Adolescent obesity is a serious public health concern. The aim of the study was to determine whether obese adolescents can adapt metabolically to changes in dietary macronutrient intake. Using a random cross-over design, 13 healthy obese volunteers (six boys and seven girls; age, 14.7 +/- 0.3 yr; body mass index, 34 +/- 1 kg/m2; body fat, 42 +/- 1%) were studied twice after 7 d of isocaloric, isonitrogenous diets with 60% carbohydrate (CHO) and 25% fat (high CHO), or 30% CHO and 55% fat (low CHO). Glucose metabolism, insulin sensitivity, and first- and second-phase insulin secretory indices were measured by stable isotope techniques and the stable labeled iv glucose tolerance test. The results were compared with those of previously studied lean adolescents. Obese adolescents increased first- and second-phase insulin secretory indices by 18 (P = 0.05) and 36% (P = 0.05), respectively, to maintain normoglycemia during the high-CHO diet because they failed to increase insulin sensitivity as did the lean adolescents. Regardless of diet, in obese adolescents, insulin sensitivity was half (P < 0.05) and first- and second-phase insulin secretory indices twice (P < 0.01), compared with the the corresponding values in lean subjects. In obese adolescents, gluconeogenesis increased by 32% during the low-CHO (high-fat diet) (P < 0.01). In obese adolescents, insulin secretory demands were increased regardless of diet. Failure to increase insulin sensitivity while receiving a high-CHO diet required a further increase in insulin secretion, which may lead to earlier beta-cell failure. A low-CHO/high-fat diet resulted in increased gluconeogenesis, which may be a prelude to the increased glucose production and hyperglycemia observed in type 2 diabetics.