The Role of IGF-Binding Proteins in Mediating the Effects of Recombinant Human IGF-I on Insulin Requirements in Type 1 Diabetes Mellitus

• Published in: The journal of clinical endocrinology and metabolism 2001-08, Vol.86 (8), p.3686-3691
• Main Authors: Crowne, E. C., Samra, J. S., Cheetham, T., Acerini, C. L., Watts, A., Holly, J. M. P., Dunger, D. B.
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Biological and medical sciences; Child; Diabetes Mellitus, Type 1 - drug therapy; Double-Blind Method; Female; Glucose Clamp Technique; Glycated Hemoglobin A - analysis; Hormones. Endocrine system; Humans; Injections, Subcutaneous; Insulin - therapeutic use; Insulin-Like Growth Factor Binding Protein 1 - blood; Insulin-Like Growth Factor Binding Protein 2 - blood; Insulin-Like Growth Factor Binding Protein 3 - blood; Insulin-Like Growth Factor Binding Proteins - blood; Insulin-Like Growth Factor I - administration & dosage; Insulin-Like Growth Factor I - metabolism; Insulin-Like Growth Factor I - therapeutic use; Insulin-Like Growth Factor II - metabolism; Male; Medical sciences; Pharmacology. Drug treatments; Placebos; Radioimmunoassay; Recombinant Proteins - administration & dosage; Recombinant Proteins - therapeutic use; Regression Analysis; Time Factors
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jcem.86.8.7722

To determine the role of IGF-binding proteins in mediating the direct effects of recombinant human IGF-I on insulin requirements in type 1(insulin-dependent) diabetes mellitus, overnight changes in IGF-I, IGF-II, and IGF-binding protein-1, -2, and -3, collected under euglycemic conditions, were compared in nine subjects after double blind, randomized, sc administration of recombinant human IGF-I (40μ g/kg) or placebo at 1800 h. On both nights a somatostatin analog infusion (300 ng/kg·h) suppressed endogenous GH production, and three timed discrete GH pulses (total, 0.029 IU/kg·night) ensured identical GH levels. After recombinant human IGF-I administration, IGF-I levels and the IGF-I/IGF-binding protein-3 ratio increased [mean ± sem:IGF-I, 401 ± 22 ng/ml; placebo, 256 ± 20 ng/ml (P = 0.0002); IGF-I, 0.108 ± 0.006; placebo, 0.074 ± 0.004 (P = 0.0003), respectively], and insulin requirements decreased (IGF-I, 0.12 ± 0.03; placebo, 0.23 ± 0.03 U/kg·min; P = 0.008). The normal within-individual inverse relationships between insulin and IGF-binding protein-1 levels were observed (lag time 2 h: r =− 0.34; P < 0.01). Yet despite reduced free insulin levels (8.5 ± 1.5; placebo, 12.2 ± 1.2 mU/liter; P = 0.03), IGF-binding protein-1 levels were reduced after recombinant human IGF-I administration (53.7 ± 6.8; placebo, 82.2 ± 11.8 ng/ml; P = 0.008). The largest reductions in free insulin levels after recombinant human IGF-I and thus putative improvement in insulin sensitivity occurred in subjects with the smallest increase in the plasma IGF-I/IGF-binding protein-3 ratio (r = 0.7; P = 0.03). Taken together, these data are consistent with the hypothesis that transcapillary movement of IGF-I (perhaps mediated by IGF-binding protein-1), out of the circulation facilitates altered insulin sensitivity. These data have important implications for risk-benefit assessment of recombinant human IGF-I therapy in type 1 diabetes mellitus.