DM1 results from the autoimmune destruction of insulin-producing beta cells (islets) of the pancreas. In addition to the presence of diabetes susceptibility genes, an unknown environmental insult presumably triggers the autoimmune process. A variety of studies has produced conflicting data regarding a host of environmental factors. These include cow’s milk feeding at an early age, viral infectious agents (Coxsackie virus, cytomegalovirus, mumps, rubella), vitamin D deficiency, and perinatal factors. DM1 is thought to be primarily a T cell–mediated disease.
Antibodies to islet cell antigens may be seen months to years before the onset of beta cell dysfunction (Fig. 171-1). These include islet cell antibodies, insulin autoantibodies, antibodies to tyrosine phosphatase IA-2, antibodies to glutamic acid decarboxylase, and others. The risk for diabetes increases with the number of antibodies detected in the serum. In individuals with one detectable antibody only, the risk is only 10% to 15%; in individuals with three or more antibodies, the risk is 55% to 90%. When 80% to 90% of the beta cell mass have been destroyed, the remaining beta cell mass is insufficient to maintain euglycemia and clinical manifestations of diabetes result (see Fig. 171-1).
The annual incidence of DM1 is increasing steadily but with significant geographic differences. In the United States, the annual incidence is approximately 20 in 100,000. The annual incidence in children ranges from a high of 40 in 100,000 among Scandinavian populations to less than 1 in 100,000 in China. The prevalence of DM1 in the United States is highest in non-Hispanic whites followed by African Americans, Hispanic, and American Indians.
Genetic determinants play a role in the susceptibility to DM1, although the mode of inheritance is complex and multigenic. Siblings or offspring of patients with diabetes have a risk of 2% to 8% for the development of diabetes; an identical twin has a 30% to 50% risk. The human leukocyte antigen (HLA) region on chromosome 6 provides the strongest determinant of susceptibility, accounting for approximately 40% of familial inheritance of DM1. Specific class II DR and DQ HLA alleles (HLA DR3 and HLA DR4) increase the risk of developing DM1, whereas other specific HLA alleles exert a protective effect. More than 90% of children with DM1 possess HLA DR3 alleles, HLA DR4 alleles, or both. The insulin gene region variable number tandem repeat on chromosome 11 is also linked to DM1 susceptibility. There is evidence for association, beyond HLA, of more than 100 other loci with DM1. Genetic factors do not fully account for susceptibility to DM1; environmental factors also play a role.
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Polyuria Failure to Thrive
Hyperglycemia results when insulin secretory capacity becomesinadequate to enhance peripheral glucose uptake and to suppress hepatic and renal glucose production. Insulin deficiencyusually first causes postprandial hyperglycemia and then fastinghyperglycemia. Ketogenesis is a sign of more complete insulin deficiency. Lack of suppression of gluconeogenesis and glycogenolysis further exacerbates hyperglycemia while fatty acidoxidation generates the ketone bodies: β-hydroxybutyrate, acetoacetate, and acetone. Protein stores in muscle and fat stores in adipose tissue are metabolized to provide substrates for gluconeogenesis and fatty acid oxidation.