Genetically proxied glucokinase activation and risk of diabetic complications: Insights from phenome-wide and multi-omics mendelian randomization

IF 6.1 3区医学 Q1 ENDOCRINOLOGY & METABOLISM

Diabetes research and clinical practice Pub Date : 2025-05-13 DOI:10.1016/j.diabres.2025.112246

Ziqi Zhang , Yanxiao Xie , Zhenlin Bu , Yingying Xiang , Wei Sheng , Ying Cao , LeShen Lian , Li Zhang , Wei Qian , Guang Ji

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Abstract

Aims

This study aims to assess the benefits and adverse effects of long-term glucokinase (GK) activation from a genetic perspective.

Methods

We identified genetic variants in the GCK gene associated with glycated hemoglobin (HbA1c) levels from a genome-wide association study (GWAS) involving 146,806 individuals, which served as proxies for glucokinase activation. To assess the effects and potential pathways of GK activation on a range of diabetic complications and safety outcomes, we integrated drug-target Mendelian randomization (MR), lipidome-wide and proteome-wide MR, phenome-wide MR, and colocalization analyses.

Results

Genetically proxied GK activation was associated with reduced risks of several predefined diabetic complications, including cardiovascular diseases, stroke and diabetic retinopathy. No kidney-related benefits were observed. Safety analysis revealed a relationship between GK activation and elevated AST levels, while impaired interaction between GK and glucokinase regulatory protein (GKRP) was associated with dyslipidemia, increased liver fat content, AST, systolic blood pressure, and uric acid. Phenome-wide MR suggested that GK activation may have potential benefits for lung function and fluid intelligence score.

Conclusions

Our genetic evidence supports GK as a promising target for reducing the risk of specific diabetic complications. These findings require further validation through cohort studies and randomized controlled trials in patients with diabetes.

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基因介导的葡萄糖激酶激活和糖尿病并发症的风险：来自全现象和多组学孟德尔随机化的见解

目的本研究旨在从遗传学角度评估长期激活葡萄糖激酶（GK）的益处和不良影响。方法：我们从一项涉及146,806人的全基因组关联研究（GWAS）中发现了与糖化血红蛋白（HbA1c）水平相关的GCK基因的遗传变异，该基因可作为葡萄糖激酶激活的替代指标。为了评估GK激活对一系列糖尿病并发症和安全性结果的影响和潜在途径，我们整合了药物靶向孟德尔随机化（MR）、脂质组和蛋白质组全范围MR、全现象MR和共定位分析。结果基因介导的GK激活与几种预先定义的糖尿病并发症（包括心血管疾病、中风和糖尿病视网膜病变）的风险降低相关。没有观察到与肾脏相关的益处。安全性分析显示GK激活与AST水平升高之间存在关系，而GK与葡萄糖激酶调节蛋白（GKRP）相互作用受损与血脂异常、肝脂肪含量、AST、收缩压和尿酸升高有关。全现象MR提示GK激活可能对肺功能和液体智力评分有潜在的益处。结论遗传证据支持GK作为降低特定糖尿病并发症风险的有希望的靶点。这些发现需要通过糖尿病患者的队列研究和随机对照试验进一步验证。

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 research and clinical practice 医学-内分泌学与代谢

CiteScore

10.30

自引率

3.90%

发文量

862

审稿时长

32 days

期刊介绍： Diabetes Research and Clinical Practice is an international journal for health-care providers and clinically oriented researchers that publishes high-quality original research articles and expert reviews in diabetes and related areas. The role of the journal is to provide a venue for dissemination of knowledge and discussion of topics related to diabetes clinical research and patient care. Topics of focus include translational science, genetics, immunology, nutrition, psychosocial research, epidemiology, prevention, socio-economic research, complications, new treatments, technologies and therapy.