MOLECULAR GENETICS OF EARLY-ONSET NON-INSULIN-DEPENDENT (TYPE 2) DIABETES MELLITUS

Abstract

NIDDM is one of the most common metabolic diseases affecting -5% of the world population. However despite much research, the genetic and nongenetic factors that contribute to its development remain largely unknown. Careful clinical studies of subjects with NIDDM whose onset occurred during childhood or adolescence have identified a familial form of diabetes termed maturity-onset diabetes of the young or MODY. Its early age of onset, autosomal dominant mode of inheritance and availability of multigenerational pedigrees make MODY an attractive model for identifying diabetes-susceptibility genes using genetic approaches. Such studies have shown tight linkage between DNA markers on chromosome 20 and MODY in a large Michigan family of German origin as well as with DNA polymorphisms in the glucokinase gene on chromosome 7 in French and British families. Although the diabetes-susceptibility gene on chromosome 20 has not been identified, mutations in the glucokinase gene have been shown to be the cause of MODY in -60% of French subjects with this form of NIDDM. The demonstration that mutations in the glucokinase gene can cause diabetes suggests that NIDDM may be, at least in part, a disorder of glucose metabolism. This implies that genes encoding other glycolytic and gluconeogenic enzymes, especially those that control rate-limiting steps in these pathways, are candidates for contributing to the development of this genetically heterogeneous disorder. Genetic studies of early-onset NIDDM have provided a belter understanding of its causes and have pointed to cellular pathways that are important for the maintenance of glucose homeostasis and whose perturbation may contribute to the development of the more common late-onset forms of NIDDM.