Dorzagliatin, a dual-acting glucokinase activator, increases insulin secretion and glucose sensitivity in glucokinase-maturity-onset diabetes of the young (GCK-MODY) 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 symbol GCK) 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.