GENETIC AND METABOLIC HETEROGENEITY OF MATURITY-ONSET DIABETES OF THEYOUNG

Maturity-onset diabetes of the young (MODY) is an autosomal dominant s ubtype of NIDDM characterized by early age of onset, MODY has been use d as a model for genetic studies of NIDDM because the availability of large multigenerational MODY families makes the performance of linkage analyses easier. So far, three MODY genes have been localized and ide ntified on chromosomes 20q (the hepatocyte nuclear factor-4 alpha gene [HNF-4 alpha/MODY1]), 7p (the glucokinase gene [GCK/MODY2]), and 12q (the hepatocyte nuclear factor-1 alpha gene [HNF-1 alpha/MODY3]). Abou t 20% of MODY families are not linked to these three loci, suggesting that at least one additional locus remains to be localized and identif ied, The genetic heterogeneity of MODY is associated with clinical and metabolic heterogeneity, Mutations in GCK/MODY2 result in mild chroni c hyperglycemia caused by reduced pancreatic beta-cell responsiveness to glucose and decreased net accumulation of hepatic glycogen and incr eased hepatic gluconeogenesis after meals, In contrast, MODY1 and MODY 3 are characterized by severe insulin secretory defects and by major h yperglycemia associated with microvascular complications, The recent i dentification of MODY1 and MODY3 as the genes encoding two physiologic ally related transcription factors opens entirely new perspectives in the understanding of the molecular basis of the different forms of NID DM.