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

Glucokinase activator (GKA) has shown potential in influencing cardio-cerebrovascular diseases (CVDs), yet its metabolic mechanism remains unclear. Circulating metabolites play a significant role in the etiology of CVDs. We hypothesized that the effects of GKA on cardio-cerebrovascular outcomes are mediated through circulating metabolites. We selected genetic variants associated with GCK mRNA expression levels and HbA1c as genetic instruments for GKA. Data on 168 circulating metabolites measured by nuclear magnetic resonance spectroscopy, along with information on atrial fibrillation (AF), heart failure (HF), coronary artery disease (CAD), myocardial infarction (MI), and stroke, were retrieved from large-scale datasets. Using two-sample Mendelian randomization analysis, we investigated the causal associations between GKA and CVDs. Furthermore, we performed two mediation analyses-two-step MR and multivariable MR (MVMR)-to identify potential mediating metabolites. Genetically predicted GKA was significantly associated with a reduced risk of AF (OR = 0.71 [95% CI 0.54, 0.95], P = 0.019) and stroke (OR = 0.97 [95% CI 0.96, 0.98], P = 4.82 × 10-5). No causal relationships were found between GKA and heart failure, coronary artery disease, or myocardial infarction. Among 168 circulating metabolites, 36 were associated with GKA, with 1 mediating the effect of AF. This study supported the association of GKA with a reduced risk of AF and stroke. The average diameter of very-low-density lipoprotein (VLDL) particles mediated the protective effect of GKA against AF. Further research is needed to clarify the detailed mechanisms of GKA's effects on these metabolites and their translation into reduced CVDs risk, especially considering different ethnic groups.