NN414, a SUR1/Kir6.2-selective potassium channel opener, reduces blood glucose and improves glucose tolerance in the VDF Zucker rat
NN414, a SUR1/Kir6.2-selective potassium channel opener, reduces blood glucose and improves glucose tolerance in the VDF Zucker rat
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DOI：
10.2337/diabetes.52.10.2513
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发表时间：
2003-10-01
期刊：
影响因子：
7.7
通讯作者：
Sturis, J
中科院分区：
文献类型：
--
作者：
Carr, RD;Brand, CL;Sturis, J
一种新型钾通道开放剂化合物 NN414，对 ATP 敏感钾通道的 SUR1/Kir6.2 亚型具有选择性，用于检查减少轻度 2 型糖尿病的雄性温哥华糖尿病脂肪 (VDF) Zucker 大鼠模型中 β 细胞工作量的效果。将两种为期 3 周的 NN414 慢性给药方案与适当的媒介物处理对照进行比较。在第一组中，大鼠接受 NN414（继续组；1.5 mg/kg，口服，每日两次），在此期间进行口服葡萄糖耐量试验 (OGTT)（给药第 19 天），并测量原位灌注胰腺制剂（第 21 天）的胰岛素分泌。第二组接受 NN414（停药组；相同剂量），但在 OGTT 前 2 天用媒介物治疗替代积极治疗，并在胰腺灌注研究前再继续治疗 2 天。 NN414 显着降低基础血糖，治疗 3 周后平均下降 0.64 mmol/l（P < 0.0001）。 OGTT期间的葡萄糖偏移和高胰岛素血症在继续组、停止组和媒介物组之间显着不同（葡萄糖曲线下面积[AUC]：分别为640 +/- 29、740 +/- 27和954 82 mmol (.) l(-1) (.) min(-1)，P < 0.0001；胰岛素AUC：38.9 +/- 4.2，分别为 44.2 +/- 4.2 和 55.1 +/- 2.6 nmol (.) l(-1) (.) min(-1)，P < 0.0001)。与媒介物相比，两个治疗组在胰腺灌注 4.4 mmol/l 葡萄糖期间的高胰岛素血症均显着降低（P < 0.0005）。相对于基础值计算，胰岛素分泌对葡萄糖从 4.4 mmol/l 逐步增加至 16.6 mmol/l 的反应性，与媒介物相比，继续组显着改善（P < 0.01）。总之，对 VDF 大鼠施用 NN414 3 周可降低基础高血糖，改善葡萄糖耐量，减少 OGTT 期间的高胰岛素血症，并改善体外胰岛素分泌反应性。因此，NN414可能代表了一种预防和治疗糖耐量受损和2型糖尿病的新方法。
A novel potassium channel opener compound, NN414, selective for the SUR1/Kir6.2 subtype of the ATP-sensitive potassium channel, was used to examine the effect of reducing beta-cell workload in the male Vancouver diabetic fatty (VDF) Zucker rat model of mild type 2 diabetes. Two chronic dosing protocols of NN414 of 3 weeks' duration were compared with appropriate vehicle-treated controls. In the first group, rats received NN414 (continued group; 1.5 mg/kg p.o. twice daily), during which an oral glucose tolerance test (OGTT) (on day 19 of dosing) was performed and insulin secretion from an in situ perfused pancreas preparation (on day 21) was measured. The second group received NN414 (discontinued group; same dose), but active treatment was replaced by vehicle treatment 2 days before the OGTT and for a further 2 days before the perfused pancreas study. Basal glucose was significantly reduced by NN414, with the fall averaging 0.64 mmol/l after 3 weeks of treatment (P < 0.0001). The glucose excursion and hyperinsulinemia during the OGTT were significantly different between the continued, discontinued, and vehicle groups (glucose area under the curve [AUC]: 640 +/- 29, 740 +/- 27, and 954 82 mmol (.) l(-1) (.) min(-1), respectively, P < 0.0001; insulin AUC: 38.9 +/- 4.2, 44.2 +/- 4.2, and 55.1 +/- 2.6 nmol (.) l(-1) (.) min(-1), respectively, P < 0.0001). Hyperinsulinemia during the pancreas perfusion with 4.4 mmol/l glucose was significantly reduced in both treatment groups versus vehicle (P < 0.0005). Insulin secretory responsiveness to a step increase in glucose from 4.4 to 16.6 mmol/l, calculated relative to basal, was significantly improved in the continued group versus vehicle (P < 0.01). In conclusion, administration of NN414 for 3 weeks in VDF rats reduces basal hyperglycemia, improves glucose tolerance, and reduces hyperinsulinemia during an OGTT and improves insulin secretory responsiveness ex vivo. NN414 may therefore represent a novel approach to the prevention and treatment of impaired glucose tolerance and type 2 diabetes.