Genetic evidence for the effects of glucokinase activation on frailty-related outcomes: A Mendelian randomisation study

IF 5.7 2区医学 Q1 ENDOCRINOLOGY & METABOLISM Diabetes, Obesity & Metabolism Pub Date : 2025-03-04 DOI:10.1111/dom.16312

Rong Hua MPhil, Mai Shi PhD, Elaine Chow PhD, Aimin Yang PhD, Yin Ting Cheung PhD

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Abstract

Aims

We aimed to use the Mendelian randomisation (MR) design to investigate the potential causal effects of glucokinase (GK) activation on frailty-related outcomes and to explore the potential mediating effects of metabolic and inflammatory biomarkers.

Materials and Methods

Seventeen independent single-nucleotide polymorphisms (SNPs) located within the GCK gene and significantly correlated with the glycated haemoglobin (HbA_1c) level were used as genetic proxies for the effect of GK activation. We employed two-sample MR analysis to assess the relationship between genetically proxied GK activation and multifactorial frailty-related outcomes (frailty index, grip strength, walking pace, appendicular lean mass [ALM] and telomere length) We also explored the potential mediating effects using two-step MR.

Results

Genetically proxied GK activation was significantly associated with a lower frailty index (beta: −0.161 per 1% decrease in HbA_1c level due to GK activation, 95% confidence interval: −0.282 to −0.040, false discovery rate-adjusted p = 0.011). Additionally, GK activation showed significant associations with increased grip strength, higher ALM, faster walking pace and longer telomere length. GK activation also demonstrated a significant indirect effect on total grip strength and telomere length by reducing C-reactive protein levels (proportion of mediation: 6.79% to 8.21%).

Conclusion

Our study provides genetic evidence supporting the causal effects of GK activation on lowering the risk of frailty. These findings suggest that GK activators (GKAs) may aid in the management of frailty and sarcopaenia in people with diabetes; however, future randomized controlled trials are necessary to validate these results and establish their clinical applicability.

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葡萄糖激酶激活对虚弱相关结果影响的遗传证据：一项孟德尔随机研究。

目的：我们旨在使用孟德尔随机化（MR）设计来研究葡萄糖激酶（GK）激活对虚弱相关结果的潜在因果影响，并探索代谢和炎症生物标志物的潜在介导作用。材料和方法：将GCK基因中与糖化血红蛋白（HbA1c）水平显著相关的17个独立单核苷酸多态性（snp）作为GK激活效应的遗传指标。我们采用两样本MR分析来评估遗传代理的GK激活与多因素脆弱相关结果（脆弱指数、握力、步行速度、阑尾瘦质量[ALM]和端粒长度）之间的关系。我们还使用两步MR探索了潜在的中介效应。结果：遗传代理的GK激活与较低的脆弱指数(β：GK激活导致的HbA1c水平每降低1%降低-0.161,95%置信区间：-0.282至-0.040，假发现率调整后p = 0.011)。此外，GK激活与握力增强、高ALM、更快的步行速度和更长的端粒长度显著相关。GK激活还通过降低c反应蛋白水平间接影响总握力和端粒长度（中介比例：6.79%至8.21%）。结论：我们的研究提供了遗传证据支持GK激活对降低衰弱风险的因果效应。这些发现表明，GK激活剂（gka）可能有助于糖尿病患者的虚弱和肌少症的管理；然而，需要未来的随机对照试验来验证这些结果并建立其临床适用性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Diabetes, Obesity & Metabolism 医学-内分泌学与代谢

CiteScore

10.90

自引率

6.90%

发文量

319

审稿时长

3-8 weeks

期刊介绍： Diabetes, Obesity and Metabolism is primarily a journal of clinical and experimental pharmacology and therapeutics covering the interrelated areas of diabetes, obesity and metabolism. The journal prioritises high-quality original research that reports on the effects of new or existing therapies, including dietary, exercise and lifestyle (non-pharmacological) interventions, in any aspect of metabolic and endocrine disease, either in humans or animal and cellular systems. ‘Metabolism’ may relate to lipids, bone and drug metabolism, or broader aspects of endocrine dysfunction. Preclinical pharmacology, pharmacokinetic studies, meta-analyses and those addressing drug safety and tolerability are also highly suitable for publication in this journal. Original research may be published as a main paper or as a research letter.