HIGH-DOSE INTRAVENOUS, BUT NOT LOW-DOSE SUBCUTANEOUS, INSULIN-LIKE GROWTH-FACTOR-I THERAPY INDUCES SUSTAINED INSULIN SENSITIVITY IN SEVERELY RESISTANT TYPE-I DIABETES-MELLITUS

We have previously demonstrated weekly iv insulin-like growth factor-I (IGF-I; 500 mu g/kg) bolus therapy to be effective in inducing sustai ned insulin sensitivity in a patient with type I diabetes mellitus and massive insulin resistance. The present study was undertaken to deter mine the efficacy of daily sc IGF-I in the treatment of two severely i nsulin-resistant type I diabetic patients (requiring in excess of 3500 U insulin/day) compared to weekly iv IGF-I therapy. Prolonged insulin sensitivity was achieved in both patients after weekly 500 mu g/kg iv bolus infusions of IGF-I, with sc insulin requirements falling to app roximately 1 U/kg day. Smaller iv doses (250 mu g/ kg) of IGF-I were i neffective in acutely lowering serum glucose or inducing sustained ins ulin sensitivity. However, even this smaller IGF-I dose resulted in ac ute symptomatic hypophosphatemia, which could be prevented by coadmini stration of potassium phosphate. With sc administered IGF-I (up to 10 mg twice daily), insulin appeared to control patient glucose concentra tions, but severe insulin resistance returned within 72 h of discontin uing IGF-I therapy. IGF-I dosing was decreased to the lowest concentra tion that maintained euglycemia (7.5 mg in the morning and 2.5 mg in t he evening). However, severe arthropathy in both patients and neurolog ical symptoms including multiple cranial nerve palsies in one patient were associated with chronic therapy. We conclude that both iv and sc administered IGF-I can precipitate acute symptomatic hypophosphatemia. Chronic low dose sc therapy may be associated with severe neuropathy and arthropathy, and does not induce the sustained insulin sensitivity associated with high dose intermittent bolus IGF-I therapy.