[Diabetes mellitus and molecular biology]

There are two approaches to identify diabetes-susceptibility genes. One approach is to isolate and characterize genes expressed in the beta-cell and in insulin target tissues whose mutation or altered expression may contribute to the development of diabetes mellitus. Another approach is to clone a diabetes-susceptibility gene by a reverse genetic strategy. The first step for this strategy is to identify a DNA polymorphism that is linked to the disease locus. Using the strategy of the first approach, several candidate genes were examined. Among these genes, the mutation of insulin genes and insulin receptor genes was found in the patient with diabetes. By cDNA cloning or PCR-direct sequencing methods, we identified several mutations in the insulin receptor genes of four insulin-resistant diabetic patients. At least two mutants of insulin receptor genes were expressed in Chinese hamster ovary cells and these mutated receptors showed impaired ability to transduce insulin action in these cultured cells. The expression of these mutant genes in animals such as transgenic mice will be indispensable to establish the relationship between the gene mutation and the abnormality found in the patient. Using the strategy of the second approach, Bell et al. recently reported that the gene responsible for MODY (maturity-onset diabetes of the young) is tightly linked to the adenosine deaminase gene on chromosome 20q. However, this strategy will not be applicable for identification of diabetes-susceptibility genes of NIDDM, since this disorder is likely to be genetically heterogenous, with mutations in several different genes able to cause hyperglycemia, and this heterogeneity could confound the linkage analysis.