Genetically proxied glucokinase activation and risk of diabetic complications: Insights from phenome-wide and multi-omics mendelian randomization
Authors' conclusion
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.
Study context
- Population
- GCK variants associated with HbA1c from a genome-wide association study (GWAS) of 146,806 individuals, as proxies for glucokinase (GK) activationGWAS
- Participants
- 146,806 participants
- Comparison
- Genetically proxied GK activation
- Outcome
- Risk of predefined diabetic complications
Methodological detailsdrug-target Mendelian randomization (MR), lipidome-wide and proteome-wide MR, phenome-wide MR, colocalization analyses
- Drug-target MR
- Lipidome-wide and proteome-wide MR
- Phenome-wide MR
- Colocalization analyses
Main finding
As reported in the abstract
Predefined diabetic complications
- GK activation associated with reduced risks of several predefined diabetic complications, incl. CVD, stroke and DR
- No kidney-related benefits observed
Further findings
Phenome-wide MR
- GK activation may have potential benefits for lung function and fluid intelligence score
Safety
Safety outcomes
- GK activation associated with elevated AST levels
- Impaired GK–GKRP interaction associated with dyslipidemia, increased liver fat content, AST, systolic blood pressure and uric acid
Original publication
Genetically proxied glucokinase activation and risk of diabetic complications: Insights from phenome-wide and multi-omics mendelian randomization. Diabetes Res Clin Pract. Published 13 May 2025. doi:10.
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