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

ObjectivesObservational 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.MethodsWe 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.ResultsType 2 diabetes mellitus was significantly associated with both the frailty index (β = 0.029, 95% confidence interval: 0.014-0.043, p<i> </i>=<i> </i>6.00 × 10^-5) and the Fried Frailty Phenotype (β = 0.025, 95% confidence interval: 0.016-0.033, p<i> </i>=<i> </i>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<i> </i>=<i> </i>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<i> </i>=<i> </i>7.39 × 10^-8) and the Fried Frailty Phenotype (β = 0.013, 95% confidence interval: 0.001-0.024, p<i> </i>=<i> </i>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<i> </i>><i> </i>0.05), supporting the reliability of the results.ConclusionsOur 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.