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Key Points

  • Disease summary:

    • Diabetes mellitus type 1 (T1DM) is a disorder of insulin secretion which can be subdivided into type 1A (immune mediated) and type 1B (nonimmune mediated).

    • The vast majority of T1DM is type 1A, characterized by both acute and chronic sequelae of hyperglycemia.

    • T1DM has a peak age of onset before the age of 20 years and is the commonest form of diabetes seen in children in the United States.

    • Because insulin production is impaired, T1DM is characterized by an absolute requirement for exogenous insulin and, unlike type 2 diabetes (T2DM), frequently presents as a medical emergency with hyperglycemia, dehydration, and ketoacidosis.

  • Differential diagnosis:

    • Neonatal diabetes, T2DM, maturity-onset diabetes of the young (MODY)

  • Monogenic forms:

    • While there is no monogenic form of DM type 1A, there is a monogenic autosomal recessive form of type 1B. This ketosis-prone DM (KPDM) is caused by mutations in the PAX4 gene. Clinically distinct from type 1A, KPDM is characterized by an intermittent absolute requirement for insulin.

  • Family history:

    • Risk of T1DM in the general population is 0.5%, while, the presence of an affected sibling is associated with a disease risk of 6% to 10%. The risk associated with an affected parent varies with gender. Offspring of an affected father have a risk of 6%, while offspring of an affected mother have a risk of only 2%.

  • Twin studies:

    • Monozygotic twins have a concordance rate of 45%, compared with a 25% concordance rate for dizygotic twins.

  • Environmental factors:

    • Unlike T2DM, lifestyle factors of diet and exercise are not implicated in the development of autoimmune T1DM; however, some associations have been noted between obesity and the development of T1DM. Past studies have suggested exposure to cow’s milk, and certain viral illnesses (Coxsackie B, rubella, and mumps), may increase the risk of T1DM in some patients. Recent cohort analysis examining the effects of early exposure to cow’s milk calls this long-standing theory into question.

  • Genome-wide associations:

    • While much of the genetic susceptibility to T1DM is attributable to the human leukocyte antigen (HLA) region, many other associations exist. Please see Table 54-1 and Table 54-2 for review of candidate genes and loci.

  • Pharmacogenomics:

    • At this time, no pharmacogenetic testing has been established in guiding treatment of T1DM. Mechanisms elucidated by candidate genes and phenotype-modifying alleles may drive future research into possible pharmacogenomic applications.

Table 54-1Type 1 Diabetes Association With HLA Typing

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