Pathophysiology of Immune-Mediated (Type 1) Diabetes Mellitus
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BioDrugs 2001; 15 (5): 291-301 1173-8804/01/0005-0291/$22.00/0 © Adis International Limited. All rights reserved.
Pathophysiology of Immune-Mediated (Type 1) Diabetes Mellitus Potential for Immunotherapy Michal Abel and Marcin Krokowski Institute of Paediatrics, Medical University of Lodz, Lodz, Poland
Abstract
Type 1 diabetes mellitus is a chronic T cell-mediated disease resulting from autoimmune destruction of pancreatic β-cells. This process leads to progressive and irreversible failure of insulin secretion. Development of the disease involves both genetic and environmental factors. Genetic predisposition is mainly connected with the human leucocyte antigen (HLA) region, which encodes structures responsible for antigen presentation. A comprehensive molecular understanding of the pathogenesis of the disease is essential for the design of rational and well tolerated means of prevention. This paper describes recent experimental and clinical findings and elucidates the current possibilities for immunotherapy of type 1 diabetes. The nature of breakdown of self-tolerance and the mechanisms involved in its recovery are discussed.
1. Epidemiology Type 1 diabetes mellitus is one of the most frequently occurring chronic diseases in puberty. The disease occurs more frequently among Caucasians than in other ethnic groups. The incidence of type 1 diabetes ranges from the highest in Finland (>40 per 100 000 person years)[1,2] and Sardinia (>30 per 100 000 person years)[3,4] to the lowest in Korea (0.7 per 100 000 person years),[5] Japan and China.[4,6,7] These differences in incidence could be due to a combination of genetic and environmental factors specific for racially distinct populations. 2. Natural History of the Disease Type 1 diabetes results from selective autoimmune destruction of pancreatic β-cells. The natural course of type 1 diabetes can be demonstrated to be a progressive decline in endogenous insulin secretion. This process involves both genetic and
environmental factors and leads to total insulin deficiency. The loss of immunological tolerance to pancreatic β-cells initiates constant, successive destruction of insulin-producing cells. Initially, the decline in insulin secretion capacity occurs without any noticeable symptoms.[8] The first sign of the pathological process is the presence of a specific humoral response. [9] The detection of islet cell antibodies (ICA), glutamic acid decarboxylase antibodies (GADA), anti-tyrosine phosphatase antibodies (IA-2) and anti-endogenous insulin antibodies (IAA) makes the diagnosis of autoimmune type 1 diabetes possible at its preclinical phase.[10,11] Further β-cell destruction results in an impaired insulin response to an intravenous glucose tolerance test (IVGTT).[12] An IVGTT is usually recommended when ICA >40 Juvenile Diabetes Foundation (JDF) units, and/or GADA with IA-2 or IAA, are present.[11] Decreased first-phase insulin release is the sign of significant β-cell dysfunction.[13]
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Postprandial hyperglycaemia and increased fasting blood glucose are ev
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