Glucokinase (GK) is the rate-limiting enzyme of hepatic glucose metabolism and acts as a sensor for glucose-stimulated insulin release in β-cells. Glucokinase catalyses the conversion of glucose to glucose-6 phosphate. It catalyses a key regulatory step in the liver to control the formation of glycogen. Heterozygous loss-of-function mutations in the GK gene in man lead to a form of diabetes mellitus, known as maturity-onset diabetes of the young, type II. There are rare activating mutations in the human GK gene that cause significant hyperinsulinaemia associated with significant blood-glucose-lowering. Activating GK will cause pronounced blood glucose lowering in type II diabetes in humans. GKA50 is a potent glucokinase activator (EC50=33 nM at 5 mM glucose). It also stimulates insulin release from mouse islets of Langerhans and MIN6 cells. In addition, GKA50 shows significant glucose-lowering in high fat-fed female rats.
GKA50 enhances INS-1 cell proliferation with EC50 values ranging from 1 to 2 μM. Its treatment reduces apoptosis induced by chronic high glucose in INS-1 cells. Moreover, GKA50 activates human glucokinase enzymatic activity with an EC50 of 0.022 μM. In addition, GKA50 also stimulates insulin secretion in the pancreatic insulinoma cell line, INS-1, with an EC50 of 0.065 μM. Furthermore, the direct binding of GKA50 to GK is essential for its anti-apoptotic effect. It reduces chronic-high-glucose-induced apoptosis via modulation of glucokinase and apoptotic protein BAD. Furthermore, GKA50 gives significant glucose-lowering in an oral glucose tolerance test.
In summary, GKA50 is a potent glucokinase activator. GKA50 stimulates insulin release from mouse islets of Langerhans and MIN6 cells. It also shows significant glucose lowering in high-fat-fed female rats.