Patients with mutations affecting insulin receptor function may maintain some degree of metabolic control. The hypothesis has been put forth that in these patients, fuels may be metabolized through pathways (i.e. receptor activation) that become relevant in such abnormal conditions. The aim of our study was to evaluate the metabolic effects of insulin-like growth factor-I (IGF-I) in a 19-yr-old patient with homozygous mutation of the insulin receptor alpha-subunit. Her metabolic and hormonal features were marked hyperglycemia (11-33 mmol/L) and hyperinsulinemia (1000-2000 pmol/L); normal free fatty acids and lactate; low IGF-I; glycerol, alanine, and pyruvate below the normal range; and elevated beta-hydroxybutyrate. Unlike diabetic ketoacidosis, no triglyceride or protein breakdown was present, suggesting a compensatory mechanism, possibly sustained by the insulin concentration acting on IGF-I receptors. Subcutaneous administration of IGF-I (40, 80, and 120 micrograms/kg), although not affecting plasma glucose, resulted in a rapid decrease in free fatty acids and prevented the rise of beta-hydroxybutyrate levels compared to placebo. Therefore, IGF-I can exert direct metabolic effects in vivo, probably through activation of its own receptor, even at a concentration not affecting blood glucose levels. Furthermore, these findings are consistent with the hypothesis that IGF-I receptors may be activated by high insulin levels, providing lipid and protein regulation in patients with nonfunctional insulin receptors.