Genetic, immunological, and metabolic determinants of risk for type 1 diabetes mellitus in families.

Prospective studies of the relatives of people with Type 1 diabetes can provide insights into risk factors for processes leading to the ultimate destruction of the pancreatic islet 8-cells. Relatives ascertained through the Children's Hospital of Pittsburgh diabetes registry were followed and rates of conversion to diabetes were determined. We studied the role of genetic and immunological markers, and used the oral glucose tolerance test (OGTT) to study metabolic disturbances among first-degree relatives. A group of siblings was serotyped for the HLA-A and -B antigens, and the degree of HLA haplotype sharing with the diabetic sibling was established. Later, islet cell antibody (ICA) assays were performed, and subjects were followed to determine the predictive value of ICA testing for the subsequent development of diabetes. The rate of conversion to diabetes among the siblings was 14 times greater than the rate observed in the general population from which they come. This is comparable to rates observed by other centres following relatives of people with Type 1 diabetes. Impaired glucose tolerance (by National Diabetes Data Group (USA) criteria) carried a three-fold greater risk for subsequent Type 1 diabetes than did a normal OGTT. Those relatives with detectable ICA were about 50 times more likely to convert to diabetes than were those without ICA. In a group of siblings in whom HLA haplotype sharing was determined, the prevalence of detectable ICA was greater among those who were HLA-identical to the diabetic sibling (9.9 %) than among those who were haplo-identical (5.3 %) or completely dissimilar (2.4 %) at the HLA-A and -B regions. Similarly, the incidence of Type 1 diabetes was greater among those who were HLA-identical (8.4 per 103 sibling-years), than among those who were not HLA-identical to the proband (4.2 per 103). The greatest risk for subsequent diabetes was found among HLA-identical siblings who were ICA-positive. Approximately 7 % of those who were HLA non-identical or haplo-identical and ICA-positive became diabetic within 5 years, while more than 30 % of HLA-identical siblings who were ICA-positive became diabetic during the 5 years after ICA were detected.