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Genetically proxied glucokinase activation and risk of diabetic complications: Insights from phenome-wide and
Ziqi Zhang1, Yanxiao Xie2, Zhenlin Bu3
1Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
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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