Genetic obesity unmasks nonlinear interactions between murine type 2 diabetes susceptibility loci

Nonlinear interactions between obesity and genetic risk factors are thought to determine susceptibility to type 2 diabetes, We used genetic obesity as a tool to uncover latent differences in diabetes susceptibility between tw o mouse strains, C57BL/6J (B6) and BTBR. Although both BTBR and B6 lean mic e are euglycemic and glucose tolerant, lean BTBR x B6 F1 male mice are prof oundly insulin resistant, We hypothesized that the genetic determinants of the insulin resistance syndrome might also predispose genetically obese mic e to severe diabetes. Introgressing the ob allele into BTBR revealed large differences in diabetes susceptibility between the strain backgrounds. In a population of F2-ob/ob mice segregating for BTBR and B6 alleles, we observ ed large variation in pancreatic compensation for the underlying insulin re sistance, me also detected two loci that substantially modify diabetes seve rity, and a third locus that strongly links to fasting plasma insulin level s, Amplification of the genetic signal from these latent diabetes susceptib ility alleles in F2-ob/ob mice permitted discovery of an interaction betwee n the two loci that substantially increased the risk of severe type 2 diabe tes.