BackgroundAlthough pharmacological effects of SGLT2 inhibitors on the development of frailty and sarcopenia were known, the role of SGLT1 remained less clear. The present study investigated the possible effect of SGLT1 inhibition on these conditions and explored potential mediators.MethodsA two‐sample Mendelian randomization (MR) analysis was performed to assess the effect of SGLT1 inhibition on frailty index (FI) and low grip strength in individuals aged 60 years and older using both the FNIH and EWGSOP criteria. Subsequently, a two‐step MR analysis was conducted to investigate the mediating role of insulin resistance phenotype and identify potential mediators of the effect of SGLT1 inhibition on the FI and low grip strength from 1558 plasma proteins and 1352 metabolites.ResultsGenetically predicted SGLT1 inhibition was associated with decreased FI (β: −0.290 [95% CI: −0.399, −0.181]) and reduced risk of low grip strength in individuals aged 60 years and older under both FNIH (β: −0.796 [95% CI: −1.216, −0.376]) and EWGSOP criteria (β: −0.287 [95% CI: −0.532, −0.041]). The two‐step MR analysis demonstrated the role of insulin resistance phenotype in mediating SGTL1 inhibition on alleviating frailty (mediation proportion = 19.56% [95% CI: 8.42%, 30.70%]). After screening, 24 proteins and 16 metabolites were identified as mediators of the impact of SGLT1 inhibition on FI. Additionally, 13 proteins and 16 metabolites were found to mediate the effect of SGLT1 inhibition on low grip strength according to FNIH criteria while 22 proteins and 6 metabolites were shown to mediate the impact of SGLT1 inhibition on low grip strength under EWGSOP criteria.ConclusionsSGLT1 inhibition potentially mitigated frailty and sarcopenia through several biological mediators, shedding new light for therapeutic intervention.

中文翻译：

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SGLT1 抑制对虚弱和肌肉减少症的影响：一项介导孟德尔随机化研究


背景尽管已知 SGLT2 抑制剂对虚弱和肌肉减少症发展的药理作用，但 SGLT1 的作用仍不清楚。本研究调查了 SGLT1 抑制对这些情况的可能影响，并探讨了潜在的介质。方法进行双样本孟德尔随机化 （MR） 分析，以评估 SGLT1 抑制对 60 岁及以上个体虚弱指数 （FI） 和低握力的影响，同时使用 FNIH 和 EWGSOP 标准。随后，进行了两步 MR 分析，以研究胰岛素抵抗表型的中介作用，并确定 SGLT1 抑制对 1558 种血浆蛋白和 1352 种代谢物的 FI 和低握力影响的潜在介质。结果遗传学预测的 SGLT1 抑制与 FI 降低（β：-0.290 [95% CI：-0.399，-0.181]）和 60 岁及以上个体的握力低风险相关，根据 FNIH （β： -0.796 [95% CI： -1.216， -0.376]）和 EWGSOP 标准（β：-0.287 [95% CI：-0.532，-0.041]）。两步 MR 分析证明了胰岛素抵抗表型在介导 SGTL1 抑制对缓解虚弱的作用 （中介比例 = 19.56% [95% CI： 8.42%， 30.70%]）。经过筛选，24 种蛋白质和 16 种代谢物被鉴定为 SGLT1 抑制对 FI 影响的介质。此外，根据 FNIH 标准，发现 13 种蛋白质和 16 种代谢物介导 SGLT1 抑制对低握力的影响，而 22 种蛋白质和 6 种代谢物被证明介导 SGLT1 抑制对 EWGSOP 标准下低握力的影响。结论SGLT1 抑制可能通过多种生物介质减轻虚弱和肌肉减少症，为治疗干预提供新的思路。