Glucokinase (GCK) is a hexokinase enzyme that catalyzes phosphorylation of glucose to glucose-6-phosphate, serving as a rate-limiting step in glucose metabolism 1. Primarily expressed in pancreatic β-cells and liver, GCK functions as a glucose sensor due to its low glucose affinity, allowing enzymatic activity to vary within physiological glucose concentrations 1. This property enables GCK to regulate insulin secretion in response to blood glucose levels and facilitate hepatic glucose uptake and glycogen synthesis 1. Beyond glucose metabolism, GCK participates in transcriptional regulation of metabolic traits through interactions with its regulator GKRP, influencing hepatic fat accumulation and circulating lipid species via reductive stress-mediated ChR7 activation 2. GCK dysfunction causes diverse monogenic diabetes disorders with distinct mechanisms. Loss-of-function mutations cause GCK-MODY, characterized by mild fasting hyperglycemia with minimal vascular complications and near-complete penetrance (89-97%) across clinical settings 34. Conversely, gain-of-function mutations cause hyperinsulinemic hypoglycemia, characterized by excessive insulin secretion and severe hypoglycemia 1. GCK mutations also account for ~2% of diazoxide-unresponsive congenital hyperinsulinism cases 5. Beyond diabetes, emerging evidence suggests GCK activation improves cardiac survival following ischemia-reperfusion injury by enhancing glucose metabolism and mitochondrial respiration 6.