Effects of SGLT2 selective inhibitor ipragliflozin on hyperglycemia, hyperlipidemia, hepatic steatosis, oxidative stress, inflammation, and obesity in type 2 diabetic mice
Effects of SGLT2 selective inhibitor ipragliflozin on hyperglycemia, hyperlipidemia, hepatic steatosis, oxidative stress, inflammation, and obesity in type 2 diabetic mice
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DOI：
10.1016/j.ejphar.2013.05.014
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发表时间：
2013-09-05
影响因子：
5
通讯作者：
Shibasaki, Masayuki
中科院分区：
文献类型：
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作者：
Tahara, Atsuo;Kurosaki, Eiji;Shibasaki, Masayuki
钠葡萄糖共转运体2(SGLT(2))负责大多数葡萄糖在肾脏的重吸收，已被认为是治疗2型糖尿病的新靶点。本研究观察了SGLT2选择性抑制剂伊普格列齐对高脂饮食和链脲佐菌素-烟酰胺诱导的2型糖尿病小鼠的治疗作用，这些小鼠表现为胰岛素分泌受损、胰岛素抵抗、高脂血症、肝脏脂肪变性和肥胖。单次服用伊帕格列星可剂量依赖性地增加尿糖排泄，降低血糖和血浆胰岛素水平，并改善葡萄糖耐量。重复服用四周的伊帕格列齐不仅改善了糖耐量、高血糖和高胰岛素血症，而且还损害了胰岛素分泌、高脂血症、肝脏脂肪变性和肥胖，并伴随着尿糖排泄的增加。此外，伊帕格列齐降低了血浆和肝脏氧化应激生物标志物(硫代巴比妥酸反应物质和蛋白质羰基)和炎症标志物(白介素6、肿瘤坏死因子a、单核细胞趋化蛋白1和C反应蛋白)的水平，并通过血浆转氨酶水平评估改善了肝脏损伤。这些结果表明，SGLT2选择性抑制剂ipragliflzin不仅可以改善2型糖尿病小鼠的高血糖，还可以改善糖尿病/肥胖相关的代谢异常，并提示ipragliflzin可能有助于治疗2型糖尿病合并代谢综合征。(C)2013爱思唯尔B.V.保留所有权利。
The sodium glucose cotransporter 2 (SGLT(2)) is responsible for most glucose reabsorption in the kidney and has been proposed as a novel therapeutic target for the treatment of type 2 diabetes. In the present study, the therapeutic effects of SGLT2 selective inhibitor ipragliflozin were examined in high-fat diet and streptozotocin-nicotinamide-induced type 2 diabetic mice which exhibit impaired insulin secretion, insulin resistance, hyperlipidemia, hepatic steatosis, and obesity. Single administration of ipragliflozin dose-dependently increased urinary glucose excretion, reduced blood glucose and plasma insulin levels, and improved glucose intolerance. Four-week repeated administration of ipragliflozin improved not only glucose tolerance, hyperglycemia, and hyperinsulinemia but also impaired insulin secretion, hyperlipidemia, hepatic steatosis, and obesity with a concomitant increase in urinary glucose excretion. In addition, ipragliflozin reduced plasma and liver levels of oxidative stress biomarkers (thiobarbituric acid reactive substances and protein carbonyl) and inflammatory markers (interleukin 6, tumor necrosis factor a, monocyte chemotactic protein 1, and c-reactive protein), and improved liver injury as assessed by plasma levels of aminotransferases. These results demonstrate that SGLT2 selective inhibitor ipragliflozin improves not only hyperglycemia but also diabetes/obesity-associated metabolic abnormalities in type 2 diabetic mice and suggest that ipragliflozin may be useful in treating type 2 diabetes with metabolic syndrome. (C) 2013 Elsevier B.V. All rights reserved.