TY - JOUR
T1 - 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
AU - Saukkonen, Tero
AU - Amin, Rakesh
AU - Williams, Rachel M.
AU - Fox, Charles
AU - Yuen, Kevin C.
AU - White, Martin A.
AU - Umpleby, A. Margot
AU - Acerini, Carlo L.
AU - Dunger, David B.
PY - 2004/9
Y1 - 2004/9
N2 - 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.
AB - 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.
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U2 - 10.1210/jc.2004-0243
DO - 10.1210/jc.2004-0243
M3 - Article
C2 - 15356074
AN - SCOPUS:4544238815
SN - 0021-972X
VL - 89
SP - 4634
EP - 4641
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
IS - 9
ER -