Assessment of relationships between frailty and diabetes: A two-sample Mendelian randomization study

Objectives Observational studies have suggested a unidirectional association between frailty and diabetes; however, their causal relationship remains unclear. This study aimed to investigate the bidirectional causal associations between frailty and diabetes to provide more definitive evidence. Methods We conducted a two-sample Mendelian randomization study using genome-wide association study data to examine the bidirectional causal relationship between frailty—measured by the frailty index and Fried Frailty Phenotype—and diabetes, including type 2 diabetes mellitus, type 1 diabetes mellitus, fasting glucose, fasting insulin, and glycated hemoglobin. The inverse variance–weighted method was used for the primary analysis. Pleiotropy was assessed using the Mendelian randomization–Egger intercept and Mendelian randomization–PRESSO methods. Sensitivity analyses were performed using the leave-one-out approach and Cochran’s Q test to ensure robustness of the findings. Results Type 2 diabetes mellitus was significantly associated with both the frailty index (β = 0.029, 95% confidence interval: 0.014–0.043, p = 6.00 × 10 −5 ) and the Fried Frailty Phenotype (β = 0.025, 95% confidence interval: 0.016–0.033, p = 2.78 × 10 −9 ). Type 1 diabetes mellitus demonstrated a weaker positive association with the Fried Frailty Phenotype (β = 0.004, 95% confidence interval: 0.0004–0.009, p = 0.031). Among diabetes-related clinical traits, only glycated hemoglobin demonstrated significant associations with both the frailty index (β = 0.049, 95% confidence interval: 0.031–0.067, p = 7.39 × 10 −8 ) and the Fried Frailty Phenotype (β = 0.013, 95% confidence interval: 0.001–0.024, p = 0.021). Reverse Mendelian randomization analyses indicated that frailty was significantly associated with an increased risk of type 2 diabetes mellitus and higher levels of glycated hemoglobin, but not with type 1 diabetes mellitus. Sensitivity analyses indicated no significant evidence of pleiotropy or heterogeneity (p > 0.05), supporting the reliability of the results. Conclusions Our findings suggest a bidirectional causal relationship between frailty and both type 2 diabetes mellitus and glycated hemoglobin. However, the association between type 1 diabetes mellitus and frailty remains inconclusive and requires further research. These results provide important evidence to guide the prevention and clinical management of frailty and diabetes.