Department of Biology, Gilead Palo Alto Inc., Palo Alto, CA 94304, USA.
J Pharmacol Exp Ther. 2011 Apr;337(1):50-8. doi: 10.1124/jpet.110.176396. Epub 2011 Jan 12.
In addition to its anti-ischemic and antianginal effects, ranolazine has been shown to lower hemoglobin A(1c) (HbA(1c)) in patients with coronary artery disease and diabetes. The present study was undertaken to test the hypothesis that ranolazine lowers HbA(1c) because of improved glucose homeostasis in an animal model. Diabetes in mice was induced by giving multiple low doses of streptozotocin. Ranolazine was given twice daily via an oral gavage (20 mg/kg) for 8 weeks. Fasting plasma glucose levels were significantly lower in the ranolazine-treated group (187 ± 19 mg/dl) compared with the vehicle group (273 ± 23 mg/dl) at 8 weeks. HbA(1c) was 5.8 ± 0.4% in the vehicle group and 4.5 ± 0.2% in the ranolazine-treated group (p < 0.05). Glucose disposal during the oral glucose tolerance test (OGTT) and insulin tolerance test were not different between the two groups; however, during OGTT, peak insulin levels were significantly (p < 0.05) higher in ranolazine-treated mice. Mice treated with ranolazine had healthier islet morphology and significantly (p < 0.01) higher β-cell mass (69 ± 2% per islet) than the vehicle group (50 ± 5% per islet) as determined from hematoxylin and eosin staining. The number of apoptotic cells was significantly (p < 0.05) less in the pancreas of the ranolazine-treated group (14 ± 2% per islet) compared with the vehicle group (24 ± 4% per islet). In addition, ranolazine increased glucose-stimulated insulin secretion in rat and human islets in a glucose-dependent manner. These data suggest that ranolazine may be a novel antidiabetic agent that causes β-cell preservation and enhances insulin secretion in a glucose-dependent manner in diabetic mice.
除了抗缺血和抗心绞痛作用外，雷诺嗪已被证明可降低患有冠状动脉疾病和糖尿病的患者的血红蛋白 A1c（HbA1c）。本研究旨在检验以下假说，即雷诺嗪通过改善动物模型中的葡萄糖稳态来降低 HbA1c。通过给予多次小剂量链脲佐菌素诱导小鼠糖尿病。通过口服灌胃（20mg/kg）每天两次给予雷诺嗪 8 周。在第 8 周时，雷诺嗪治疗组的空腹血糖水平明显低于对照组（187±19mg/dl）（273±23mg/dl）。对照组的 HbA1c 为 5.8±0.4%，而雷诺嗪治疗组为 4.5±0.2%（p<0.05）。两组之间口服葡萄糖耐量试验（OGTT）和胰岛素耐量试验期间的葡萄糖清除率没有差异；然而，在 OGTT 期间，雷诺嗪治疗组的胰岛素峰值明显更高（p<0.05）。用雷诺嗪治疗的小鼠胰岛形态更健康，胰岛β细胞质量显著增加（每个胰岛 69±2%），高于对照组（每个胰岛 50±5%）（通过苏木精和伊红染色确定）。与对照组（每个胰岛 24±4%）相比，雷诺嗪治疗组的胰岛中凋亡细胞的数量明显减少（p<0.05）（每个胰岛 14±2%）。此外，雷诺嗪以葡萄糖依赖性方式增加了大鼠和人胰岛的葡萄糖刺激的胰岛素分泌。这些数据表明，雷诺嗪可能是一种新型的抗糖尿病药物，可导致β细胞保存，并以葡萄糖依赖性方式增强糖尿病小鼠的胰岛素分泌。
