The effects of the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor-?2 gene on insulin sensitivity and insulin metabolism interact with size at birth

Type 2 diabetes is known to be associated with a small body size at birth. Body size at birth is an indicator of the intrauterine environment. There is also a well-established association between the peroxisome proliferator-activated receptor (PPAR)-?2 gene and type 2 diabetes. We therefore assessed whether the effects of the Pro12Ala polymorphism of the PPAR-?2 gene on insulin sensitivity and insulin concentrations in adult life are modified by size at birth. We found that the effects of the Pro12Pro and Pro12Ala polymorphisms of the PPAR-?2 gene in elderly people depended on their body size at birth. The well-known association between small body size at birth and insulin resistance was seen only in individuals with the high-risk Pro12Pro allele. In those who had low birth weight, the Pro12Pro polymorphism of the PPAR-?2 gene was associated with increased insulin resistance (P < 0.002) and elevated insulin concentrations (P < 0.003). These interactions between the effects of the Pro12Ala polymorphisms of the PPAR-?2 gene on adult traits and the effects of birth weight link two previously unknown associations together within the context of type 2 diabetes. We suggest that these findings reflect gene-environment interaction