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.
| MHC Class (Chromosome Location) | HLA Type | Relative Risk or Odds Ratio | Frequency of Risk Allele | Putative Functional Significance | Associated Disease Phenotype |
|---|---|---|---|---|---|
| Class I (6p21.3) | HLA-A8 | RR 2.12 | Interaction with TCR and KIR | ||
| HLA-A W15 | RR >1.5 | Interaction with TCR and KIR | |||
| HLA-B*39 | RR>1.5 | Interaction with TCR and KIR | |||
| Class II (6p21.1) | HLA-DR3 (B8) | Risk increased (OR ~6.8) | 15% nondiabetic population | Presentation of antigens to CD4+ cells | Increased association with autoantibodies, especially GADA |
| HLA-DR4 (B15) | Risk increased (OR ~6.8) Fathers with DR4 are more likely to transmit DR4 to their offspring than are mothers with DR4. Patients with both B8 and B15 antigens have greatly increased risk (synergistic effect on IDDM predisposition) | 22% nondiabetic population; 43% diabetic population; DR3/DR4 occurs in 35% diabetic population | Presentation of antigens to CD4+ cells. Associated with insulin-reactive clonally expanded T cells | Increased association with autoantibodies, especially GADA. Shows antibody response to exogenous insulin | |
| HLA-DRB1*04 | Risk increased | Presentation of antigens to CD4+ cells | Associated with insulin and IA-2 autoantibodies | ||
| HLA-DQA1*0301 | Risk increased | Presentation of antigens to CD4+ cells | Associated with insulin and IA-2 autoantibodies | ||
| HLA-DQB1*0302 | Risk increased (OR ~6.8) | Presentation of antigens to CD4+ cells | Associated with insulin and IA-2 autoantibodies | ||
| HLA-DQw8 | Risk increased | Presentation of antigens to CD4+ cells | Associated with autoantibodies, especially GADA | ||
| HLA-DQw1.2 | Risk decreased (RR is 0.37 for DQw1.2/DQw8, indicating dominant protective effect of DQw1.2) | 2.3% of diabetic population; 36.7% of nondiabetic population | Presentation of antigens to CD4+ cells | ||
| HLA-DQA1*0102-DQB1*0602 | Risk decreased | Presentation of antigens to CD4+ cells | Protective effect may occur after disease process has started (association with + antibodies in absence of clinical disease) | ||
| HLA-DR2 | Risk decreased | Presentation of antigens to CD4+ cells | |||
| MICA: MHC class I chain-related gene A (6p21.3) | MICA5 | Increased risk for T1DM diagnosis age <25 | Binds NKG2D and stimulates NK and T-cell effect or functions | Early age of onset. | |
| MICA5.1 | Increased risk for T1DM only for diagnosis at age >25, and in combination with high-risk MHC class II haplotypes | Binds NKG2D and stimulates NK and T-cell effect or functions | Late age of onset (also confers risk for LADA) |
| Candidate Gene (Chromosome Location) | Associated Variant (DB SNP) | Odds Ratio | Putative Functional Significance |
|---|---|---|---|
| PTPN22 (1p13.2) | rs2476601 | OR 2.05 | Lymphoid protein tyrosine phosphatase, nonreceptor type 22. LYP downregulates signaling from T-cell receptor, the mutation enhances function leading to increased T-cell suppression. |
| BACH2 (6q15) | rs11755527 | OR 1.13 | Basic leucine zipper transcription factor 2 |
| TNFAIP3 (6q23.3) | rs6920220 | OR 1.09 | Tumor necrosis factor, alpha-induced protein 3 |
| rs10499194 | OR 0.90 | ||
| PTPN2 (18p11.21) | rs45450798 | OR 1.28 | Protein tyrosine phosphatase, nonreceptor type 2 |
| rs478582 | OR 0.83 | ||
| CD226 (18q22.2) | rs763361 | OR 1.16 | CD226 molecule |
| TAGAP (6q25.3) | rs1738074 | T-cell activation GTPase-activating protein (coregulated with IL-2) | |
| SH2B3 (12q24) | rs3184504 | Lymphocyte adaptor protein | |
| KIAA0350 (16p13) | rs2903692 | Predicted to encode a sugar-binding C-type lectin | |
| rs725613 | |||
| rs17673553 | |||
| ERBB3 (12q13.2) | rs2292239 | OR 1.31 | Tyrosine kinase type cell-surface receptor, HER3 |
Diagnostic Criteria and Clinical Characteristics
Fasting plasma glucose greater than or equal to 126 mg/dL (6.7 mmol/L) plus symptoms or on greater than one occasion
Random plasma glucose greater than or equal to 200 mg/dL (11.1 mmol/L) plus symptoms
75 g oral glucose tolerance test leading to 2-hour plasma glucose greater than or equal to 200 mg/dL
As of January 2010, the use of glycosylated hemoglobin (HbA1c) criteria for the diagnosis of DM has been accepted by the American Diabetes Association. In addition to the established criteria earlier, these guidelines allow for HbA1c greater than or equal to 6.5% to be considered diagnostic of diabetes, with HbA1c 5.7% to 6.4% classified as prediabetes. In the case of T1DM, the International Expert Committee recommendations on which these guidelines were based specified that HbA1c should be used only in the absence of classic clinical symptoms.
Unlike T2DM, T1DM frequently presents with ketoacidosis. Therefore, a young lean patient presenting with clear ketoacidosis can receive a diagnosis of T1DM without further confirmatory testing. The overweight patient warrants further investigation given the increasing incidence of T2DM in childhood.
Diagnostic evaluation for T1DM should include
Insulin or C-peptide less than 5 μU/mL, or 0.6 ng/mL is suggestive of T1DM. Note that a patient with T2DM in a high glucose state may temporarily have low C-peptide, but insulin secretion function should recover following the acute episode.
Glutamic acid decarboxylase (GAD) antibodies—titers are high in T1DM.
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