 diversity. This occurred prior to significant islet T-cell accumulation (day 7) or frank diabetes (day 10-14). Vβ13(+) transcripts increased in LEW.1WR1 islets during diabetes progression but not in resistant rats. We also analyzed transcript clonality of rat TCR-Vα5, ortholog of the dominant TCR-Vα chain found on insulin B:9-23-reactive T-cells in NOD islets. We observe clonal expansion of Vα5(+) transcripts in pre-diabetic LEW.1WR1 islets, suggesting that rat Vα5 is also an important component of islet autoantigen recognition. These data provide additional evidence that genome-encoded TCR sequences are important determinants of genetic susceptibility to T1D.Diabetes 10/2013; 63(2). DOI:10.2337/db13-0462 · 8.47 Impact Factor
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ABSTRACT: Type 1 diabetes mellitus (T1DM) is characterized by recognition of beta cell proteins as self-antigens, called autoantigens (AAgs), by patients' own CD4+ and CD8+ T cells and/or the products of self-reactive B cells, called autoantibodies. These AAgs are divided into two categories on the basis of beta-cell-specificity. The list of the targets associated with beta cell-specific AAgs is continuously growing. Many T1DM-associated AAgs are well characterized and have important clinical applications for disease prediction, diagnosis, and antigen-specific tolerance immunotherapy. Identification of T1DM-associated AAgs provides insight into the pathogenesis of T1DM and to understanding the clinical aspects of the disease. Since many excellent reviews have covered the previously identified T1DM-associated AAgs exhaustedly, here we only focus on several recently discovered T1DM-AAgs (PDX1, ZnT8, CHGA, and IAAP).American Journal of Translational Research 01/2013; 5(4):379-92. · 3.23 Impact Factor