Indirect Effects of Body Mass Index Growth on Glucose Dysregulation via Inflammation: Causal Moderated Mediation Analysis

Objective: No existing studies have examined the mediating role of chronic inflammation between obesity and dysregulated glucose homeostasis in adolescent samples. This study evaluated whether C-reactive protein (CRP), an inflammation biomarker, mediated the effects of growth (annual increase) in body mass index (BMI) on glycated hemoglobin (HbA_1c). Methods: BMI and biomarker data were used from wave I to wave IV of the National Longitudinal Study of Adolescent to Adult Health (Add Health study; 4,545 adolescents; mean age = 14.9 years; 55.7% female) with valid CRP data. A causal moderated mediation analysis evaluated the direct and indirect effects of BMI slope on HbA_1c via CRP across gender, with demographic and clinical characteristics as model covariates. Results: The participants displayed a linear BMI growth of 0.53–0.58 kg/m²/year throughout adolescence, with substantial interindividual variation. The BMI slope showed positive direct and indirect effects on HbA_1c via CRP across gender, and there was a significant exposure-mediator interaction effect. A standardized increase in the BMI slope raised the probability of an abnormal HbA_1c value by 6.0–8.5% in participants with various profiles. The total natural indirect effect accounted for 13.3–15.9% of the total effect in males and 21.2–22.7% in females. Conclusions: The findings provide support for the inflammation mechanism in the effects of adiposity on glucose homeostasis. In adolescents, excess BMI growth was linked with a higher risk of glucose dysregulation either directly or indirectly via chronic inflammation.