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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #158: Immunopathogenesis of Type 1 Diabetes in Western Society Part 1

Jan 1, 2019
 

Introduction

Type 1 diabetes (T1DM), formerly referred to as insulin dependent diabetes mellitus (IDDM) and juvenile diabetes, is considered a chronic autoimmune disease. Over time, the disease process results in the virtually complete elimination of pancreatic β cells and lifelong insulin deficiency. In turn, patients become dependent on daily insulin injections to maintain an acceptable level of metabolic control. It is widely accepted that T1DM is a complex, multifactorial disease in which genetic predisposition and environmental exposures promote the triggering of multiple autoimmune responses against β cells.

 

While a variety of putative environmental factors have been described [1], including infectious agents, dietary and other factors, true etiologic/triggering environmental agents and causal mechanisms remain to be identified. On the other hand, several susceptibility loci have been identified, and many mapped to known genes with predominant function or effects on immune mechanisms, largely supporting a dominant role for an immune-mediated pathogenesis. This is corroborated by the presence of both humoral and cellular autoimmune responses against several islet cell autoantigens near the time of diagnosis. Moreover, in prospective studies, similar responses are observed in nondiabetic first-degree relatives preceding disease development. The most extensively studied autoantigens include insulin/proinsulin, glutamic acid decarboxylase (GAD65), the tyrosine phosphatase-like protein IA-2, the islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP), and the cation efflux transporter ZnT8 [2]. Standardized radio-immunoassays measure autoantibodies to insulin, GAD65, IA-2, and ZnT8, which are diagnostic and predictive markers employed as screening tools in natural history studies and prevention trials [3].

The disease commonly develops in children or adolescents, with incidence peaking around 10–14 years of age [4]. Prospective studies in genetically at-risk cohorts demonstrate that islet autoimmunity can be triggered during early childhood [5]. However, T1DM is also diagnosed in adults [4]. Some adult patients with milder presentation are diagnosed with latent onset diabetes of the adult (LADA); it has been proposed that 442 LADA may fundamentally be a clinical expression of T1DM characterized by later triggering and/or slower progression [6], perhaps occurring in individuals with attenuated genetic susceptibility [7]. The disease incidence and prevalence vary in children from different countries and populations within an approximate 350-fold spread [4]. The lowest incidence rates (0.1–1/100,000) are reported in Asian populations (China, Japan) and some South American countries. The highest incidence rates, ranging from 5 to 60/100,000, are reported in Caucasian populations of the Western world [8]. Northern European countries such as Finland and Sweden have very high incidence and prevalence, but a similarly high incidence is reported in Sardinia, an island in the Mediterranean Sea [9]. During the past few decades the worldwide disease incidence has been rising 2–5% annually, albeit not uniformly in various countries and throughout time periods [8]. Moreover, many studies indicate that T1DM is becoming more common in younger children (<5 years old) [4,8,10]. The prevalence of T1DM in the United States, where the population comprises multiple racial and ethnic groups, is approximately 1/300 by age 18; data from the SEARCH study indicate that incidence and prevalence rates are higher (roughly by 30–50%, depending on ethnic and age groups compared) in non-Hispanic whites (>20/100,000 in youth less than 20 years old) compared to Hispanic, African Americans, and American Indians [4].

Overall, epidemiologic data show that T1DM is more prevalent in the Western world, especially affecting, albeit not exclusively, Caucasians of Northern European descent. This chapter focuses on reviewing recent and major findings about the disease pathogenesis that are largely originated by studies in patients from the Western society.

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