Gck, or glucokinase, is a key enzyme in glucose metabolism. It plays a central role in glucose sensing and insulin secretion in pancreatic β -cells, as well as glycogen synthesis in the liver. It is thus crucial for maintaining glucose homeostasis [3].

Heterozygous inactivating mutations of the Gck gene cause GCK-MODY, a common form of Maturity Onset Diabetes of the Young. GCK-MODY is characterized by fasting hyperglycemia, with a low risk for chronic vascular complications and often misdiagnosed as type 1 or type 2 diabetes [1]. Homozygous inactivating GCK mutations lead to permanent neonatal diabetes mellitus (PNDM), while heterozygous activating GCK mutations result in hyperinsulinemic hypoglycemia (HH) [3,4,6]. The penetrance of pathogenic GCK variants is similar across clinically referred probands, family members, and clinically unselected cohorts, highlighting its potential as a candidate for the American College of Medical Genetics secondary gene list [2]. Dorzagliatin, a glucokinase activator, has shown effectiveness in lowering HbA1c levels in GCK-MODY patients [5].

In conclusion, Gck is essential for glucose metabolism, regulating insulin secretion and glycogen synthesis. Genetic mutations in Gck are associated with various monogenic diabetes disorders and hypoglycemic conditions. Understanding Gck's role through genetic models can help in better diagnosing and treating these related diseases.

References:

1. Hulín, J, Škopková, M, Valkovičová, T, Gašperíková, D, Staník, J. 2020. Clinical implications of the glucokinase impaired function - GCK MODY today. In Physiological research, 69, 995-1011. doi:. https://pubmed.ncbi.nlm.nih.gov/33129248/

2. Mirshahi, Uyenlinh L, Colclough, Kevin, Wright, Caroline F, Weedon, Michael N, Patel, Kashyap A. 2022. Reduced penetrance of MODY-associated HNF1A/HNF4A variants but not GCK variants in clinically unselected cohorts. In American journal of human genetics, 109, 2018-2028. doi:10.1016/j.ajhg.2022.09.014. https://pubmed.ncbi.nlm.nih.gov/36257325/

3. Abu Aqel, Yasmin, Alnesf, Aldana, Aigha, Idil I, Teo, Adrian, Abdelalim, Essam M. 2024. Glucokinase (GCK) in diabetes: from molecular mechanisms to disease pathogenesis. In Cellular & molecular biology letters, 29, 120. doi:10.1186/s11658-024-00640-3. https://pubmed.ncbi.nlm.nih.gov/39245718/

4. Osbak, Kara K, Colclough, Kevin, Saint-Martin, Cecile, Ellard, Sian, Gloyn, Anna L. . Update on mutations in glucokinase (GCK), which cause maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemic hypoglycemia. In Human mutation, 30, 1512-26. doi:10.1002/humu.21110. https://pubmed.ncbi.nlm.nih.gov/19790256/

5. Zhao, Yilin, Ma, Yumin, Ba, Tianhao, Ren, Qian, Ji, Linong. . Hypoglycemic Response to Dorzagliatin in a Patient With GCK-MODY. In Diabetes care, 47, 1140-1142. doi:10.2337/dc23-2417. https://pubmed.ncbi.nlm.nih.gov/38691834/

6. Gloyn, Anna L. . Glucokinase (GCK) mutations in hyper- and hypoglycemia: maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemia of infancy. In Human mutation, 22, 353-62. doi:. https://pubmed.ncbi.nlm.nih.gov/14517946/