Insulin Signaling Through the Insulin Receptor Increases Linear Growth Through Effects on Bone and the GH–IGF-1 Axis

Abstract Context Childhood overnutrition is associated with increased growth and bone mineral density (BMD) vs the opposite for undernutrition. The role of insulin receptor (InsR) signaling in these phenotypes is unclear. Rare disease patients with hyperinsulinemia and impaired InsR function (homozygous [−/−] or heterozygous [+/−] INSR pathogenic variants, type B insulin resistance [TBIR]) model increased InsR signaling, while patients with intact InsR function (congenital generalized lipodystrophy, CGL) model decreased InsR signaling. Objective This work aimed to understand mechanisms whereby InsR signaling influences growth. Methods A cross-sectional comparison was conducted of CGL (N = 23), INSR−/− (N = 13), INSR+/− (N = 17), and TBIR (N = 8) at the National Institutes of Health. Main outcome measures included SD scores (SDS) for height, body mass index, insulin-like growth factor (IGF)-1, and BMD, and IGF binding proteins (IGFBP)-1 and -3. Results INSR-/− vs CGL had higher insulin (median 266 [222-457] vs 33 [15-55] mcU/mL), higher IGFBP-1 (72 350 [55 571-103 107] vs 6453 [1634-26 674] pg/mL), lower BMI SDS (−0.7 ± 1.1 vs 0.5 ± 0.9), lower height SDS (−1.9[−4.3 to −1.3] vs 1.1 [0.5-2.5]), lower BMD SDS (−1.9 ± 1.4 vs 1.9 ± 0.7), and lower IGFBP-3 (0.37 [0.19-1.05] vs 2.00 [1.45-2.67] μg/mL) (P < .05 for all). INSR +/− were variable. Remission of TBIR lowered insulin and IGFBP-1, and increased IGF-1 and IGFBP-3 (P < .05). Conclusion Patients with hyperinsulinemia and impaired InsR function exhibit impaired growth and lower BMD, whereas elevated InsR signaling (CGL) causes accelerated growth and higher BMD. These patients demonstrate that insulin action through the InsR stimulates direct anabolic effects in bone and indirect actions through the growth hormone (GH)–IGF-1 axis. TBIR patients exhibit abnormalities in the GH axis that resolve when InsR signaling is restored, supporting a causal relationship between InsR and GH axis signaling.