Type 2 diabetes mellitus (T2DM) is a common metabolic disease that can lead to a wide range of complications and impose a significant economic burden to society. Frailty is a disease associated with the accumulation of health deficits that may affect the quality of life of T2DM patients. This Mendelian randomization (MR) study explores the bidirectional causality between T2DM and frailty. All the data was available online at the IEU OpenGWAS project for this study, with the original data for T2DM coming from the pooled statistics of 468,298 participants in the UK biobank, and for frailty from the pooled summary statistics of a total of 175,226 participants in the UK biobank and Swedish TwinGene. The populations were all of European ancestry. Inverse variance weighting (IVW) was the main analytical method for assessing the causal effects of exposure and outcome, in addition, we also complemented weighted median and MR-Egger methods. Heterogeneity tests were performed with Cochran Q statistic and I2 statistic, and horizontal pleiotropy tests were detected through an intercept term in the MR-Egger regression model and MR-PRESSO. A sensitivity analysis was further performed with the leave-one-out method to estimate the impact of individual genetic variants on the overall outcomes. At the gene level, we identified 63 single nucleotide polymorphisms (SNPs) associated with T2DM and 14 SNPs associated with frailty for MR analysis. In the bidirectional MR analysis, the MR-Egger intercept and MR-PRESSO revealed no horizontal pleiotropy (P >
.05), while significant heterogeneities were found by the heterogeneity test (P <
.05). IVW results showed that frailty significantly increased the risk of T2DM (OR = 2.33, 95% confidence interval [CI] = 1.66-3.26, P <
.001), and the similar result existed in the reverse MR analysis (OR = 1.04, 95% CI = 1.02-1.06, P <
.001). A bidirectional causal relationship exists between T2DM and frailty, with intervention for either disease reducing the risk of the other.