Glucokinase Regulatory Protein as a Putative Target for Gestational Diabetes Mellitus and Related Complications: Evidence From the Mendelian Randomization Study

IF 3 2区医学 Q2 ENDOCRINOLOGY & METABOLISM

Journal of Diabetes Pub Date : 2025-02-08 DOI:10.1111/1753-0407.70056

Weian Mao, Guiquan Wang, Xiao Wang, Yan Shen, Shuai Yuan, Lin Wang, Haiyan Yang, Yan Li, Kai Chen, Jun Liu, Xi Dong, Yue Zhao, Liangshan Mu

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引用次数: 0

Abstract

Background

Gestational diabetes mellitus (GDM) is one of the most common complications of pregnancy and is highly associated with adverse perinatal outcomes and long-term health problems for the mother and offspring. However, there are respective limitations in the pharmacological strategies for the current treatment of GDM. Glucokinase regulatory protein (GCKR) has been associated with GDM in observational studies and animal experiments and thus represents a potential drug target of interest for investigation.

Methods

We applied two-sample Mendelian randomization (MR) and colocalization analysis using summary-level data from genome-wide association studies of GCKR and GDM. Two-step MR was used to explore the mediating effects of several metabolic factors on the association. We also applied MR to explore the associations of GCKR levels with GDM-related outcomes. Finally, we performed a phenome-wide association study (PheWAS) to query the potential effects of altered GCKR levels across multiple health categories.

Results

We found a significant association between elevated GCKR levels and GDM (OR = 3.466, 95% CI = 2.401–5.002, p = 3.16 × 10⁻¹¹), also supported by the colocalization analysis ([P_coloc] = 0.997). The estimates were replicated in an independent study (OR = 2.640, 95% CI = 1.983–3.513, p = 2.84 × 10⁻¹¹, P_coloc = 0.983). Elevated GCKR levels were also associated with higher risk of type 2 diabetes (OR = 2.183, 95% CI = 1.846–2.581, p = 6.53 × 10⁻²⁰). Two-step MR suggested that fasting glucose, fasting insulin, and triglycerides partly mediated the causal relationship. PheWAS found that targeting GCKR may improve renal function and glucose homeostasis but cause dyslipidemia and uric acid abnormalities.

Conclusions

This study provided novel evidence that circulating GCKR levels are causally implicated in GDM and related complications, suggesting that it may be a promising target for treatment.

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葡萄糖激酶调节蛋白作为妊娠期糖尿病及相关并发症的假定靶点：来自孟德尔随机化研究的证据

妊娠期糖尿病（GDM）是妊娠期最常见的并发症之一，与不良的围产期结局和母亲和后代的长期健康问题高度相关。然而，目前治疗GDM的药理学策略存在各自的局限性。葡萄糖激酶调节蛋白（GCKR）在观察性研究和动物实验中与GDM有关，因此代表了研究的潜在药物靶点。方法利用GCKR和GDM全基因组关联研究的汇总数据，采用双样本孟德尔随机化（MR）和共定位分析。两步磁共振（Two-step MR）研究了几种代谢因子在这种关联中的中介作用。我们还应用MR来探讨GCKR水平与gdm相关结果的关系。最后，我们进行了一项全现象关联研究（PheWAS），以查询多种健康类别中GCKR水平改变的潜在影响。结果我们发现GCKR水平升高与GDM之间存在显著相关性（OR = 3.466, 95% CI = 2.401-5.002, p = 3.16 × 10−11），共定位分析也支持这一结果（[Pcoloc] = 0.997）。这些估计在独立研究中得到了重复（OR = 2.640, 95% CI = 1.983-3.513, p = 2.84 × 10−11,Pcoloc = 0.983）。GCKR水平升高也与2型糖尿病的高风险相关（OR = 2.183, 95% CI = 1.846-2.581, p = 6.53 × 10−20）。两步磁共振提示空腹血糖、空腹胰岛素和甘油三酯部分介导了因果关系。PheWAS发现靶向GCKR可以改善肾功能和葡萄糖稳态，但会引起血脂异常和尿酸异常。本研究提供了新的证据，证明循环GCKR水平与GDM及其相关并发症有因果关系，表明它可能是一个有希望的治疗靶点。

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

Journal of Diabetes ENDOCRINOLOGY & METABOLISM-

CiteScore

6.50

自引率

2.20%

发文量

审稿时长

>12 weeks

期刊介绍： Journal of Diabetes (JDB) devotes itself to diabetes research, therapeutics, and education. It aims to involve researchers and practitioners in a dialogue between East and West via all aspects of epidemiology, etiology, pathogenesis, management, complications and prevention of diabetes, including the molecular, biochemical, and physiological aspects of diabetes. The Editorial team is international with a unique mix of Asian and Western participation. The Editors welcome submissions in form of original research articles, images, novel case reports and correspondence, and will solicit reviews, point-counterpoint, commentaries, editorials, news highlights, and educational content.