Gckr, which encodes glucokinase regulatory protein (GKRP), is a key regulator of hepatic glucokinase (GCK). GCKR influences the hepatic cytosolic NADH/NAD+ ratio, a state known as reductive stress. This reductive stress is involved in multiple metabolic pathways, as it can activate the transcription factor ChREBP, which is associated with various metabolic traits [1].

Common genetic variants in Gckr, such as rs1260326, have pleiotropic effects on cardiometabolic traits and hematological parameters. These variants are associated with an increased risk of multiple diseases. For instance, they are related to non-alcoholic fatty liver disease (NAFLD), gestational diabetes mellitus (GDM), the transition from asymptomatic hyperuricaemia to gout, and end-stage kidney disease in Chinese patients with type 2 diabetes [2,3,4,5,6]. In the context of NAFLD, the T allele carriers of Gckr rs780094 and rs1260326 polymorphisms have a predisposition to the disease [4].

In conclusion, Gckr plays a crucial role in regulating metabolic pathways, especially those related to glucose and lipid metabolism. The study of Gckr gene polymorphisms through genetic models can help reveal its role in various disease conditions, including metabolic and kidney-related diseases. These findings may contribute to the prediction of disease risk and the development of targeted therapeutic strategies.

References:

1. Singh, Charandeep, Jin, Byungchang, Shrestha, Nirajan, Mootha, Vamsi K, Goodman, Russell P. 2023. ChREBP is activated by reductive stress and mediates GCKR-associated metabolic traits. In Cell metabolism, 36, 144-158.e7. doi:10.1016/j.cmet.2023.11.010. https://pubmed.ncbi.nlm.nih.gov/38101397/

2. Zhu, Manning, Lv, Yaer, Peng, Yanqing, Tian, Jiawei, Sun, Litao. 2023. GCKR and ADIPOQ gene polymorphisms in women with gestational diabetes mellitus. In Acta diabetologica, 60, 1709-1718. doi:10.1007/s00592-023-02165-1. https://pubmed.ncbi.nlm.nih.gov/37524927/

3. Yeh, Kuan-Hung, Hsu, Lung-An, Teng, Ming-Sheng, Chou, Hsin-Hua, Ko, Yu-Lin. 2022. Pleiotropic Effects of Common and Rare GCKR Exonic Mutations on Cardiometabolic Traits. In Genes, 13, . doi:10.3390/genes13030491. https://pubmed.ncbi.nlm.nih.gov/35328045/

4. Li, Jiaying, Zhao, Yuening, Zhang, Hongxiang, Yang, Xiaoqin, Zhu, Liyan. . Contribution of Rs780094 and Rs1260326 Polymorphisms in GCKR Gene to Non-alcoholic Fatty Liver Disease: A Meta-Analysis Involving 26,552 Participants. In Endocrine, metabolic & immune disorders drug targets, 21, 1696-1708. doi:10.2174/1871530320999201126202706. https://pubmed.ncbi.nlm.nih.gov/33243135/

5. Sandoval-Plata, Gabriela, Morgan, Kevin, Abhishek, Abhishek. 2021. Variants in urate transporters, ADH1B, GCKR and MEPE genes associate with transition from asymptomatic hyperuricaemia to gout: results of the first gout versus asymptomatic hyperuricaemia GWAS in Caucasians using data from the UK Biobank. In Annals of the rheumatic diseases, 80, 1220-1226. doi:10.1136/annrheumdis-2020-219796. https://pubmed.ncbi.nlm.nih.gov/33832965/

6. Wang, Ke, Shi, Mai, Yang, Aimin, Chan, Juliana C N, Chow, Elaine. 2022. GCKR and GCK polymorphisms are associated with increased risk of end-stage kidney disease in Chinese patients with type 2 diabetes: The Hong Kong Diabetes Register (1995-2019). In Diabetes research and clinical practice, 193, 110118. doi:10.1016/j.diabres.2022.110118. https://pubmed.ncbi.nlm.nih.gov/36243233/