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Abstract：
BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) and SGLT1 inhibitors may have additional beneficial metabolic effects on circulating metabolites beyond glucose regulation, which could contribute to a reduction in the burden of cerebral small vessel disease (CSVD). Accordingly, we used Mendelian Randomization (MR) to examine the role of circulating metabolites in mediating SGLT2 and SGLT1 inhibition in CSVD.
METHODS: Genetic instruments for SGLT1/2 inhibition were identified as genetic variants, which were both associated with the expression of encoding genes of SGLT1/2 inhibitors and glycated hemoglobin A1c (HbA1c) level. A two-sample two-step MR was used to determine the causal effects of SGLT1/2 inhibition on CSVD manifestations and the mediating effects of 1400 circulating metabolites linking SGLT1/2 inhibition with CSVD manifestations.
RESULTS: A lower risk of deep cerebral microbleeds (CMBs) and small vessel stroke (SVS) was linked to genetically predicted SGLT2 inhibition. Better white matter structure integrity was also achieved, as evidenced by decreased mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD), as well as lower deep (DWMH) and periventrivular white matter hyperintensity (PWMH) volume. Inhibiting SGLT2 could also lessen the incidence of severe enlarged perivascular spaces (EPVS) located at white matter, basal ganglia (BG) and hippocampus (HIP). SGLT1 inhibition could preserve white matter integrity, shown as decreased MD of white matter and DWMH volume. The effect of SGLT2 inhibition on SVS and MD of white matter through the concentration of 4-acetamidobutanoate and the cholesterol to oleoyl-linoleoyl-glycerol (18:1 to 18:2) ratio, with a mediated proportion of 30.3% and 35.5% of the total effect, respectively.
CONCLUSIONS: SGLT2 and SGLT1 inhibition play protective roles in CSVD development. The SGLT2 inhibition could lower the risk of SVS and improve the integrity of white matter microstructure via modulating the level of 4-acetamidobutanoate and cholesterol metabolism. Further mechanistic and clinical studies research are needed to validate our findings.
METHODS: Genetic instruments for SGLT1/2 inhibition were identified as genetic variants, which were both associated with the expression of encoding genes of SGLT1/2 inhibitors and glycated hemoglobin A1c (HbA1c) level. A two-sample two-step MR was used to determine the causal effects of SGLT1/2 inhibition on CSVD manifestations and the mediating effects of 1400 circulating metabolites linking SGLT1/2 inhibition with CSVD manifestations.
RESULTS: A lower risk of deep cerebral microbleeds (CMBs) and small vessel stroke (SVS) was linked to genetically predicted SGLT2 inhibition. Better white matter structure integrity was also achieved, as evidenced by decreased mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD), as well as lower deep (DWMH) and periventrivular white matter hyperintensity (PWMH) volume. Inhibiting SGLT2 could also lessen the incidence of severe enlarged perivascular spaces (EPVS) located at white matter, basal ganglia (BG) and hippocampus (HIP). SGLT1 inhibition could preserve white matter integrity, shown as decreased MD of white matter and DWMH volume. The effect of SGLT2 inhibition on SVS and MD of white matter through the concentration of 4-acetamidobutanoate and the cholesterol to oleoyl-linoleoyl-glycerol (18:1 to 18:2) ratio, with a mediated proportion of 30.3% and 35.5% of the total effect, respectively.
CONCLUSIONS: SGLT2 and SGLT1 inhibition play protective roles in CSVD development. The SGLT2 inhibition could lower the risk of SVS and improve the integrity of white matter microstructure via modulating the level of 4-acetamidobutanoate and cholesterol metabolism. Further mechanistic and clinical studies research are needed to validate our findings.
摘要：
背景：钠-葡萄糖协同转运蛋白2（SGLT2）和SGLT1抑制剂可能对葡萄糖调节以外的循环代谢产物具有额外的有益代谢作用，这可能有助于减轻脑小血管病（CSVD）的负担。因此，我们使用孟德尔随机化(MR)检查循环代谢物在CSVD中介导SGLT2和SGLT1抑制中的作用.
方法：SGLT1/2抑制的遗传工具被鉴定为遗传变异，两者均与SGLT1/2抑制剂编码基因的表达和糖化血红蛋白A1c（HbA1c）水平相关。使用两个样本的两步MR来确定SGLT1/2抑制对CSVD表现的因果效应以及将SGLT1/2抑制与CSVD表现联系起来的1400种循环代谢物的中介效应。
结果：深部脑微出血（CMBs）和小血管卒中（SVS）的风险较低与基因预测的SGLT2抑制有关。还实现了更好的白质结构完整性，如平均扩散系数(MD)降低所证明的，轴向扩散率（AD），和径向扩散系数(RD)，以及较低的深度（DWMH）和腹周白质高强度（PWMH）体积。抑制SGLT2还可以减少位于白质的严重扩大的血管周围间隙（EPVS）的发生率，基底神经节（BG）和海马（HIP）。SGLT1抑制可以保持白质的完整性，显示为白质MD和DWMH体积减少。SGLT2抑制通过4-乙酰氨基丁酸酯的浓度和胆固醇与油酰基-亚油酰基-甘油（18：1至18：2）的比例对白质的SVS和MD的影响，介导比例占总效应的30.3%和35.5%，分别。
结论：SGLT2和SGLT1抑制在CSVD发展中起保护作用。SGLT2抑制可以通过调节4-乙酰氨基丁酸和胆固醇代谢的水平来降低SVS的风险并改善白质微观结构的完整性。需要进一步的机械和临床研究来验证我们的发现。
方法：SGLT1/2抑制的遗传工具被鉴定为遗传变异，两者均与SGLT1/2抑制剂编码基因的表达和糖化血红蛋白A1c（HbA1c）水平相关。使用两个样本的两步MR来确定SGLT1/2抑制对CSVD表现的因果效应以及将SGLT1/2抑制与CSVD表现联系起来的1400种循环代谢物的中介效应。
结果：深部脑微出血（CMBs）和小血管卒中（SVS）的风险较低与基因预测的SGLT2抑制有关。还实现了更好的白质结构完整性，如平均扩散系数(MD)降低所证明的，轴向扩散率（AD），和径向扩散系数(RD)，以及较低的深度（DWMH）和腹周白质高强度（PWMH）体积。抑制SGLT2还可以减少位于白质的严重扩大的血管周围间隙（EPVS）的发生率，基底神经节（BG）和海马（HIP）。SGLT1抑制可以保持白质的完整性，显示为白质MD和DWMH体积减少。SGLT2抑制通过4-乙酰氨基丁酸酯的浓度和胆固醇与油酰基-亚油酰基-甘油（18：1至18：2）的比例对白质的SVS和MD的影响，介导比例占总效应的30.3%和35.5%，分别。
结论：SGLT2和SGLT1抑制在CSVD发展中起保护作用。SGLT2抑制可以通过调节4-乙酰氨基丁酸和胆固醇代谢的水平来降低SVS的风险并改善白质微观结构的完整性。需要进一步的机械和临床研究来验证我们的发现。
