Background and purposeObservational studies have shown that sarcopenia and diabetic nephropathy (DN), are closely related; however, the causal relationship is unclear. This study aims to address this issue using a bidirectional Mendelian randomization (MR) study.MethodologyWe data from genome-wide association studies including appendicular lean mass (n = 244,730), grip strength (right: n = 461,089, left: n = 461026), walking speed (n = 459,915), and DN (3283 cases and 181,704 controls) to conduct a bidirectional MR study. First, we conducted a Forward MR analysis to evaluate the causality of sarcopenia on the risk of DN from the genetic perspective with appendicular lean mass, grip strength, and walking speed as exposure and DN as the outcome. Then, DN as the exposure, we performed a Reverse MR analysis to determine whether DN impacted the appendicular lean mass, grip strength, and walking speed of the appendices. Finally, a series of sensitivity studies, such as heterogeneity tests, pleiotropy evaluations, and Leave-one-out analyses, were conducted to assess the MR analysis’s accuracy further.ResultsAccording to a forward MR analysis, a genetically predicted decrease in appendicular lean mass is associated with an increased risk of developing DN risk (inverse variance weighting[IVW]: odd ratio [OR] = 0.863, 95% confidence interval [CI] 0.767-0.971; P = 0.014). According to reverse MR results, grip strength decreased as DN progressed (IVW: right β = 0.003, 95% CI: - 0.021 to - 0.009, P = 5.116e-06; left β = 0.003, 95% CI: - 0.024 to - 0.012, P = 7.035e-09). However, the results of the other MR analyses were not statistically different.ConclusionNotably, our findings suggest that the causal relationship between sarcopenia and DN cannot be generalized. According to analysis of the individual characteristic factors of sarcopenia, reducing in appendicular lean mass increases the risk of developing DN and DN is linked to reduced grip strength. But overall, there is no causal relationship between sarcopenia and DN, because the diagnosis of sarcopenia cannot be determined by one of these factors alone.