Leptin receptors are present on beta-cells as well as on muscle and fat cells, thus enabling leptin to modulate both insulin secretion and insulin action. Leptin inhibits especially the glucose-stimulated insulin secretion from pancreatic cells. The leptin receptor (LEPR) gene could thus play a role in the regulation of glucose and insulin after an oral glucose load. Therefore, the relationship between LEPR polymorphisms and glucose and insulin response to an oral glucose tolerance test (OGTT) was investigated. Three LEPR polymorphisms (Lys(109)Arg, Gln(223)Arg, and Lys(656)Asn) were typed on genomic DNA of 358 overweight and obese women, aged 18-60 yr. Based on an OGTT, 269 subjects were defined with normal glucose tolerance, and 89 with impaired glucose tolerance (IGT). Associations between genotypes and glucose metabolism were analyzed with a general linear models procedure in pre- and postmenopausal women separately, after adjusting the data for age and fat mass. In postmenopausal women with IGT (n = 24), associations were found with Lys(109)Arg and Lys(656)Asn for fasting insulin (P = 0.05) and with Lys(109)Arg and Gln(223)Arg for the insulin response to an OGTT (P < 0.02). In the same group, trends were found with Lys(656)Asn for fasting glucose as well as in response to the OGTT. In premenopausal women with IGT (n = 65), associations were found with Lys(109)Arg and Lys(656)Asn for overall glucose response to the glucose load. In contrast, no associations with insulin or glucose were found in women with normal glucose tolerance. In conclusion, these data indicate that LEPR polymorphisms are associated with insulin and glucose metabolism in women with impaired glucose homeostasis.