Joint trajectories of adiposity and systemic inflammation and incident diabetes among older adults: a bi-cohort prospective study with mediation analysis

Abstract

Background Obesity and chronic low-grade inflammation are established risk factors for type 2 diabetes, yet their joint longitudinal evolution and combined contribution to diabetes incidence remain poorly characterized in aging populations. Objective To identify joint trajectories of adiposity and systemic inflammation, evaluate their associations with incident diabetes, and quantify the mediating role of glycated hemoglobin (HbA1c) across two independent cohorts. Methods This prospective study included 3,733 diabetes-free adults aged ≥50 years from the English Longitudinal Study of Ageing (ELSA, n = 1,778) and the Health and Retirement Study (HRS, n = 1,955), with approximately 8 years of follow-up. Group-based multi-trajectory modeling identified joint trajectory groups under two strategies: general adiposity (body mass index paired with log-transformed C-reactive protein) and central adiposity (waist-to-height ratio paired with log-transformed C-reactive protein). Associations with incident diabetes were estimated using Cox proportional hazards models pooled via random-effects meta-analysis. Mediation analysis quantified the proportion statistically mediated through mid-wave HbA1c. Results Four trajectory groups were identified under each strategy in both cohorts. A graded association was observed: the highest-risk group exhibited substantially elevated diabetes risk under both general adiposity (pooled HR 6.00, 95% CI 3.71–9.70) and central adiposity strategies (pooled HR 5.69, 95% CI 3.37–9.59) after full adjustment. Under the conservative outcome definition, HbA1c mediated 13.7–27.5% of the total effect (25.7–44.8% under the original definition representing an upper bound). Trajectory classification yielded modestly higher C-statistics over baseline cross-classification (ΔC 0.061–0.067, statistically significant in HRS), with significant net reclassification improvement primarily driven by event cases. Results were consistent across strategies and cohorts. Conclusion Co-evolving trajectories of adiposity and systemic inflammation exhibit a graded association with incident diabetes in older adults, partially mediated through glycemic deterioration. Trajectory modeling offered modest discriminative gains over single-time-point assessment. These findings support concurrent adiposity-inflammation monitoring for diabetes risk stratification in aging populations.