8026 Growth Hormone Receptor (GHR) is Independently Associated with Body Composition and Glycemic Measures in Youth with Type 2 Diabetes (T2D)
Authors: Lu C , Wolfs D , El ghormli L , Laffel L M , Patti M E , Isganaitis E 
Published: October 2024

Disclosure: C. Lu: None. D. Wolfs: None. L. El ghormli: None. L.M. Laffel: None. M. Patti: Advisory Board Member; Self; Fractyl Health. Consulting Fee; Self; AstraZeneca, Hamni, MBX Biosciences. Grant Recipient; Self; Dexcom. E. Isganaitis: None.

Background: T2D is more severe in youth than in adults, with growth and puberty as potential drivers. Growth hormone (GH) action, which peaks during puberty, also regulates carbohydrate metabolism. We previously showed that higher plasma levels of GHR are associated with hyperglycemia, insulin resistance, and decreased insulin secretion in youth with T2D. Plasma GHR is higher in obesity, and reductions in GHR after bariatric surgery may mediate improvements in glycemia. The association of GHR with body composition in youth with T2D has not been previously studied. Hypothesis: We hypothesize that the association of GHR with glycemic outcomes in youth with T2D is mediated by differences in body composition, and that associations between GHR and body composition differ by sex. Methods: Utilizing plasma samples from Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study (N=398), we examined association of plasma GHR (ELISA; ng/mL) with a) body composition measures including zBMI, absolute lean mass (kg), percent body fat (dual-energy x-ray absorptiometry), and b) glycemic outcomes including hemoglobin A1c (HbA1c), fasting glucose (mg/dL), 1/fasting C-peptide (mL/ng), C-peptide index (ng/mL per mg/dL), and C-peptide oral disposition index (CODI; mL/uU x ng/mL per mg/dL), stratified by sex. Linear regressions were adjusted for age, race/ethnicity, and Tanner stage in the base models, with additional adjustments for HbA1c, zBMI, lean mass, or percent fat. Results: This subcohort of youth with T2D from the TODAY study included 150 males and 248 females, mean age 13.9 ± 2.0 years. Females had lower zBMI (+2.2 ± 0.4 vs. +2.3 ± 0.5, p=0.005), lower lean mass (51 ± 10 vs. 59 ± 14, p&lt;0.001), and higher percent body fat (39 ± 5 vs. 34 ± 6, p&lt;0.001). Higher log2 GHR was associated with higher zBMI (B=0.44, SE=0.04, p&lt;0.001), higher lean mass (B=4.3, SE=1.2, p&lt;0.001), and higher percent fat (B=4.4, SE=0.7, p&lt;0.001), even after adjustment for HbA1c, and without sex-specific differences. Higher log2 GHR was associated with higher HbA1c (B=0.35, SE=0.08, p&lt;0.001), higher fasting glucose (B=9.0, SE=2.6, p&lt;0.001), lower 1/fasting C-peptide (B=-0.17, SE=0.01, p&lt;0.001), and lower CODI (B=-0.001, SE=0.001, p=0.02). These associations did not change with further adjustments for zBMI, lean mass, or percent fat, suggesting that associations between GHR and glycemia are independent of obesity or body composition. In analyses stratified by sex, the effect of GHR on CODI was attenuated after adjustment for lean mass in males only. Conclusion: Plasma GHR is independently associated with body composition and glycemia in youth with T2D. There were no sex differences in associations of GHR with HbA1c and insulin resistance. However, the association of GHR with beta cell function may be mediated by lean mass in boys but not in girls, although power was more limited in the sex-stratified analyses.

Presentation: 6/3/2024