Type I diabetes is a multifactorial disease which, similar to other au
toimmune conditions, results from an interaction between genetic and e
nvironmental factors. The development of type I diabetes is thought to
be influenced by four different factors: (1) a genetic predisposition
, (2) viral infections, (3) environmental toxins and other factors, an
d (4) autoimmune reactivity. A number of genes have been shown to be a
ssociated with IDDM, however a single critically essential gene has no
t been found. Strong associations exist for the HLA class I alleles Bg
and B15 and for the class II alleles DR3 and DR3. The strongest linka
ge of diabetes risk is found for alleles of the HLA-DQ locus, HLA-Dw3
and Dw4, while HLA-DR2 and -DR5 confer protection from IDDM. The conco
rdance for type I diabetes amongst monozygotic twins is between 25-55
%, which indicates an essential contribution of environmental factors
to the development of IDDM: viral infections are regarded as triggers
of the autoimmune process. A tropism for islet beta-cells is in partic
ular discussed for rubella, coxsackie B6, cytomegalie, mumps and influ
enza viruses. As an example, it has been found that 50 % of children w
ith prenatal rubella virus infection contract IDDM later in life. Toxi
ns and other environmental factors also seem to be involved in the aet
iopathogenesis of IDDM. The role of nitrosamines or nitrophenyl urea h
as not yet been determined. However, the mechanism of the diabetogenic
action of toxins like streptozotocin has been clarified in animal mod
els. Finally, autoimmune phenomena are associated with the development
of overt type I diabetes. On the basis of these immunological finding
s Nerup and coworkers have developed a model of the autoimmune pathoge
nesis of IDDM, which has stimulated many important studies. Presently,
there is a focus on the central role of interleukin 1 in the immunost
imulatory cascade, on the production of antibodies against HL4-DR2 glu
tamic add decarboxylase HLA-DR5 (GAD, 64k antigen) and against I HL4-D
R7 other islet cell and insulin epitopes in the pathogenesis of IDDM.
The further elucidation of these pathogenetic factors will provide new
impulses for the therapy and prevention of IDDM.