SAT048 Insulin Signaling Through The Insulin Receptor Increases Bone Mineral Density And Linear Growth Through Its Effects On Bone

Disclosure: R.M. Tuska: None. M.C. Okawa: None. M. Lightbourne: None. J.C. Reynolds: None. A. Layne: None. R.J. Brown: None. Context: Overnutrition and obesity associates with increased childhood growth and higher bone mineral density (BMD), whereas undernutrition associates with impaired growth and lower BMD. Increased vs decreased insulin signaling in bone may be partly responsible for these phenotypes. Patients with lipodystrophy syndromes (LD, characterized by deficient adipose tissue) have pathway selective insulin resistance (IR) causing impairment of some insulin signaling pathways while others are overstimulated by compensatory hyperinsulinemia. These patients thus serve as models of increased insulin signaling in bone without confounding by increased body mass. By contrast, patients with homozygous pathogenic variants of the insulin receptor (INSR-/-), have impairment of all insulin signaling pathways and thus model decreased insulin signaling in bone. We hypothesized that patients with LD would have tall stature and high BMD due to hyperinsulinemia, whereas those with INSR would have short stature and low BMD due to lack of insulin signaling despite hyperinsulinemia. Methods. We compared patients with genetic forms of generalized LD (GLD, (N=30), partial LD (PLD, (N=104), and INSR-/- (N=10). Whole body and site-specific (1/3 radius, Total Hip, femoral neck, and spine) DXA scans were obtained. Height Standard Deviation Scores (SDS) were calculated based on sex and age-matched normative data for patients <20 y old and based on sex-specific 20-y-old normative data for patients ≥ 20 y. Similarly, height-adjusted BMD SDS were calculated using BMDCS reference data. Blood was collected after an 8-12 hour fast for measurement of insulin. Results. All groups had hyperinsulinemia, which was highest in INSR-/- followed by PLD and CGL (423.3 mcU/ml [161.0,1000]; 31.0 mcU/ml [17.1,62.2]; 26.1 mcU/ml [11.2, 52.4]; p<0.0001). Patients with GLD and PLD had tall stature and high BMD vs the general population, whereas INSR -/- had short stature and low BMD. GLD had the greatest whole-body and site-specific BMD SDS followed by PLD and INSR -/- (Whole Body: 1.9±0.9, 0.4±1.3, -1.9± 0.1, p <0.0001; 1/3 Radius: 1.2± 1.2, 0.1± 1.6, -1.5± 1.2, p = 0.0002; Femoral Neck: 1.4±1.0, -0.7±1.3, -1.9±0.8, p <0.0001; Total Hip: 2.0±1.0, -0.3±1.3, -2.0±1.2, p <0.0001; Spine: 1.5±1.0, 0.5±1.6, -1.7±0.7, p <0.0001). All BMD SDS in each group differed from the population mean of 0, except for 1/3 radius in PLD. Similarly, GLD had the greatest height SDS followed by PLD and INSR-/- (0.5± 1.0, 0.3± 1.2, -2.5± 1.4, p<0.0001), all of which differed from the population mean. Conclusions: Patients with non-selective insulin resistance (INSR-/-) lack insulin signaling in bone, contributing to short stature and low BMD. Pathway selective insulin resistance, as observed in patients with GLD and PLD, contributes to compensatory hyperinsulinemia thus increasing insulin signaling in bone, which contributes to tall stature and high BMD. Presentation: Saturday, June 17, 2023