To examine mechanisms underlying the development of insulin resistance during normal puberty, sequential 8 and 40 mU/m2.min euglycemic insulin clamp and hyperglycemic clamp studies were performed in 14 healthy prepubertal and 19 pubertal children. Both groups had comparable rates of glucose turnover and plasma levels of branched chain amino acids and FFA at baseline. The low as well as the high insulin dose stimulated peripheral glucose uptake much more effectively in prepubertal children (P less than 0.05). In contrast, suppression of hepatic glucose production (60% at low dose in both groups, pNS) and lowering of substrates in response to insulin was not affected by puberty at either dose. During the hyperglycemic clamp pubertal children showed enhanced insulin responses and in turn a sharper fall in amino acids (P less than 0.05 vs. prepubertals). Our data suggest that insulin resistance during puberty is restricted to peripheral glucose metabolism. Selective insulin resistance leading to compensatory hyperinsulinemia may serve to amplify insulin's effect on amino acid metabolism, thereby facilitating protein anabolism during this period of rapid growth.