Serum IGF1 and linear growth in children with congenital leptin deficiency before and after leptin substitution

Abstract

Background: Evidence from in vitro and rodent studies suggests that leptin, a key signal of long-term energy reserves, promotes IGF1 synthesis and linear growth. This effect of leptin has not been fully investigated in humans. The aim of our study was to investigate the effect of leptin substitution on growth factors and linear growth in children with congenital leptin deficiency (CLD).

Methods: In this cohort study we included eight pediatric patients (six males), age 0.9-14.8 years, who were diagnosed with CLD and received leptin substitution at our University Medical Center. We calculated standard deviation scores (SDS) for serum levels of IGF1 and IGFBP3, IGF1/IGFBP3 molar ratio, and height at baseline (T0) and 12 months (T12) after the initiation of substitution with metreleptin.

Results: All patients had severe obesity (BMI-SDS mean ± SD: 4.14 ± 1.51) at T0 and significant BMI-SDS reduction to 2.47 ± 1.05 at T12. At T0, all patients were taller than the mid-parental median, yet had low IGF1 and IGF1/IGFBP3 molar ratios (IGF1-SDS[Formula: see text]_T0: -1.58 ± 0.92, IGF1/IGFBP3 molar ratio-SDS[Formula: see text]_T0: -1.58 ± 0.88). At T12, IGF1-SDS increased significantly (∆_T0-12: 1.63 ± 1.40, p = 0.01), and IGFBP3-SDS and IGF1/IGFBP3 molar ratio-SDS showed a trend toward an increase. In the three children within the childhood growth period (post-infancy, pre-puberty) height-SDS increased (∆height-SDS_T0-12: 0.57 ± 0.06, p = 0.003) despite substantial weight loss.

Conclusions: These results in CLD patients are contrary to observations in children with idiopathic obesity who typically have above-mean IGF1 levels that decrease with weight loss, and therefore suggest that leptin increases IGF1 levels and promotes linear growth.

Fig. 1. Changes in BMI-, IGF1-, IGF1/IGFBP3 molar ratio-, and height-SDS under leptin substitution.

Individual BMI-SDS (A), IGF1-SDS (B), IGF1/IGFBP3 molar ratio-SDS (C), and height-SDS (D) at the initiation (T0) and 12 months after (T12) leptin substitution in eight patients with congenital leptin deficiency. SDS standard deviation score.