DIABETES - FROM PHENOTYPES TO GENOTYPES

Diabetes mellitus comprises a heterogeneous group of diseases which ha ve chronic hyperglycaemia in common as well as the resulting microvasc ular, macrovascular and neurological complications of this condition. Familial studies have provided strong evidence for the existence of ge netic determinants in the different types of diabetes. In particular, monozygotic twin studies have indicated a higher rate of concordance i n non-insulin-dependent (NIDDM) than in insulin-dependent diabetes mel litus (IDDM). In IDDM, 8 susceptibility loci have been identified, not ably the HLA complex and insulin promotor gene. Rigourous family studi es have identified monogenic subtypes representing 10-15% of all NIDDM . MODY(2) related to glucokinase gene mutations, MODY(1) and MODY(3) s econdary to mutation of hepatic nuclear factors, and diabetes resultin g from deletion or mutation of mitochondrial DNA. Most NIDDM result fr om polygenic heredity, and susceptibility genes conducive to increased receptivity to deleterious environmental influences are now under inv estigation, such as beta(3) adrenergic receptor, FABP(2) and OB. Preci se analysis of phenotypes in the remaining families or systematic scre ening of the genome could allow the genes of each subtype to be identi fied. Finaly, susceptibility genes for the increased severity and freq uency of vascular complications have been identified, such as angioten sin converting enzyme, aldose reductase and aldehyde dehydrogenase gen es. This progress has been facilitated by developments in molecular bi ology.