The Impact of SGLT1 Inhibition on Frailty and Sarcopenia: A Mediation Mendelian Randomization Study.

IF 8.9 1区医学 Journal of Cachexia, Sarcopenia and Muscle Pub Date : 2024-10-30 DOI:10.1002/jcsm.13614

Bang-Bang Huang, Yu-Jie Zhang, Guang-Feng Ruan, Xing Yu, Qin Liu, Mei-Jin Zhang, Ming-Zhong Yu, Ai Chen, Ye-Bei Liang, Liang-Di Xie, Li Luo

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Abstract

Background: Although 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.

Methods: A 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.

Results: Genetically 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.

Conclusions: SGLT1 inhibition potentially mitigated frailty and sarcopenia through several biological mediators, shedding new light for therapeutic intervention.

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SGLT1 抑制剂对虚弱和肌肉疏松症的影响：调解孟德尔随机化研究

背景：尽管人们知道 SGLT2 抑制剂对虚弱和肌肉疏松症发展的药理作用，但 SGLT1 的作用仍然不太清楚。本研究调查了 SGLT1 抑制剂对这些病症可能产生的影响，并探讨了潜在的中介因素：方法：采用 FNIH 和 EWGSOP 标准，对 60 岁及以上人群进行双样本孟德尔随机化（MR）分析，评估 SGLT1 抑制对虚弱指数（FI）和低握力的影响。随后，进行了两步 MR 分析，研究胰岛素抵抗表型的中介作用，并从 1558 种血浆蛋白和 1352 种代谢物中找出 SGLT1 抑制对虚弱指数和低握力影响的潜在中介因子：根据 FNIH（β：-0.796 [95% CI：-1.216, -0.376]）和 EWGSOP（β：-0.287 [95% CI：-0.532, -0.041]）标准，遗传预测 SGLT1 抑制与 FI 下降（β：-0.290 [95% CI：-0.399, -0.181]）和 60 岁及以上人群低握力风险降低相关。两步 MR 分析表明，胰岛素抵抗表型对抑制 SGTL1 减轻虚弱起着中介作用（中介比例 = 19.56% [95% CI: 8.42%, 30.70%]）。经过筛选，有 24 种蛋白质和 16 种代谢物被确定为 SGLT1 抑制对虚弱影响的介导因子。此外，根据 FNIH 标准，发现 13 种蛋白质和 16 种代谢物可介导 SGLT1 抑制对低握力的影响；根据 EWGSOP 标准，22 种蛋白质和 6 种代谢物可介导 SGLT1 抑制对低握力的影响：结论：SGLT1抑制可通过多种生物介质减轻虚弱和肌肉疏松症，为治疗干预提供了新的思路。

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来源期刊

Journal of Cachexia, Sarcopenia and Muscle Medicine-Orthopedics and Sports Medicine

自引率

12.40%

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期刊介绍： The Journal of Cachexia, Sarcopenia, and Muscle is a prestigious, peer-reviewed international publication committed to disseminating research and clinical insights pertaining to cachexia, sarcopenia, body composition, and the physiological and pathophysiological alterations occurring throughout the lifespan and in various illnesses across the spectrum of life sciences. This journal serves as a valuable resource for physicians, biochemists, biologists, dieticians, pharmacologists, and students alike.