Diabetes is a heterogeneous group of diseases with the common feature of hyperglycemia, however, resulting from combinations of defects in at least 40 genes and a variety of environmental agents. T1aD is caused by lack of insulin due to autoimmune destruction of the pancreatic islet beta-cells. The immune system fails to maintain tolerance to beta-cell autoantigens, often in the setting of the HLA-DRB1*03, DQB1*0201, DRB1*04, DQB1*0302, and/or the HLA-DRB1*0901, DQB1*0303 haplotypes. Chronic inflammation in the islets leads, usually after years, and rarely in just months or days, to insulin-dependent diabetes. T1aD is defined by the presence of autoantibodies to the beta-cell antigens detected before, at or after clinical diagnosis: autoantibodies to insulin (IAA), the tyrosine phosphatase insulinoma antigen (IA-2A), glutamic acid decarboxylase (GADA), and zinc transporter 8 (ZnT8A). One and usually more of these autoantibodies are present in 85% to 95% of newly diagnosed T1aD patients, but this proportion varies depending on patient's age, the number and quality of the assays used, and ethnicity. A small number of T1aD patients may be negative for all islet autoantibodies at diagnosis, despite presence of the autoantibodies prior or after diagnosis (our own observations from the Diabetes Autoimmunity Study in the Young [7
The rate of β-cell destruction is quite variable - rapid in younger children and those with high risk HLA genotypes, especially DRB1*03, DQB1*0201, DRB1*04, DQB1*0302, and slower in adolescents and adults and those with lower-risk HLA genotypes. This may explain a higher proportion of slowly progressing T1D reported in Asian and African populations where a larger proportion of the patients carry neutral or protective HLA-DR, DQ genotypes. In Japan, ~10% of children with diabetes are diagnosed with "slowly progressing T1D." Most are picked on a school-children screening for glucosuria. While their progression to full insulin dependence is slower, 90% have islet autoantibodies or HLA genotypes consistent with classical T1aD (Nan Tajima, personal communication, 2010).
Some patients, particularly children and adolescents, may present with ketoacidosis as the first manifestation of the disease. Others have modest hyperglycemia that can rapidly decompensate in the presence of infection or other stress. Still others, particularly adults, may retain residual β-cell function sufficient to prevent ketoacidosis for many years; such individuals eventually also become dependent on insulin for survival and are at risk for ketoacidosis. At this latter stage of the disease, there is little or no insulin secretion, as manifested by low or undetectable levels of plasma C-peptide. Immune-mediated diabetes commonly occurs in childhood and adolescence, but it can occur at any age, even in the 8th and 9th decades of life. In Western countries, more than half of T1D patients are diagnosed after the age of 20 years.