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The role of IGF-binding proteins in mediating the effects of recombinant human IGF-I on insulin requirements in type 1 diabetes mellitus

Lookup NU author(s): Professor Timothy Cheetham

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Abstract

To determine the role of IGF-binding proteins in mediating the direct effects of recombinant human IGF-l 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, se administration of recombinant human IGF-I (40 mug/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-l administration, IGF-l 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-1, 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-/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-l therapy in type I diabetes mellitus.

Publication metadata

Author(s): Cheetham T; Crowne EC; Samra JS; Acerini CL; Watts A; Holly JMP; Dunger DB

Publication type: Article

Publication status: Published

Journal: Journal of Clinical Endocrinology and Metabolism

Year: 2001

Volume: 86

Issue: 8

Pages: 3686-3691

ISSN (print): 0021-972X

ISSN (electronic): 1945-7197

Publisher: The Endocrine Society

URL: http://dx.doi.org/10.1210/jc.86.8.3686

DOI: 10.1210/jc.86.8.3686

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