Objective: The minor G-allele of FOXO3A rs2802292 has been associated with longevity. We aimed to investigate whether a phenotype related to healthy metabolic aging could be identified in individuals carrying the longevity-associated FOXO3A rs2802292 G-allele.

Research Design and Methods: rs2802292 was genotyped in a phenotypically well-characterized population of young and elderly twins (n = 190) and in the population-based Inter99 cohort (n = 5768). All participants underwent oral glucose tolerance tests, and the twin population was additionally examined with an iv glucose tolerance test and a hyperinsulinemic, euglycemic clamp. Basal and insulin-stimulated FOXO3A mRNA expression was assessed in skeletal muscle biopsies from the twin population.

Results: In the twin sample, carriers of the minor G-allele of rs2802292 showed reduced fasting plasma insulin [per allele effect (ß) = -13% (-24; -1) (95% confidence interval), P = 0.03] and lower incremental area under the curve 0–120 min for insulin after an oral glucose load [ß = -14% (-23; -5), P = 0.005]. The G-allele was associated with increased peripheral insulin action [glucose disposal rate clamp, ß = 0.85 mg · kgfat-free mass-1 · min-1 (0.049; 1.64), P = 0.04] and lower hepatic insulin resistance index [ß = -13% (-25; -1), P = 0.03]. Furthermore, carriers of the G-allele had increased basal FOXO3A mRNA expression in skeletal muscle compared with T-allele carriers [ß = 16% (0; 33), P = 0.047]. In the Inter99 sample, we found an association with reduced incremental area under the curve 0–120 min for insulin after an oral glucose load [ß = -3% (-5; -0.07), P = 0.04], but this association was not significant after adjustment for body mass index.

Conclusion: Our data indicate that the minor G-allele of FOXO3A rs2802292 is associated with enhanced peripheral and hepatic insulin sensitivity in our small twin cohort, which may be mediated through increased FOXO3A mRNA expression, although no major metabolic impact of rs2802292 was found in the large Inter99 cohort.