293-LB：Dorzagliatin，一种葡萄糖激酶激活剂，可恢复 2 型糖尿病人胰岛的葡萄糖感应,Diabetes

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293-LB：Dorzagliatin，一种葡萄糖激酶激活剂，可恢复 2 型糖尿病人胰岛的葡萄糖感应
Diabetes ( IF 6.2 ) Pub Date : 2023-06-20 , DOI: 10.2337/db23-293-lb
JEFFEREY ROMAN ₁ , QIUSHA ZHU ₁ , YUE YUAN ₁ , CHANGHONG LI ₁ , LI CHEN ₁ , NICOLAI M. DOLIBA ₁

Affiliation

简介：葡萄糖激酶 (GK) 被认为是 2 型糖尿病 (T2D) 的药物靶标，可恢复 β 细胞中的葡萄糖感应。然而，MK-0941等GK激活剂的临床成功有限，在终止的临床试验中导致低血糖和其他严重不良事件。相比之下，新型 GK 激活剂 dorzagliatin（一种已批准的 T2D 疗法）显示 T2D 患者的 HbA1c 持续降低，并且没有严重的不良事件。本研究的目的是比较 dorzagliatin 与其他 GK 激活剂（包括 MK-0941）对 GK 酶动力学和 T2D 供体胰岛功能的影响。方法：对通过综合胰岛分配计划获得的 8 名 T2D 供体和 38 名对照者的胰岛进行胰岛素分泌评估。葡萄糖步进和葡萄糖斜坡灌注方案均用于评估葡萄糖刺激的胰岛素分泌（GSIS）。使用分子动力学分析进行 GK-GK 激活剂结合。还使用了人类胰腺分析计划的公开数据。结果：与即使在非常低的葡萄糖水平下也能强烈激活 GK 酶的 MK-0941 不同，dorzagliatin 对 GK 的激活是葡萄糖剂量依赖性的。这可以通过分子动力学分析来解释，分子动力学分析显示 dorzagliatin 与 GK 的结合亲和力低于 MK-0941。与对照相比，T2D 胰岛在响应高葡萄糖和 IBMX 时表现出 GSIS 葡萄糖阈值右移和/或 GSIS 最大速率 (Vmax) 降低，并且 dorzagliatin 恢复了阈值和 Vmax。相比之下，MK-0941 在极低的葡萄糖浓度下诱导快速且短暂的胰岛素峰值，但对高葡萄糖的反应减弱。结论：在孤立的 T2D 胰岛中，dorzagliatin 恢复了正常的葡萄糖阈值和 Vmax，并且与 MK-0941 相比具有更宽的剂量范围。这些发现可以解释为什么 MK-0941 会导致低血糖，而 dorzagliatin 可以改善 T2D 患者的血糖，而不会出现任何严重不良事件。披露 J. Roman：无。朱问：员工；南京升瑞医药科技有限公司。袁元：员工；南京升瑞医药科技有限公司。C.李：员工；华领医药、南京升锐医药科技。陈丽：员工；华医. NM Doliba：没有。与 MK-0941 相比，dorzagliatin 可以恢复正常的葡萄糖阈值和 Vmax，并且具有更宽的剂量范围。这些发现可以解释为什么 MK-0941 会导致低血糖，而 dorzagliatin 可以改善 T2D 患者的血糖，而不会出现任何严重不良事件。披露 J. Roman：无。朱问：员工；南京升瑞医药科技有限公司。袁元：员工；南京升瑞医药科技有限公司。C.李：员工；华领医药、南京升锐医药科技。陈丽：员工；华医. NM Doliba：没有。与 MK-0941 相比，dorzagliatin 可以恢复正常的葡萄糖阈值和 Vmax，并且具有更宽的剂量范围。这些发现可以解释为什么 MK-0941 会导致低血糖，而 dorzagliatin 可以改善 T2D 患者的血糖，而不会出现任何严重不良事件。披露 J. Roman：无。朱问：员工；南京升瑞医药科技有限公司。袁元：员工；南京升瑞医药科技有限公司。C.李：员工；华领医药、南京升锐医药科技。陈丽：员工；华医. NM Doliba：没有。员工; 南京升瑞医药科技有限公司。袁元：员工；南京升瑞医药科技有限公司。C.李：员工；华领医药、南京升锐医药科技。陈丽：员工；华医. NM Doliba：没有。员工; 南京升瑞医药科技有限公司。袁元：员工；南京升瑞医药科技有限公司。C.李：员工；华领医药、南京升锐医药科技。陈丽：员工；华医. NM Doliba：没有。

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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.

更新日期：2023-06-20

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