Insulin signaling through the insulin receptor increases linear growth through effects on bone and the GH-IGF-1 axis
Marinna C Okawa, Rebecca M Tuska, Marissa Lightbourne, Brent S Abel, Mary Walter, Yuhai Dai, Elaine Cochran, Rebecca J Brown- Biochemistry (medical)
- Clinical Biochemistry
- Endocrinology
- Biochemistry
- Endocrinology, Diabetes and Metabolism
Abstract
Context
Childhood overnutrition is associated with increased growth and bone mineral density (BMD), versus 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]) vs patients with intact InsR function (congenital generalized lipodystrophy, CGL) model increased vs decreased InsR signaling.
Objective
Understand mechanisms whereby InsR signaling influences growth.
Design/Participants/Intervention/Setting
Cross-sectional comparison of CGL (N=23), INSR-/- (N=13), INSR+/- (N=17), and TBIR (N=8) at the National Institutes of Health.
Main Outcome Measures
Standard deviation scores (SDS) for height, BMI, insulin-like growth factor (IGF)-1, and BMD; 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 (72350[55571,103107] vs 6453[1634,26674] pg/mL), lower BMI (-0.7±1.1 vs 0.5±0.9), lower height (-1.9[-4.3, -1.3] vs 1.1[0.5,2.5]), lower BMD (-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] ug/mL), P<0.05 for all. INSR +/- were variable. Remission of TBIR lowered insulin and IGFBP-1, and increased IGF-1 and IGFBP-3 (P<0.05).
Conclusions
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 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.