Mendelian Randomization Analyses Indicate a Causal Association Between Sodium-Glucose Cotransporter-1 Inhibition and Mitochondrial Function

Introduction: The role of sodium-glucose cotransporter-1 (SGLT1) in mitochondrial biology function remains unclear. This study aimed to investigate the causal association between SGLT1 inhibition and mitochondrial biology function via Mendelian randomization (MR) analysis. Methods: A two-sample MR study was conducted to evaluate the association of SGLT1 inhibition with mitochondrial biology. The identification of genetic instruments for SGLT1 inhibition as genetic variants was achieved, and these were found to be associated with the expression of the SLC5A1 gene and glycated hemoglobin level (HbA1c). The principal analysis employed was the random inverse variance weighted (IVW) algorithm. The weighted median and the MR-Egger method are supplementary methods for IVW analysis. Sensitivity analyses were performed to assess the reliability of the results. Results: The results indicated that genetically predicted SGLT1 inhibition was positively related with mitochondrial Serine tRNA ligase (βIVW = 1.40 95% confidence interval (CI) 0.59, 2.22), NADH dehydrogenase ubiquinone 1 beta subcomplex subunit 8 (βIVW = 2.35 95% CI 1.00, 3.69), and other up-regulated mitochondrial components. Meanwhile, SGLT1 inhibition was negatively associated with mitochondrial Glutaredoxin-2 (βIVW = -2.52 95% CI -3.56, -1.48), Pyruvate carboxylase (βIVW = -1.07 95% CI -1.89, -0.26), Mitochondrial glutamate carrier 2 (βIVW = -1.78 95% CI -2.62, -0.93), and other down-regulated mitochondrial components in European population. Discussion: This study found that SGLT1 inhibition is causally associated with NDUFB8, MICU3, MLYCD, SOD2, Serine tRNA ligase, MCAD, REXO2, SIRT5, TIM14, ETHE1, HOGA, GRX2, PC, and MTC2. By regulating these proteins, SGLT1 contributes to the modulation of mitochondrial biological function. It is imperative that further basic and clinical studies be conducted to elucidate the mechanisms underlying this causal relationship. Conclusion: We determined for the first time that genetically predicated SGLT1 inhibition is causally linked to a variety of mitochondrial biology processes in the European population.