293-LB: Dorzagliatin, a Glucokinase Activator, Restores Glucose-Sensing in Type 2 Diabetic Human Islets

Introduction: Glucokinase (GK) has been considered a drug target for type 2 diabetes (T2D) to restore glucose sensing in beta cells. However, GK activators such as MK-0941 have had limited clinical success, causing hypoglycemia and other serious adverse events in terminated clinical trials. In contrast, the novel GK activator dorzagliatin, an approved therapy for T2D, showed sustained reduction in HbA1c in T2D patients and no serious adverse events. The purpose of the current study is to compare the effects of dorzagliatin with other GK activators, including MK-0941, on GK enzyme kinetics and the function of islets from T2D donors. Methods: Insulin secretion was assessed in islets from 8 T2D donors and 38 controls obtained through the Integrated Islet Distribution Program. Both glucose step and glucose ramp perifusion protocols were used to assess glucose-stimulated insulin secretion (GSIS). GK-GK activator binding was performed using molecular dynamics analysis. Publicly available data from the Human Pancreas Analysis Program were also used. Results: Unlike MK-0941 which strongly activates GK enzyme even at very low glucose levels, dorzagliatin activation of GK is glucose dose-dependent. This can be explained by molecular dynamics analysis showing dorzagliatin binds to GK with less affinity than MK-0941. T2D islets showed a right-shifted glucose threshold for GSIS and/or a reduction in the maximal rate of GSIS (Vmax) compared to controls in response to high glucose and IBMX, and dorzagliatin recovers both the threshold and Vmax. In contrast, MK-0941 induces a rapid and transient insulin spike at very low glucose concentrations but has a reduced response to high glucose. Conclusion: In isolated T2D islets, dorzagliatin recovers both the normal glucose threshold and Vmax and has a wider dose range compared to MK-0941. These findings may explain why MK-0941 causes hypoglycemia whereas dorzagliatin improves blood glucose without any serious adverse events in T2D patients. Disclosure J. Roman: None. Q. Zhu: Employee; Nanjing AscendRare Pharmaceutical Technology. Y. Yuan: Employee; Nanjing AscendRare Pharmaceutical Technology. C. Li: Employee; Hua Medicine, Nanjing AscendRare Pharmaceutical Technology. L. Chen: Employee; Hua Medicine. N. M. Doliba: None.