[Biological and clinical analyses of the mechanism of growth retardation and the effect of recombinant human insulin-like growth factor-1 (rhIGF-1) treatment on glucose metabolism and growth in leprechaunism with severe insulin resistant diabetes].
Leprechaunism is the most severe form of insulin resistant diabetes and accompanied with growth retardation. Previously, we identified two mutations of insulin receptor (IR) gene in a patient with leprechaunism. In the present study, we assessed the biological actions of IGF-1 in the patient's fibroblasts and investigated short and long term effects of recombinant human IGF-1 (rhIGF-1) treatment on glucose metabolism and growth in the patient. The patient's fibroblasts had normal binding of IGF-1, normal phosphorylation of the beta-subunit of IGF-1 receptor (IGF-1R) and normal incorporation of thymidine in response to IGF-1. The subcutaneous administration of rhIGF-1 at the single dose of 0.4 mg/kg revealed a half life of IGF-1 as short as 90 minutes, and her serum IGFBP-3 level was extremely low. She was treated with rhIGF-1 for about 6 years by both subcutaneous injection (SI) before each meal and continuous subcutaneous infusion (CSI). The administration of rhIGF-1 at the total daily dose of 1.6 mg/kg sustained serum total IGF-1 level within normal range and maintained her growth rate and HbA1c level within nearly normal ranges. Therefore, the treatment with rhIGF-1 was thought to be effective in lowering plasma glucose levels in the patient because these mutant IRs had no dominant negative effects on endogenous IGF-1 Rs. The results suggested that the treatment with a high dose of rhIGF-1 by both SI and CSI is effective for preventing the postnatal growth retardation and normalizing glucose metabolism in patients with genetic form of extremely severe insulin resistant diabetes and that IGF-1 deficient state and partial GH resistance such as the impairment of the production of IGF-1 and IGFBP-3 may contribute to the growth retardation.
Kato
M
M
Department of Pediatrics, Hokkaido University School of Medicine, Sapporo, Japan.
D000015:Abnormalities, Multiple; D002648:Child; D003920:Diabetes Mellitus / Q000378:metabolism / Q000628:therapy*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D006130:Growth Disorders / Q000209:etiology / Q000628:therapy*; D006801:Humans; D007333:Insulin Resistance; D007334:Insulin-Like Growth Factor I / Q000008:administration & dosage* / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D011994:Recombinant Proteins / Q000008:administration & dosage
D011994:Recombinant Proteins; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D005947:Glucose