Long-term effect of recombinant human insulin-like growth factor I on metabolic and growth control in a patient with leprechaunism.

ABSTRACT

Leprechaunism is the most severe form of insulin resistance, manifesting with abnormal glucose metabolism and retarded growth. In the present study, we investigated the biological actions of recombinant human insulin-like growth factor I (rhIGF-I) in fibroblasts derived from a patient with leprechaunism. In the same patient, we also investigated the pharmacokinetics of IGF-I and the long-term effect of rhIGF-I treatment on metabolic control and physical growth. The patient's fibroblasts showed normal binding of IGF-I, normal phosphorylation of the beta-subunit of the IGF-I receptor, and normal [3H]thymidine incorporation in response to IGF-I. The fibroblast studies suggested that the patient would respond to IGF-I therapy, but certainly did not exclude the possibility of IGF-I resistance in vivo. Administration of recombinant human GH at the dose of 2.0 IU/kg for 3 consecutive days induced a minimal response of serum total IGF-I and IGF-binding protein-3 (IGFBP-3), suggesting partial GH resistance. To increase the serum total IGF-I level, we administered rhIGF-I with combination therapy of intermittent and continuous s.c. injection. This sustained the serum total IGF-I level, but not the serum IGFBP-3 level, within the normal range. The patient was treated with combination therapy of rhIGF-I by both s.c. injection and continuous s.c. infusion for 6 yr and 10 months. Administration of rhIGF-I at total daily dose of 1.6 mg/kg maintained her growth rate and hemoglobin A1c level nearly within the normal range. These findings suggest 1) that this leprechaun patient has an IGF-I-deficient state and partial GH resistance, as reflected by impaired production of IGF-I and IGFBP-3; 2) that rhIGF-I treatment works effectively for preventing postnatal growth retardation and normalizing glucose metabolism in patients with extreme insulin resistance; 3) that this treatment requires relatively higher dose of rhIGF-I; and 4) that treatment appears to be safe and devoid of adverse effects.