Genetic determinants of type 2 diabetes mellitus: lessons learned from family studies

Non insulin dependent diabetes mellitus (Type 2) is a multifactorial disease, with a polygenic inheritance and environmental factors contributing to its clinical expression. The search for the genetic determinants of Type 2 diabetes began when several genes involved in the mechanisms of insulin secretion or action were cloned, localized in the human genome, and when informative polymorphisms were described within or in the vicinity of these genes. It then became possible to compare, in groups of patients and normoglycaemic controls from various populations, the frequency of the different alleles of polymorphic markers of various candidate genes (e.g. insulin, insulin receptor, glucose transporters). The conflicting results observed in these studies can be ascribed to the small size of the population samples, to the genetic heterogeneity of Type 2 diabetes mellitus, but also to the methodology used therein. Indeed, these studies searched for a correlation between the frequency of certain alleles or genotypes and the phenotype of diabetes (studies of associations in affected populations compared to healthy controls). However in order to attribute to a gene the responsibility for a disease it is necessary to demonstrate the cotransmission in affected kindreds of a morbid allele of the gene along with the disease (familial or linkage analysis). The aim of this review is to summarize the results of family studies of Type 2 diabetes and Maturity Onset Diabetes of the Young (MODY), particularly with concern to the mutations described in candidate genes, and the implication of glucokinase in these disorders.