Dorzagliatin, a Dual-Acting Glucokinase Activator, Increases Insulin Secretion and Glucose Sensitivity in Glucokinase Maturity-Onset Diabetes of the Young and Recent-Onset Type 2 Diabetes

Glucokinase-maturity-onset diabetes of the young (GCK-MODY) is caused by heterozygous inactivating mutations in glucokinase (GK, gene symbolGCK) and impaired glucose sensing. We investigated effects of dorzagliatin, a novel allosteric GK activator, on insulin secretion rates (ISR) and beta-cell glucose-sensitivity (βCGS) in GCK-MODY and recent-onset type 2 diabetes. In a double-blind, randomized cross-over study, eight participants with GCK-MODY and 10 with type 2 diabetes underwent 2-hour 12-mmol/L hyperglycemic clamps following a single oral dose of dorzagliatin 75mg or matched placebo. Effects of dorzagliatin on wild-type and mutant GK enzyme activity were investigated using a nicotinamide adenine dinucleotide phosphate (NADP+) coupled assay with glucose-6-phosphate dehydrogenase (G6PD) in vitro. In GCK-MODY, dorzagliatin significantly increased absolute and incremental second-phase ISR versus placebo but not the acute insulin response. Dorzagliatin improved βCGS in GCK-MODY with a upward and leftward shift in ISR-glucose response. Dorzagliatin increased basal ISR in type 2 diabetes with smaller changes in second-phase ISR compared with GCK-MODY. In vitro, dorzagliatin directly reduced the glucose half saturation concentration (S0.5) of wild-type GK and selected GK mutants to varying degrees. Dorzagliatin directly restored enzyme activity of select GK mutants and enhanced wild-type GK activity, thereby correcting the primary defect of glucose sensing in GCK-MODY.