Effects of Dorzagliatin, a Glucokinase Activator, on α- and β-Cell Function in Individuals With Impaired and Normal...

Dorzagliatin is a dual-acting allosteric activator of glucokinase (GCK). Dorzagliatin improved second-phase insulin secretion in individuals with type 2 diabetes and heterozygous carriers of GCK mutations. We investigated the effects of dorzagliatin on pancreatic insulin, glucagon, and glucagon-like-peptide 1 (GLP-1) secretion in individuals with impaired glucose tolerance (IGT) and normal glucose tolerance (NGT). In a double-blind, randomized, crossover, single-dose study, 9 participants with IGT and 10 with NGT underwent 2-h 12 mmol/L hyperglycemic clamp following a single dose of dorzagliatin 50 mg or matched placebo. Plasma insulin, C-peptide, glucagon, and total GLP-1 levels were measured at regular intervals. There were no differences in first-phase insulin after the dorzagliatin dose in either group. Dorzagliatin significantly increased second-phase insulin secretion rate and β-cell glucose sensitivity by 1.3-fold compared with placebo in IGT but remained similar in NGT. Dorzagliatin increased basal plasma insulin in the NGT group only. Glucagon (area under the curve0-120 min = 161 ± 58 vs. 234 ± 70 pmol*min/L [mean ± SD]; P = 0.01) was suppressed after dorzagliatin in the NGT group but not the IGT group. Plasma glucagon was positively correlated with total GLP-1 levels. Dorzagliatin did not affect insulin sensitivity in either group. Dorzagliatin has different actions on β- and α-cells depending on glucose tolerance, increasing second-phase insulin secretion in IGT while enhancing glucose-suppression of glucagon secretion in NGT.

Dorzagliatin is a dual-acting allosteric glucokinase (GCK) activator that increases β-cell glucose sensitivity and second-phase insulin in GCK monogenic diabetes of the young. Actions of dorzagliatin on α- and β-cell function in normal and impaired glucose tolerance are unknown. In this study, dorzagliatin increased second-phase insulin in individuals with impaired glucose tolerance while suppressing glucagon in participants with normal glucose tolerance during a hyperglycemic clamp. With increasing glucose, plasma glucagon and total GLP-1 levels declined progressively. A modest to moderate positive correlation between glucagon and total GLP-1 was observed under both dorzagliatin and placebo treatments.