117-LB: Glucokinase Activator Dorzagliatin (HMS5552) Regulates GLP-1 Release in T2D Patients and Is Synergistic with Sitagliptin and Empagliflozin in Optimizing Beta-Cell Function

Abstract

Glucokinase (GK) is a glucose sensor and plays a central role in glucose homeostasis through regulation of threshold of hormone release from α and β cell that controls blood glucose set point. Based on this concept, Dorzagliatin as a glucose sensitizer for the treatment of diabetes has completed pivotal registration trial in China with desirable outcome. GLP-1 is an important hormone involved in β cell secretory function and such plays an important role in glucose homeostasis. It has been debated over the last decade on whether GK is involved in GLP-1 secretion. The dominant reports support the GLP-1 secretory organ is intestine L cell and the secreted hormone traveled to pancreas regulating β cell secreting function. Others suggested β cell regulates GLP-1 secretion from α cell through paracrine and is mediated through GLP-1 receptor on β cell. Here we report that a glucokinase activator Dorzagliatin stimulates GLP-1 release in T2D patients and is synergistic with Sitagliptin, a DDP-IV inhibitor, to increase circulating active GLP-1 in T2D patients with AUEC0-4h of 94.9% over Dorzagliatin. Increase of total GLP-1 was observed in the Dorzagliatin treatment with AUEC0-4h increase of 103.6% and Cmax increase of 141% compared with Dorzagliatin in combination with Sitagliptin. The effect on β cell function is also seen in patients taking Dorzagliatin together with Sitagliptin and Empagliflozin, a SGLT-2 inhibitor, in the OGTT study with increased C-peptide secretion AUEC0-4h of 46.6% (p < 0.01) and 20.4%, Cmax of 52.5% (p < 0.01) and 22%, respectively. Furthermore, the C-peptide secretion increased in combination treatment with AUEC0-4h of 30.3% (p < 0.05) and Cmax of 31%(p < 0.01), compared with Empagliflozin alone. In both combination studies with Sitagliptin and Empagliflozin, reduction of glucose AUEC0-4h is 33.1% and 37.6% with reduction glucose Cmax of 13.9% and 27.8% over Sitagliptin and Empagliflozin alone. Disclosure L. Chen: Board Member; Self; Hua Medicine. J. Zhang: Employee; Self; Hua Medicine. R. Yang: Employee; Self; Hua Medicine. L. Feng: Employee; Self; Hua Medicine. Hua medicine: n/a.