Gck-flox Mouse

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

Mutations in the Gck gene are associated with various monogenic diabetes disorders. Heterozygous inactivating mutations cause GCK-MODY, a form of Maturity Onset Diabetes of the Young, characterized by fasting hyperglycemia, low risk for chronic vascular complications, and often misdiagnosed as type 1 or type 2 diabetes [1]. Homozygous inactivating mutations lead to permanent neonatal diabetes mellitus (PNDM) [3,4,6]. On the other hand, heterozygous activating mutations result in hyperinsulinemic hypoglycemia (HH) [3,4,6]. The penetrance of pathogenic Gck variants is similar across different cohorts (89%-97%) [2]. In addition, the glucokinase activator dorzagliatin was effective and safe in a patient with GCK-MODY, providing potential for precise treatment [5].

In conclusion, Gck is essential for glucose metabolism, regulating insulin secretion and glycogen synthesis. The study of Gck-related mutations through genetic models helps to understand the pathogenesis of monogenic diabetes disorders such as GCK-MODY, PNDM, and HH, which may provide insights for developing targeted therapeutic interventions [3].