The sodium-glucose co-transporter 2 inhibitor empagliflozin improves diabetes-induced vascular dysfunction in the streptozotocin diabetes rat model by interfering with oxidative stress and glucotoxicity.
The sodium-glucose co-transporter 2 inhibitor empagliflozin improves diabetes-induced vascular dysfunction in the streptozotocin diabetes rat model by interfering with oxidative stress and glucotoxicity.
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DOI：
10.1371/journal.pone.0112394
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Daiber A
中科院分区：
文献类型：
--
作者：
Oelze M;Kröller-Schön S;Welschof P;Jansen T;Hausding M;Mikhed Y;Stamm P;Mader M;Zinßius E;Agdauletova S;Gottschlich A;Steven S;Schulz E;Bottari SP;Mayoux E;Münzel T;Daiber A
在糖尿病中，血管功能障碍的特征在于由于氧化应激增加而导致的内皮功能受损。恩格列净作为一种选择性钠-葡萄糖协同转运蛋白2抑制剂（SGLT 2 i），通过增强尿糖排泄为2型糖尿病的治疗提供了一种新方法。本研究的目的是检测恩格列净治疗是否通过降低葡萄糖毒性和相关血管氧化应激改善I型糖尿病大鼠的内皮功能障碍。通过静脉注射链脲佐菌素（60 mg/kg）诱导Wistar大鼠的I型糖尿病。注射后1周，通过饮用水给予恩格列净（10和30 mg/kg/d），持续7周。血管功能通过等长张力记录进行评估，氧化应激参数通过化学发光和荧光技术进行评估，蛋白质表达通过Western blot进行评估，mRNA表达通过RT-PCR进行评估，胰岛功能通过血清中胰岛素ELISA和胰腺组织免疫组织化学染色进行评估。通过斑点印迹分析和晚期糖基化终产物（AGE）受体（AGEs）的mRNA表达来评估AGE信号传导。恩格列净治疗降低了糖尿病大鼠的血糖水平，使内皮功能（主动脉环）正常化，并降低了主动脉血管（二氢乙锭染色）和血液（佛波酯/酵母聚糖A刺激的化学发光）中的氧化应激。此外，SGLT 2 i治疗逆转了糖尿病动物中的促炎表型和葡萄糖毒性（AGE/AGEs信号传导）。恩格列净可改善1型糖尿病大鼠的高血糖症，预防内皮功能障碍的发生，降低氧化应激，改善代谢状况。这些临床前观察结果说明了这类新型抗糖尿病药物的治疗潜力。
In diabetes, vascular dysfunction is characterized by impaired endothelial function due to increased oxidative stress. Empagliflozin, as a selective sodium-glucose co-transporter 2 inhibitor (SGLT2i), offers a novel approach for the treatment of type 2 diabetes by enhancing urinary glucose excretion. The aim of the present study was to test whether treatment with empagliflozin improves endothelial dysfunction in type I diabetic rats via reduction of glucotoxicity and associated vascular oxidative stress. Type I diabetes in Wistar rats was induced by an intravenous injection of streptozotocin (60 mg/kg). One week after injection empagliflozin (10 and 30 mg/kg/d) was administered via drinking water for 7 weeks. Vascular function was assessed by isometric tension recording, oxidative stress parameters by chemiluminescence and fluorescence techniques, protein expression by Western blot, mRNA expression by RT-PCR, and islet function by insulin ELISA in serum and immunohistochemical staining of pancreatic tissue. Advanced glycation end products (AGE) signaling was assessed by dot blot analysis and mRNA expression of the AGE-receptor (RAGE). Treatment with empagliflozin reduced blood glucose levels, normalized endothelial function (aortic rings) and reduced oxidative stress in aortic vessels (dihydroethidium staining) and in blood (phorbol ester/zymosan A-stimulated chemiluminescence) of diabetic rats. Additionally, the pro-inflammatory phenotype and glucotoxicity (AGE/RAGE signaling) in diabetic animals was reversed by SGLT2i therapy. Empagliflozin improves hyperglycemia and prevents the development of endothelial dysfunction, reduces oxidative stress and improves the metabolic situation in type 1 diabetic rats. These preclinical observations illustrate the therapeutic potential of this new class of antidiabetic drugs.
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影响因子：
5.8
作者：
Ferrannini, E.;Seman, L.;Woerle, H. J.
通讯作者：
Woerle, H. J.
影响因子：
4.2
作者：
Jeong, Kyung-Hwan;Lee, Tae-Won;Lim, Sung-Jig
通讯作者：
Lim, Sung-Jig
影响因子：
7.7
作者：
Forbes, JM;Cooper, ME;Osicka, TM
通讯作者：
Osicka, TM
影响因子：
13.6
作者：
Coughlan, Melinda T.;Thorburn, David R.;Forbes, Josephine M.
通讯作者：
Forbes, Josephine M.
DOI：
10.1124/jpet.114.213454
发表时间：
2014-09-01
影响因子：
3.5
作者：
Hansen, Henrik H.;Jelsing, Jacob;Mayoux, Eric
通讯作者：
Mayoux, Eric