The ENPP1 K121Q polymorphism determines individual susceptibility to the insulin-sensitising effect of lifestyle intervention

The K121Q (rs1044498) single nucleotide polymorphism (SNP) in the ENPP1 gene has shown association with insulin resistance and type 2 diabetes in various ethnic populations. We hypothesised that K121Q may predict the success of lifestyle intervention in terms of improvement of insulin sensitivity. We genotyped 1,563 participants with an increased risk of type 2 diabetes for K121Q and performed correlational analyses with anthropometric data and variables of insulin sensitivity. For metabolic characterisation, all participants underwent an OGTT. A subgroup of 506 participants additionally underwent a euglycaemic-hyperinsulinaemic clamp. In 342 participants, metabolic traits and anthropometric data were re-evaluated after a 9 month lifestyle intervention. In the overall cohort, K121Q was not associated with measures of obesity, indices of glucose tolerance during OGTT and insulin sensitivity estimated from the OGTT or derived from a euglycaemic-hyperinsulinaemic clamp after appropriate adjustment. However, K121Q did significantly influence the change in insulin sensitivity during lifestyle intervention after appropriate adjustment (p (additive) = 0.0067, p (dominant) = 0.0027). Carriers of the minor allele had an impaired increase in OGTT-derived insulin sensitivity. A similar trend was obtained for clamp-derived insulin sensitivity, but did not reach significance. In our population of European ancestry, the ENPP1 SNP K121Q influenced the change in insulin sensitivity during lifestyle intervention. Thus, this SNP may determine susceptibility to environmental changes and could predict the success of lifestyle intervention.