Longitudinal association between insulin resistance and depressive symptoms in older adults: the mediating role of inflammation in the ELSA cohort.

BACKGROUND: Insulin resistance (IR) has been implicated in depression, yet the dynamic interplay between concurrent changes in IR and depressive symptoms over time, and whether systemic inflammation mediates this relationship, remains unclear. METHODS: Data were obtained from 3,404 older adults (aged ≥50 years) in the English Longitudinal Study of Ageing (ELSA) across Waves 2, 4, and 6. IR was assessed using the estimated glucose disposal rate (eGDR). Depressive symptoms were measured with the CES-D scale (0-8). C-reactive protein (CRP) was log-transformed as the mediator. Linear mixed models were used to assess the longitudinal association between changes in eGDR and CES-D score. Restricted cubic splines were applied to explore potential nonlinear dose-response relationships. Mediation analysis was conducted to test whether CRP mediated the association. Subgroup and sensitivity analyses were performed to evaluate the robustness of the findings. RESULTS: In the overall population, eGDR was significantly associated with CES-D score (P = 0.003), with no evidence of nonlinearity (P = 0.074). The overall eGDR × time interaction was not significant (P = 0.349). When stratified by joint trajectories of eGDR and CES-D, significant eGDR × time interactions were observed in two groups: the decrease-increase group (eGDR declined and CES-D increased, β = -0.018, P < 0.001), and the increase-decrease group, (eGDR increased and CES-D decreased, β = 0.021, P < 0.001). CRP partially mediated the association, with an indirect effect of -0.00092 (95% CI: -0.00155 to -0.00042), accounting for 10.8% of the total effect. Subgroup and sensitivity analyses confirmed robustness. CONCLUSIONS: The longitudinal association between IR and depressive symptoms differs across developmental trajectories and appears to be partially mediated by systemic inflammation. Our findings suggest that improvements in insulin sensitivity are associated with a lower risk of depressive symptoms in older adults.