The etiology of diabetes mellitus, like other disorders, is complex and not fully understood. Progress is being made in understanding the genetic basis of this disorder, which is a leading cause of blindness, heart disease, and kidney failure.
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Diabetes is a heterogeneous group of disorders, all characterized by elevated blood glucose level. The focus here is on the two major types of diabetes:
Type 1 (insulin-dependent diabetes mellitus [IDDM])
Type 2 (non–insulin-dependent diabetes mellitus [NIDDM])
Type 1 (insulin-dependent diabetes mellitus [IDDM]):
Is characterized by T-cell infiltration of the pancreas and destruction of the insulin-producing beta cells, usually (although not always) presents before age 40
Individuals must receive exogenous insulin to survive
In addition to T-cell infiltration of the pancreas form autoantibodies against pancreatic cells
The latter are observed long before clinical symptoms occur.
These findings, along with a strong association between type 1 diabetes and the presence of several major histocompatibility complex (MHC) class II alleles, indicate that this is an autoimmune disease. Over the past few decades, the incidence of type 1 diabetes has increased substantially.
Siblings of individuals with type 1 diabetes face a substantial elevation in risk.
6%, as opposed to a risk of approximately 0.3% to 0.5% in the general population.
The recurrence risk is also elevated when there is a diabetic parent, although this risk varies with the sex of the affected parent.
The risk for offspring of diabetic mothers is only 1% to 3%, whereas it is 4% to 6% for the offspring of diabetic fathers (because type 1 diabetes affects males and females in approximately equal proportions in the general population, this risk difference is inconsistent with the sex-specific threshold model for multifactorial traits).
Empirical risks for identical twins of people with type 1 diabetes range from 30% to 70%.
In contrast, the concordance rates for DZ twins are 5% to 10%.
The fact that type 1 diabetes is not 100% concordant among identical twins indicates that genetic factors are not solely responsible for the disorder.
There is good evidence that specific viral infections contribute to the causation of type 1 diabetes in at least some individuals, possibly by activating an autoimmune response.
The table lists the genes that cause type 1 diabetes.
Genes
Description
Alleles
In association of specific MHC class II alleles and type 1 diabetes, it is estimated that these alleles account for approximately 40% of the familial clustering of type 1 diabetes.
95% of Whites with type 1 diabetes have the human leukocyte antigen (HLA) (part of the MHC), DR3, and/or DR4 alleles, whereas only approximately 50% of the general White population has either of these alleles.
If an affected proband and a sibling are heterozygous for the DR3 and DR4 alleles, the sibling’s risk of developing type 1 diabetes is nearly 20% (i.e., approximately 40 times higher than the risk in the general population).
Along with the presence of aspartic acid at position 57 of the HLA DQ chain is strongly associated with resistance to type 1 diabetes.
Those who do not have this amino acid at position 57 (and instead are homozygous for a different amino acid) are 100 times more likely to develop type 1 diabetes.
The aspartic acid substitution alters the shape of the HLA class II molecule and thus its ability to bind and present peptides to T cells.
Altered T-cell recognition helps protect individuals with the aspartic acid substitution from an autoimmune episode.
Insulin gene
It is located on the short arm of chromosome 11, is another logical candidate for type 1 diabetes susceptibility.
Polymorphisms within and near this gene are tested for association with type 1 diabetes.
It is estimated that inherited genetic variation in the insulin region accounts for approximately 10% of the familial clustering of type 1 diabetes.
Others
More than 50 additional genes have been shown to be associated with susceptibility to type 1 diabetes.
Cytotoxic T-lymphocyte associated antigen 4 (CTLA4): encodes a protein involved in the regulation of T-cell proliferation.
PTPN22 : encodes a lymphoid-specific tyrosine phosphatase that negatively regulates T-cell activation.
Variation in the latter gene has been associated with several other autoimmune diseases, including:
Systemic lupus erythematosus (SLE)
Rheumatoid arthritis
Autoimmune thyroid disease
