Abstract
Background: While parental type 2 diabetes (T2D) is a known risk factor for offspring T2D, the differential impact of maternal versus paternal transmission remains debated. Methods: This prospective family-based cohort study enrolled 4508 diabetes-free adults from Northern China with a median 7.32-year follow-up. Using Cox proportional hazards models, we examined parent-of-origin effects on T2D incidence, adjusting for lifestyle, adiposity, and metabolic covariates. Results: Parental T2D conferred elevated offspring risk (adjusted HR = 1.82, 95% CI:1.44-2.30), and was predominantly driven by maternal transmission. Maternal T2D was robustly associated with offspring risk (HR = 1.89, 95% CI: 1.47-2.43), whereas paternal T2D showed no significant effect (HR = 1.27, 95% CI: 0.88-1.84). Offspring with only maternal T2D history exhibited the highest risk (HR = 2.55, 95% CI: 1.87-3.50; p = 4.70 × 10(-9)), persisting after full adjustment, while no significant association was observed for paternal diabetes. Lifestyle modified this association: healthy diet (diet score > 2 vs. ≤2: HR = 1.34 vs. 2.76; p(interaction) = 9.10 × 10(-4)) and regular exercise (regular vs. unregular: HR = 1.13 vs. 2.10; p(interaction) = 4.20 × 10(-2)) attenuated maternal transmission. Conclusions: Maternal T2D confers greater intergenerational risk than paternal T2D, with modifiable lifestyle factors mitigating this association. These findings highlight the importance of integrating maternal diabetes history into clinical risk stratification tools and prioritizing lifestyle interventions in the offspring of affected mothers to mitigate inherited risk.