Glucokinase Regulatory Protein as a Putative Target for Gestational Diabetes Mellitus and Related Complications:...

Gestational diabetes mellitus (GDM) is one of the most common complications of pregnancy and is highly associated with adverse perinatal outcomes and long-term health problems for the mother and offspring. However, there are respective limitations in the pharmacological strategies for the current treatment of GDM. Glucokinase regulatory protein (GCKR) has been associated with GDM in observational studies and animal experiments and thus represents a potential drug target of interest for investigation.

We applied two-sample Mendelian randomization (MR) and colocalization analysis using summary-level data from genome-wide association studies of GCKR and GDM. Two-step MR was used to explore the mediating effects of several metabolic factors on the association. We also applied MR to explore the associations of GCKR levels with GDM-related outcomes. Finally, we performed a phenome-wide association study (PheWAS) to query the potential effects of altered GCKR levels across multiple health categories.

We found a significant association between elevated GCKR levels and GDM (OR = 3.466, 95% CI = 2.401-5.002, p = 3.16 × 10^-11), also supported by the colocalization analysis ([P_coloc] = 0.997). The estimates were replicated in an independent study (OR = 2.640, 95% CI = 1.983-3.513, p = 2.84 × 10^-11, P_coloc = 0.983). Elevated GCKR levels were also associated with higher risk of type 2 diabetes (OR = 2.183, 95% CI = 1.846-2.581, p = 6.53 × 10^-20). Two-step MR suggested that fasting glucose, fasting insulin, and triglycerides partly mediated the causal relationship. PheWAS found that targeting GCKR may improve renal function and glucose homeostasis but cause dyslipidemia and uric acid abnormalities.

This study provided novel evidence that circulating GCKR levels are causally implicated in GDM and related complications, suggesting that it may be a promising target for treatment.