PATHOGENESIS OF TYPE-2 DIABETES - METABOLIC AND MOLECULAR IMPLICATIONS FOR IDENTIFYING DIABETES GENES

Individuals with type 2 diabetes are characterized by abnormalities in insulin action and insulin secretion, However, despite intensive inve stigation, the genes responsible for the insulin resistance and impair ed insulin secretion remain undefined. The candidate-gene approach has failed to identify any specific gene or combination of genes that can account for even a minority of adult cases of type 2 diabetes. Althou gh a number of laboratories have initiated genomewide searches to iden tify potential susceptibility loci for type 2 diabetes, consistent and reproducible linkage to satellite markers has yet to emerge. It has b eers suggested that a more precise definition of the diabetic phenotyp e may prove useful in delineating diabetogenic genes. This review prov ides an in-depth discussion of established metabolic, biochemical, and molecular abnormalities responsible for type 2 diabetes. It is antici pated that this discussion will establish a framework for the identifi cation of additional candidate genes that need to be examined and prov ide a sound scientific basis for the more precise definition of the di abetic phenotype for use in future genomewide searches.