Abstract

Type 2 diabetes mellitus is caused by a combination of insulin resistance and β cell failure. The polygenic nature of type 2 diabetes has made it difficult to study. Although many candidate genes for this condition have been suggested, in most cases association studies have been equivocal. Monogenic forms of diabetes have now been studied extensively, and the genetic basis of many of these syndromes has been elucidated, leading to greater understanding of the functions of the genes involved. Common variations in the genes causing monogenic disorders have been associated with susceptibility to type 2 diabetes in several populations and explain some of the linkage seen in genome-wide scans. Monogenic disorders are also helpful in understanding both normal and disordered glucose and insulin metabolism. Three main areas of defect contribute to diabetes: defects in insulin signalling leading to insulin resistance; defects of insulin secretion leading to hypoinsulinaemia; and apoptosis leading to decreased β cell mass. These three pathological pathways are reviewed, focusing on rare genetic syndromes which have diabetes as a prominent feature. Apoptosis seems to be a final common pathway in both type 1 and type 2 diabetes. Study of rare forms of diabetes may help ion determining new therapeutic targets to preserve or increase β cell mass and function.