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

IF 5.4 2区医学 Q1 ENDOCRINOLOGY & METABOLISM

Diabetes, Obesity & Metabolism Pub Date : 2025-03-04 DOI:10.1111/dom.16312

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

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引用次数: 0

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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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.