Lipids & metabolic liver disease
Impaired GK-GKRP interaction rather than direct glucokinase (GK) activation worsens lipid profiles and contributes to long-term complications: a Mendelian randomization study
Authors' conclusion
Impaired GK-GKRP interaction, rather than direct GK activation, may worsen lipid profiles and increase risks of MASLD and CAD. Development of future GKAs should avoid interfering with GK-GKRP interaction.
Study context
- Population
- Publicly available GWAS summary statistics; validation with individual-level data from the Hong Kong Diabetes Register (HKDR)
- Comparison
- Genetically-proxied impaired GK-GKRP interaction vs direct GK activation
- Outcome
- Lipid-related traits, risks of MASLD and cardiovascular diseases
Methodological detailstwo-sample Mendelian Randomization (MR), one-sample MR validation (Hong Kong Diabetes Register)
- Two-sample MR
- One-sample MR validation (Hong Kong Diabetes Register)
Performance
As reported in the abstract
Lipid traits, MASLD and CAD
| Test or model | OR for MASLD per 1 mmol/L lower fasting plasma glucose (FPG) | OR for coronary artery disease (CAD) |
|---|---|---|
| Impaired GK-GKRP interaction | 14.6 (95% CI 4.57-46.4) | 2.92 (95% CI 1.78-4.81) |
| GK activation | 0.69 (95% CI 0.54-0.88) |
OR for MASLD per 1 mmol/L lower fasting plasma glucose (FPG)
Impaired GK-GKRP interaction14.6 (95% CI 4.57-46.4)
GK activation— not stated in the abstract
OR for coronary artery disease (CAD)
Impaired GK-GKRP interaction2.92 (95% CI 1.78-4.81)
GK activation0.69 (95% CI 0.54-0.88)
Further findings
One-sample MR validation in HKDR
- Consistent results
Original publication
Impaired GK-GKRP interaction rather than direct GK activation worsens lipid profiles and contributes to long-term complications: a Mendelian randomization study. Cardiovasc Diabetol. Published 29 June 2024. doi:10.
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