Hu S, Wang S, Dunning B E
Metabolic and Cardiovascular Diseases, Novartis Institute for Biomedical Research, Summit, NJ 07901, USA.
Int J Exp Diabetes Res. 2001;2(1):63-72. doi: 10.1155/edr.2001.63.
Nateglinide, a novel D-phenylalanine derivative, stimulates insulin release via closure of K(ATP) channels in pancreatic beta-cell, a primary mechanism of action it shares with sulfonylureas (SUs) and repaglinide. This study investigated (1) the influence of ambient glucose levels on the insulinotropic effects of nateglinide, glyburide and repaglinide, and (2) the influence of the antidiabetic agents on glucose-stimulated insulin secretion (GSIS) in vitro from isolated rat islets. The EC50 of nateglinide to stimulate insulin secretion was 14 microM in the presence of 3 mM glucose and was reduced by 6-fold in 8 mM glucose and by 16-fold in 16 mM glucose, indicating a glucose-dependent insulinotropic effect. The actions of glyburide and repaglinide failed to demonstrate such a glucose concentration-dependent sensitization. When tested at fixed and equipotent concentrations (approximately 2x EC50 in the presence of 8 mM glucose) nateglinide and repaglinide shifted the EC50s for GSIS to the left by 1.7 mM suggesting an enhancement of islet glucose sensitivity, while glimepiride and glyburide caused, respectively, no change and a right shift of the EC50. These data demonstrate that despite a common basic mechanism of action, the insulinotropic effects of different agents can be influenced differentially by ambient glucose and can differentially influence the islet responsiveness to glucose. Further, the present findings suggest that nateglinide may exert a more physiologic effect on insulin secretion than comparator agents and thereby have less propensity to elicit hypoglycemia in vivo.
那格列奈是一种新型的D - 苯丙氨酸衍生物，它通过关闭胰腺β细胞中的K(ATP)通道来刺激胰岛素释放，这是它与磺脲类药物（SUs）和瑞格列奈共有的主要作用机制。本研究调查了：（1）环境葡萄糖水平对那格列奈、格列本脲和瑞格列奈促胰岛素作用的影响；（2）这些抗糖尿病药物对体外分离的大鼠胰岛葡萄糖刺激的胰岛素分泌（GSIS）的影响。在3 mM葡萄糖存在的情况下，那格列奈刺激胰岛素分泌的EC50为14 microM，在8 mM葡萄糖中降低了6倍，在16 mM葡萄糖中降低了16倍，表明存在葡萄糖依赖性促胰岛素作用。格列本脲和瑞格列奈的作用未显示出这种葡萄糖浓度依赖性的敏感性。当在固定且等效的浓度（在8 mM葡萄糖存在下约为2倍EC50）下进行测试时，那格列奈和瑞格列奈将GSIS的EC50向左移动了1.7 mM，表明胰岛葡萄糖敏感性增强，而格列美脲和格列本脲分别使EC50无变化和向右移动。这些数据表明，尽管不同药物有共同的基本作用机制，但不同药物的促胰岛素作用可能受到环境葡萄糖的不同影响，并且对胰岛对葡萄糖的反应性也有不同影响。此外，目前的研究结果表明，与对照药物相比，那格列奈可能对胰岛素分泌产生更生理性的影响，因此在体内引起低血糖的倾向较小。
