Although insulin secretion is commonly increased and glucose tolerance decreased in young obese patients, there is a wide individual variability of these parameters. We investigated whether common variants at the Kir6.2 (KCNJ11) and insulin variable number of tandem repeat (INS VNTR) loci are associated with insulin or glucose levels in 388 obese children. The E23K and INS VNTR alleles showed no significant association when each locus was examined individually but a clear effect when the two loci were combined for analysis. In obese children with Kir6.2 KK and class III VNTR alleles, fasting glucose was slightly but consistently greater (4.76 +/- 0.05 mM) than in those with Kir6.2 EE and class I/I VNTR alleles (4.63 +/- 0.06 mM, P = 6.10(-4)) or other genotypes (4.64 +/- 0.03 mM, P = 1.10(-3)). Obese children with KK and class III VNTR genotypes also had an early response to oral glucose diminished by approximately 36% [insulinogenic index (IGI) = 50 +/- 4] compared with Kir6.2 EE and class I/I (IGI = 78 +/- 7, P = 0.026) or other genotypes (IGI = 69 +/- 3, P = 0.001). In young European obese, the polymorphisms of Kir6.2 and INS VNTR are thus associated with a trend for lower insulin and higher glucose levels, which may reveal a possible epistatic genetic effect that may influence a prediabetic trait in young obese children.