Thrifty genotypes and phenotypes in the pathogenesis of type 2 diabetes mellitus

Dramatically high rates of type 2 diabetes mellitus (DM) have been observed in historically undernourished, recently urbanized populations. A comparable model is the high risk of DM in individuals who were growth restrained in utero and subsequently catch up in size. While it is proposed that undernutrition may somehow adversely program metabolism, both models could also be explained by genotypes that promoted survival during earlier nutritional adversity but later add to the risk of DM. Our recent studies in a contemporary birth cohort have identified two different candidate thrifty genotypes. The insulin gene VNTR III/III genotype promotes fetal growth and historically could thereby have enhanced survival during infancy. In contrast, the maternally inherited 16189 mitochondrial DNA variant is associated with restrained fetal growth and may therefore enhance the likelihood of maternal survival. Both genotypes are associated with an increased risk of adult type 2 DM in historical cohorts. However, the development of DM in individuals from contemporary birth cohorts may prove to be influenced more by genetic and other early determinants of childhood obesity.