Recent clinical advances of glucokinase activators in the treatment of diabetes mellitus type 2.

Glucokinase (GK) is an isozyme of hexokinase that catalyzes the phosphorylation of glucose. GK is present in many organs of the human body, including the liver and pancreas. GK plays an important role in promoting the synthesis of hepatic glycogen and balancing postprandial blood glucose. Mutations in the GK gene can result in the inclusion of maturity-onset diabetes of the young (MODY2) and permanent neonatal Diabetes mellitus (PNDM). Glucokinase activators (GKAs) are a class of type 2 diabetes drugs designed for this target. In various animal models of type 2 diabetes, GKAs have been shown to have the ability to decrease blood glucose, and some GKAs also have the ability to stimulate β cell proliferation. However, due to the induction of hypoglycemia and increased liver burden, many candidates stopped in phase II clinical trials. Recently, dorzagliatin has reached the primary endpoint of phase III clinical trial, which can repair the core function of GK as a blood glucose sensor, and can delay or even reverse islet β -cell damage and functional decline. This provides a promising prospect for the study of GKAs as candidates for the treatment of type 2 diabetes. This review summarizes the clinical advances in GKAs.