Changes in free insulin-like growth factor-1 and leptin concentrations during acute metabolic decompensation in insulin withdrawn patients with type 1 diabetes

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-I, 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-I 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.