Glucokinase activation or inactivation: Which will lead to t
Glucokinase, which phosphorylates glucose to form glucose-6-phosphate, plays a critical role in regulating the blood glucose levels. On the basis of data of glucokinase-knockout and transgenic mice and humans with glucokinase mutations, glucokinase was targeted for drug development aiming to augment its activity, and thereby reduce hyperglycemia in patients with diabetes.

In fact, various small molecule compounds have been developed and clinically tested as glucokinase activators. However, some have been discontinued because of efficacy and safety issues.

One of these issues is loss of the drug's efficacy over time. This unsustained glycemic efficacy may be associated with the excess glycolysis by glucokinase activation in pancreatic beta-cells, resulting in beta-cell failure. Recently, researchers have demonstrated that glucokinase haploinsufficiency ameliorated glucose intolerance by increasing beta-cell function and mass in a mouse model of diabetes.

Given that a similar phenotype has been observed in glucokinase-activated beta-cells and diabetic beta-cells, glucokinase inactivation may be a new therapeutic target for type 2 diabetes.