Genetic Factors Involved in the Pathogenesis of Type 2 Diabetes

Type 2 diabetes (T2D) represents one of the major global health problems of modern societies. Its pathogenesis is complex and it was classically characterized by pancreatic β-cell dysfunction (with diminished insulin secretion) followed by decline of the beta cell mass, peripheral insulin resistance and increased hepatic glucose production, most often associated with obesity. T2D pathogenesis involves both genetic and environmental factors. The common form of polygenic T2D is a complex disease, the genetic risk being influenced by the conjoint effects of variation at an undetermined number of genomic sites. The main methods for mapping the T2D genes were the hypothesis driven candidate gene analysis and the hypothesis free genome-wide scaning studies. The candidate gene approach led to the identification of two T2D genes now considered widely replicated: PPARG and the β-cell potassium channel (Kir6.2) gene, KCNJ11. The genome-wide linkage approach led to the identification of several loci, the most prominent being the TCF7L2 (Transcription Factor 7 Like 2) gene on chromosome 10q25.3. TCF7L2 has been replicated in almost every population examined and, with an OR of about 1.4, represents the strongest T2D gene identified so far. Finally, during the last 5 years, the genome-wide association approach led to the identification of almost 40 T2D genes. The majority of these appear to affect beta cell function. Deciphering the genetic background of T2D will contribute to the prediction of the disease in high risk subjects, with possible benefits for its prevention.