Longitudinal multimorbidity trajectories shape personalized glycaemic patterns.

Older individuals often live with diverse combinations of chronic diseases. However, whether multimorbidity contributes to glycaemic dysregulation remains unclear. Here we show that cumulative disease trajectories shape interindividual glycaemic variability throughout the ageing process. Tracking 1,398 participants in the Guangzhou Nutrition and Health Study cohort over 12 years, we develop a systemic multimorbidity index (MMI-system) that reflects the cumulative burden of chronic disorders. We also measure individual glycaemic dynamics and responses to dietary challenges using continuous glucose monitoring at the latest follow-up visit (mean age, 69.2 years). MMI-system exhibits dose-dependent associations with glycaemic variability and sensitivity to dietary challenges, independent of diabetes status. Longitudinal proteome mapping reveals that lipid homeostasis proteins explain 12.9% of the association between MMI-system and personalized dietary responses. These findings are independently validated in the China Health and Nutrition Survey cohort. Overall, our study suggests that integrating longitudinal multimorbidity profiling with circulating proteomics may enhance precision glycaemic management, offering actionable insights for dietary interventions in the older population.