ACE inhibitor improves insulin resistance in diabetic mouse via bradykinin and NO
ACE inhibitor improves insulin resistance in diabetic mouse via bradykinin and NO
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DOI：
10.1161/01.hyp.0000028979.98877.0c
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发表时间：
2002-09-01
期刊：
影响因子：
8.3
通讯作者：
Horiuchi, M
中科院分区：
文献类型：
--
作者：
Shiuchi, T;Cui, TX;Horiuchi, M
ACE抑制剂可改善胰岛素抵抗，但其机制尚未得到证实。我们推测血管紧张素转换酶抑制剂激活缓激肽-一氧化氮（NO）系统通过增加葡萄糖转运蛋白4（GLUT 4）的转位增强外周组织的葡萄糖摄取，从而改善胰岛素抵抗。ACE抑制剂，替莫普利，管理，显着降低血糖和胰岛素浓度在2型糖尿病小鼠KK-Ay。用替莫普利治疗的小鼠在葡萄糖负荷后显示出较小的血浆葡萄糖增加。我们证明，替莫普利治疗显着提高2-[H-3]-脱氧-D-葡萄糖（2-DG）的骨骼肌，但不是在白色脂肪组织的摄取。缓激肽132受体拮抗剂Hoe 140或NO合酶抑制剂L-NAME的给药减弱了替莫普利对葡萄糖的摄取。此外，我们观察到，GLUT 4的转运到质膜上的替莫普利治疗显着增强，而不影响胰岛素受体底物-1磷酸化。在L 6骨骼肌细胞中，2-DG摄取增加temocaprilat，Hoe 140抑制temocaprilat的这种作用，但不是胰岛素。这些结果表明，替莫普利将改善胰岛素抵抗和葡萄糖耐受不良，通过增加葡萄糖摄取，特别是在骨骼肌中，至少部分通过增强缓激肽-NO系统，从而GLUT 4易位。
Improvement of insulin resistance by ACE inhibitors has been suggested; however, this mechanism has not been proved. We postulated that activation of the bradykinin-nitric oxide (NO) system by an ACE inhibitor enhances glucose uptake in peripheral tissues by means of an increase in translocation of glucose transporter 4 (GLUT4), resulting in improvement of insulin resistance. Administration of an ACE inhibitor, temocapril, significantly decreased plasma glucose and insulin concentrations in type 2 diabetic mouse KK-Ay. Mice treated with temocapril showed a smaller plasma glucose increase after glucose load. We demonstrated that temocapril treatment significantly enhanced 2-[H-3]-deoxy-D-glucose (2-DG) uptake in skeletal muscle but not in white adipose tissue. Administration of a bradykinin 132 receptor antagonist, Hoe140, or an NO synthase inhibitor, L-NAME, attenuated the enhanced glucose uptake by temocapril. Moreover, we observed that translocation of GLUT4 to the plasma membrane was significantly enhanced by temocapril treatment without influencing insulin receptor substrate-1 phosphorylation. In L6 skeletal muscle cells, 2-DG uptake was increased by temocaprilat, and Hoe140 inhibited this effect of temocaprilat but not that of insulin. These results suggest that temocapril would improve insulin resistance and glucose intolerance through increasing glucose uptake, especially in skeletal muscle at least in part through enhancement of the bradykinin-NO system and consequently GLUT4 translocation.