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Changes in Free Insulin-Like Growth Factor-1 and Leptin Concentrations during Acute Metabolic Decompensation in Insulin Withdrawn Patients with Type 1 Diabetes¹

Departments of Pediatrics, Internal Medicine, and the General Clinical Research Center (N.A., S.C., T.W.J., R.H., D.S., R.S.S., W.V.T.), Yale University School of Medicine, New Haven, Connecticut 06510; and the Lilly Research Laboratories (J.H.), Eli Lilly & Co., Indianapolis, Indiana 46202

Address correspondence and requests for reprints: Dr. W. V. Tamborlane, Section of Pediatric Endocrinology, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06510. E-mail: william.tamborlane{at}yale.edu

To determine the effect of acute insulin withdrawal and its subsequent replacement on components of the insulin-like growth factor (IGF)-1 binding protein system and on circulating leptin levels in patients with type 1 diabetes. Seventeen patients (age 31 yr ± 10) with type 1 diabetes treated with continuous subcutaneous insulin infusion (HbA_1c 7.6% ± 1.0) were studied. The protocol consisted of two phases: acute insulin withdrawal of up to 8 h followed by a further 2-h period of insulin replacement. For the first phase the basal insulin infusion was stopped (at 0300 h), and for the second a single dose of either regular human or insulin lispro was given subcutaneously (0.2 U/kg). Plasma insulin, glucose, growth hormone, glucagon, IGF-1, free IGF-1, IGFBP-1, -2, -3 and leptin were measured.

Results: After interruption of the basal insulin infusion, plasma free insulin levels fell from 60 ± 12.0 pmol/L to 10.8 ± 4.2 pmol/L, and plasma glucose rose from 5.6 ± 0.4 mmol/L to 14.8 ± 1.2 mmol/L (P < 0.01). During insulin withdrawal, IGFBP-1 increased by more than 6-fold (from 32 ± 8 to 205 ± 17 ng/mL, P < 0.001), IGFBP-3 increased significantly (from 2631 ± 118 to 3053 ± 101 ng/mL, P < 0.001), and total IGF-1 levels declined modestly (from 226 ± 33 to 182 ± 26 ng/mL, P < 0.001). In contrast, free IGF-1 concentrations (0.72 ± 0.22 ng/mL at baseline) were markedly suppressed during insulin withdrawal to values below the detection limit of the assay (0.08 ng/mL) in 15 of the 17 patients (P < 0.001). Circulating plasma leptin declined markedly in females from 20 ± 3 ng/mL to 11 ± 2 ng/mL (P < 0.0001) and in males from 10 ± 2 ng/mL to 7 ± 2 ng/mL (P < 0.02). Within 2 h of insulin replacement, the changes in circulating concentrations of IGFBP-1 and IGFBP-3 were partially reversed, and free IGF-1 levels rebounded to 0.54 ± 0.22 ng/mL (P < 0.1 vs. insulin withdrawal). Growth hormone, glucagon, and IGFBP-2 levels did not change significantly throughout the study. Despite the rapid restoration of plasma insulin and substrate levels, circulating leptin levels continued to fall in the 2-h period after insulin replacement in both females and males. The marked reduction in circulating free IGF-1 after insulin withdrawal and its increase after insulin administration suggest that acute changes in IGFBP concentrations induced by insulin are important regulators of IGF-1 bioavailability in patients with type 1 diabetes. In both males and females, the rapid induction of severe insulin deficiency is associated with a consistent fall in plasma leptin levels.

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