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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

Department of Paediatrics (T.S., R.A., R.M.W., K.C.Y., M.A.W., C.L.A., D.B.D.), University of Cambridge, Cambridge CB2 2QQ, United Kingdom; Diabetes Centre (C.F.), Northampton General Hospital National Health Service Trust, Northampton NN1 5BD, United Kingdom; and Department of Diabetes and Endocrinology (A.M.U.), Guy’s, King’s and Thomas’ School of Medicine, London SE1 7EH, United Kingdom

Address all correspondence and requests for reprints to: David B. Dunger, Department of Paediatrics, University of Cambridge, Box 116, Level 8, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 2QQ, United Kingdom. E-mail: dbd25{at}cam.ac.uk.

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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