Pathomechanisms of Type 2 Diabetes Genes

Type 2 diabetes mellitus is a complex metabolic disease that is caused by insulin resistance and beta-cell dysfunction. Furthermore, type 2 diabetes has an evident genetic component and represents a polygenic disease. During the last decade, considerable progress was made in the identification of type 2 diabetes risk genes. This was crucially influenced by the development of affordable high-density single nucleotide polymorphism (SNP) arrays that prompted several successful genome-wide association scans in large case-control cohorts. Subsequent to the identification of type 2 diabetes risk SNPs, cohorts thoroughly phenotyped for prediabetic traits with elaborate in vivo methods allowed an initial characterization of the pathomechanisms of these SNPs. Although the underlying molecular mechanisms are still incompletely understood, a surprising result of these pathomechanistic investigations was that most of the risk SNPs affect beta-cell function. This favors a beta-cell-centric view on the genetics of type 2 diabetes. The aim of this review is to summarize the current knowledge about the type 2 diabetes risk genes and their variants' pathomechanisms. (Endocrine Reviews 30: 557-585, 2009)