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Glucokinase activator, circulating metabolites, and cardio-cerebrovascular diseases: a Mendelian randomization study

Xiaohan Wang1, Weimeng Cheng1, Tingting Xu1

  • 1Department of Cardiology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.

Cardiovascular Diabetology
|July 31, 2025
PubMed

Insights

Glucokinase activator (GKA) reduces the risk of atrial fibrillation and stroke. The average diameter of very-low-density lipoprotein (VLDL) particles mediates this protective effect against atrial fibrillation.

Area of Science:

  • Cardiovascular Science
  • Metabolomics
  • Genetics

Background:

  • Glucokinase activators (GKAs) show potential in managing cardio-cerebrovascular diseases (CVDs).
  • The precise metabolic mechanisms underlying GKA's effects on CVDs remain largely unelucidated.
  • Circulating metabolites are recognized as significant contributors to CVD development.

Purpose of the Study:

  • To investigate the causal relationship between GKA and various CVDs.
  • To identify circulating metabolites that mediate the effects of GKA on cardio-cerebrovascular outcomes.
  • To explore the role of GKA in influencing metabolic pathways relevant to CVDs.

Main Methods:

  • Utilized two-sample Mendelian randomization analysis with genetic variants for GKA and HbA1c.
  • Analyzed data on 168 circulating metabolites from large-scale datasets.
  • Employed two-step and multivariable Mendelian randomization (MVMR) for mediation analysis.

Main Results:

  • Genetically predicted GKA was associated with reduced risks of atrial fibrillation (AF) and stroke.
  • No significant causal associations were found between GKA and heart failure, coronary artery disease, or myocardial infarction.
  • Thirty-six out of 168 metabolites were associated with GKA, with one metabolite mediating the AF association.

Conclusions:

  • GKA is associated with a decreased risk of AF and stroke.
  • The average diameter of very-low-density lipoprotein (VLDL) particles was identified as a mediator of GKA's protective effect against AF.
  • Further research is warranted to fully elucidate GKA's metabolic mechanisms and their impact on CVD risk across diverse populations.
Abstract

Keywords:
Atrial fibrillationCardio-cerebrovascular diseasesCirculating metabolitesGlucokinase activatorMendelian randomizationStroke

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