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: Tero Saukkonen, Rakesh Amin, Rachel M Williams, Charles Fox, Kevin C Yuen, Martin A White, A Margot Umpleby, Carlo L Acerini, David B Dunger
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 89 Issue 9 Pg. 4634-41 (Sep 2004) ISSN: 0021-972X [Print] United States
• PMID: 15356074 (Publication Type: Clinical Trial, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Blood Glucose
• Insulin
• Insulin-Like Growth Factor Binding Protein 3
• Recombinant Proteins
• Human Growth Hormone
• Insulin-Like Growth Factor I

Topics

• Adolescent
• Adult
• Blood Glucose (analysis)
• Cross-Over Studies
• Diabetes Mellitus, Type 1 (metabolism)
• Dose-Response Relationship, Drug
• Double-Blind Method
• Female
• Human Growth Hormone (metabolism)
• Humans
• Insulin (blood, pharmacology)
• Insulin-Like Growth Factor Binding Protein 3 (blood, pharmacology)
• Insulin-Like Growth Factor I (analysis, pharmacology)
• Male
• Recombinant Proteins (pharmacology)
• Sex Characteristics