title: Dose-dependent effects of recombinant human insulin-like growth factor (IGF)-I/IGF binding protein-3 complex on overnight growth hormone secretion and insulin sensitivity in type 1 diabetes.
abstract: GH hypersecretion in type 1 diabetes has been implicated in the pathogenesis of insulin resistance, and microangiopathic complications, and may result from reduced circulating IGF levels. We examined the effects of recombinant human (rh)IGF-I [complexed in equimolar ratio with rhIGF binding protein (BP)-3 (rhIGF-I/IGFBP-3)] replacement on overnight GH levels and insulin sensitivity in type 1 diabetes. Fifteen subjects, 13-24 yr old (10 male), were given rhIGF-I/IGFBP-3 or placebo as a daily sc injection for 2 d. After the second injection overnight, insulin requirements for euglycemia were determined (0400-0800 h), followed by a 4-h, two-step (insulin, 0.6 and 1.5 mU/kg.min) hyperinsulinemic euglycemic [90 mg/dl (5 mmol/liter)] clamp. In each subject, the protocol was repeated on three occasions in random order. Seven subjects received placebo and rhIGF-I/IGFBP-3 (0.1 mg/kg.d and 0.4 mg/kg.d), and eight subjects received placebo and rhIGF-I/IGFBP-3 (0.2 mg/kg.d and 0.8 mg/kg.d). We found dose-dependent increases in circulating IGF-I and IGFBP-3 concentrations after rhIGF-I/IGFBP-3. These were paralleled by significant reductions in mean overnight GH levels and GH pulse amplitude. We also observed dose-dependent effects of rhIGF-I/IGFBP-3 on overnight insulin requirements for euglycemia, with reductions of up to 41%. Insulin sensitivity, defined by M-values, was improved with rhIGF-I/IGFBP-3 (0.4 and 0.8 mg/kg.d). Thus, restoration of circulating IGF-I and IGFBP-3 levels with rhIGF-I/IGFBP-3 suppresses GH secretion in adolescents with type 1 diabetes, leading to reduced insulin requirements and improvements in insulin sensitivity.
authors.affiliation: Department of Paediatrics, University of Cambridge, Box 116, Level 8, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, United Kingdom.
authors.forename: Tero
authors.initials: T
authors.lastname: Saukkonen
authors.forename: Rakesh
authors.initials: R
authors.lastname: Amin
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Williams
authors.forename: Charles
authors.initials: C
authors.lastname: Fox
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Yuen
authors.forename: Martin A
authors.initials: MA
authors.lastname: White
authors.forename: A Margot
authors.initials: AM
authors.lastname: Umpleby
authors.forename: Carlo L
authors.initials: CL
authors.lastname: Acerini
authors.forename: David B
authors.initials: DB
authors.lastname: Dunger
mesh_terms: D000293:Adolescent; D000328:Adult; D001786:Blood Glucose / Q000032:analysis; D018592:Cross-Over Studies; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D019382:Human Growth Hormone / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000097:blood / Q000494:pharmacology*; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000032:analysis / Q000494:pharmacology*; D008297:Male; D011994:Recombinant Proteins / Q000494:pharmacology; D012727:Sex Characteristics
chemical_list: D001786:Blood Glucose; D007328:Insulin; D018972:Insulin-Like Growth Factor Binding Protein 3; D011994:Recombinant Proteins; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I