Diabetes is the name given to a collection of diseases that have elevations in blood glucose levels in common. Population studies have defined cutoff levels of glycemia that are eventually associated with increased microvascular disease such as retinopathy. Two replicate fasting levels that exceed 126 mg/dl (>7 mM) are diagnostic in the absence of symptoms. Persons with fasting levels between 110 and 126 mg/dl are at risk of diabetes (impaired fasting glycemia). Replicate, 2-h glycemic responses >200 mg/dl (>11.1 mM) after a standard oral glucose tolerance test indicates diabetes also. This stage is often reached, however, before the fasting glucose levels are seen to rise. Type 1 diabetes comprises those forms of diabetes that are primarily due to insulin deficiency, however a relative insulin deficiency also is part of type 2 diabetes, which is however less severe, though it is compounded by degrees of insulin resistance, often associated with obesity. Long-term type 2 diabetes is complicated by glucose (glucosamine) toxicity, which decreases the patients' abilities to secrete insulin further, leading to diagnostic confusion with type 1 diabetes. Whereas type 2 diabetes is usually strongly familial, type 1 is much less so, having only one member of the family so affected in 90 percent of cases.
The immune-mediated form of type 1 diabetes (IMD) is most common amongst Caucasian races and is presumed present when autoantibodies to islet cells and/or to insulin and/or to defined islet proteins are detected in the presence of diabetes. However, an insulin-deficient type of diabetes in the presence of the risk HLA phenotypes is presumptive evidence. Adult onset IMD is characterized by a gradual decline in insulin secretion compared to children, a situation readily confused with type 2 diabetes unless autoantibodies to islet cell cytoplasm (ICA) and/or to glutamic acid decarboxylase (GAD65) can be detected.
The pathogenesis of IMD involves multiple genetic lesions affecting immunoregulation against self, coupled to strong influences from the environment affecting penetrance. Studies from rodent models of the disease suggest that there is a gene dose effect of quantitative trait loci, with accumulating numbers of susceptibility genes compounding the risk. There are protective genes also. The obligate genes, however, are those encoding DR and DQ A plus B chain heterodimers. Both loci are involved in human patients. The nonobese diabetic (NOD) mouse expresses no IE (DR homologous) molecules but only a unique recombinant b/d haplotype IA molecule (DQ homologous). This IAg7 is a poor antigen binder, and thus may allow leakage of autoreactive T cells from the thymus into the peripheral blood. This could account for the increased propensity to develop multiple organ-specific autoimmune diseases comprising the type 2 autoimmune polyglandular syndrome of which IMD is a part. The others include Addison disease, thyroid autoimmune disease especially Hashimoto, atrophic gastritis/pernicious anemia, vitiligo, and celiac disease. Further, poor expression of islet cell antigens by the thymus may similarly lead to defective eradication of potentially autoimmune-provoking CD4+ T cells. Similarly, some studies ...