IN-VIVO METABOLIC EFFECTS OF INSULIN-LIKE GROWTH-FACTOR-I NOT MEDIATED THROUGH THE INSULIN-RECEPTOR

Patients with mutations affecting insulin receptor function may mainta in 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 conditio ns. The aim of our study was to evaluate the metabolic effects of insu lin-like growth factor-I (IGF-I) in a 19-yr-old patient with homozygou s mutation of the insulin receptor alpha-subunit. Her metabolic and ho rmonal features were marked hyperglycemia (11-33 mmol/L) and hyperinsu linemia (1000-2000 pmol/L); normal free fatty acids and lactate; low I GF-I; glycerol, alanine, and pyruvate below the normal range; and elev ated beta-hydroxybutyrate. Unlike diabetic ketoacidosis, no triglyceri de or protein breakdown was present, suggesting a compensatory mechani sm, possibly sustained by the insulin concentration acting on IGF-I re ceptors. Subcutaneous administration of IGF-I (40, 80, and 120 mu g/kg ), although not affecting plasma glucose, resulted in a rapid decrease in free fatty acids and prevented the rise of beta-hydroxybutyrate le vels 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 Mood glucose levels. Furthermore, th ese findings are consistent with the hypothesis that IGF-I receptors m ay be activated by high insulin levels, providing lipid and protein re gulation in patients with nonfunctional insulin receptors.