In a case-control study that investigated the effect of intrauterine growth retardation (IUGR) on glucose homeostasis, 20-yr-old adults born with IUGR were shown to be hyperinsulinemic in an oral glucose tolerance test, suggestive of insulin resistance. The aim of this study was to ascertain the decreased insulin sensitivity in young IUGR-born adults compared to that in controls. We studied 26 IUGR-born subjects and 25 controls, aged 25 yr. Insulin sensitivity was assessed by peripheral glucose uptake and monitoring free fatty acid (FFA) concentrations under euglycemic hyperinsulinemic clamp. The percent body fat was significantly higher in the IUGR group (27.2 +/- 7.6% vs. 22.0 +/- 7.3%; P = 0.02), contrasting with comparable body mass index in both groups. Insulin-stimulated glucose uptake was significantly lower in IUGR-born subjects than in controls (6.7 +/- 2.9 vs. 8.0 +/- 1.9 mg/kg fat-free mass x min; P = 0.05), and the difference remained significant after adjustment for body mass index, total body fat, or waist to hip ratio. In IUGR-born subjects, insulin-stimulated FFA suppression correlated significantly with peripheral glucose uptake (r2 = 0.23; P = 0.02). First phase insulin release in the iv glucose tolerance test, adjusted for insulin sensitivity, did not significantly differ between IUGR and control groups (442 +/- 284 vs. 391 +/- 209 pmol/L; P = 0.86). In conclusion, IUGR subjects have decreased insulin-stimulated glucose uptake as early as 25 yr of age without major impairment of insulin secretion. Low glucose uptake is associated with a lesser degree of FFA suppression in adipose tissue, which suggests a role of adipose tissue at an early stage of insulin resistance in these subjects.