1887-LB: Effect of Dorzagliatin, a Dual-Acting Glucokinase Activator, on Insulin and Glucagon Secretion in Impaired and Normal Glucose Tolerance

Dorzagliatin is a novel dual-acting allosteric activator of hepatic and beta-cell glucokinase (GCK). Dorzagliatin improved second-phase insulin secretion in type 2 diabetes and heterozygous carriers of GCK mutations. We investigated the effects of dorzagliatin on insulin secretion and glucagon suppression during hyperglycemic clamps in individuals with impaired glucose tolerance (IGT) and normal controls.

In a double-blind, single-dose, randomized cross-over study, 9 participants with IGT (mean age 55±7.5years, 5 female) and 10 controls (39.5±11.8 years, 5 female) underwent 2-hour 12 mmol/l hyperglycemic clamp following a single dose of dorzagliatin 50mg or matched placebo. Insulin, C-peptide and glucagon were measured at regular intervals.

In controls, dorzagliatin significantly increased basal insulin (48.2±26.5 vs 36.8±16.6 pmol/L, p=0.0006) and second-phase insulin area under the curve (AUC) (25164 ± 22525 vs 17533 ± 12043 pmol/L.min, p=0.049) compared with placebo. Glucagon was also significantly suppressed after dorzagliatin (AUC_0-120min 161±58 vs 234±70 pmol/L.min, p=0.0009) in the control group. The IGT group showed significantly higher steady-state C-peptide response (2193±531 vs 1768±351 pmol/L, p=0.013) following dorzagliatin, but similar basal, acute insulin secretion and glucagon levels following both treatments. Dorzagliatin did not affect the insulin sensitivity in either subject group.

Dorzagliatin increased second-phase insulin secretion in IGT, while additionally suppressing glucagon and enhancing basal insulin secretion in normal controls.