Effects of dorzagliatin, a glucokinase activator, on α and β- cell function in individuals with impaired and normal glucose tolerance

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 cross-over, single-dose study, 9 participants with IGT and 10 with NGT underwent 2-hour 12 mmol/L hyperglycemic clamp following a single dose of dorzagliatin 50 mg or matched placebo. Plasma insulin, C-peptide, glucagon, total GLP-1 were measured at regular intervals. There were no differences in first-phase insulin following dorzagliatin in either group. Dorzagliatin significantly increased second-phase insulin secretion rate and β-cell glucose sensitivity by 1.3-fold compared to placebo in IGT but remained similar in NGT. Dorzagliatin increased basal plasma insulin in the NGT group only. Glucagon (Area-under-the-curve 0-120min 161±58 vs. 234±70 pmol*min/L, P = 0.01) was suppressed after dorzagliatin in NGT, but not the IGT group. Plasma glucagon was positively correlated with total GLP-1 levels. Dorzagliatin did not affect insulin sensitivity in either subject 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.