Treatment of diabetic mice with the SGLT2 inhibitor TA-1887 antagonizes diabetic cachexia and decreases mortality.
Treatment of diabetic mice with the SGLT2 inhibitor TA-1887 antagonizes diabetic cachexia and decreases mortality.
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DOI：
10.1038/s41514-017-0012-0
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发表时间：
2017
影响因子：
5
通讯作者：
Oike Y
中科院分区：
文献类型：
--
作者：
Sugizaki T;Zhu S;Guo G;Matsumoto A;Zhao J;Endo M;Horiguchi H;Morinaga J;Tian Z;Kadomatsu T;Miyata K;Itoh H;Oike Y
最近报道了钠-葡萄糖共转运体2(SGLT2i)抑制剂对糖尿病患者死亡率的有利作用，尽管其机制尚不清楚。在这里，我们研究SGLT2i对糖尿病小鼠存活的影响，并评估这些结果背后的因素。为了检验SGLT2i在严重糖尿病模型中的治疗效果，我们给遗传性糖尿病db/db小鼠喂高脂饮食，然后评估SGLT2i TA-1887治疗组和对照组小鼠之间的结果，包括糖尿病并发症。我们还比较了SGLT2i TA-1887与通过胰岛素治疗降低血糖水平的效果。未经治疗的db/db小鼠显示出显著的体重减轻或恶病质，而TA-1887治疗的小鼠并没有，而是在以后的时间点继续增加体重并降低死亡率。TA-1887治疗预防了胰岛β细胞死亡，增强了胰岛细胞质量和内源性胰岛素分泌的保存，并提高了胰岛素敏感性。此外，TA-1887治疗减轻炎症、氧化应激和细胞衰老，特别是内脏白色脂肪组织，并拮抗内皮功能障碍。Db/db小鼠的胰岛素治疗还可以预防体重减轻，并对抗炎症和氧化应激。然而，胰岛素治疗在存活和预防细胞衰老和内皮功能障碍方面的效果不如TA-1887治疗。SGLT2i治疗通过保护β细胞和胰岛素靶器官的功能，减少并发症，预防糖尿病恶病质和死亡。SGLT2i治疗可能是治疗伴有病态肥胖和严重胰岛素抵抗的2型糖尿病患者的一种有前途的治疗策略。钠-葡萄糖共转运体2抑制剂(SGLT2i)对糖尿病患者的死亡率有良好的影响，但其机制尚不清楚。熊本大学的杉崎太一研究了SGLT2i对严重糖尿病肥胖小鼠的影响，发现它们在没有病理性体重减轻或恶病质的情况下存活时间延长。与SGLT2i一样，胰岛素还可以预防恶病质，改善胰岛β细胞功能，改善胰岛素敏感性和一些器官损伤。然而，使SGLT2i变得重要的是抑制细胞衰老或血管炎症，而胰岛素促进了这些发展，这可能导致SGLT2i比胰岛素对延长生存期的贡献更大。SGLT2i在维持胰岛β细胞和胰岛素靶器官良好状态时与生存期相关，为重症糖尿病的治疗策略提供了洞察。
A favorable effect of an inhibitor of the sodium–glucose cotransporter 2 (SGLT2i) on mortality of diabetic patients was recently reported, although mechanisms underlying that effect remained unclear. Here, we examine SGLT2i effects on survival of diabetic mice and assess factors underlying these outcomes. To examine SGLT2i treatment effects in a model of severe diabetes, we fed genetically diabetic db/db mice a high-fat diet and then assessed outcomes including diabetic complications between SGLT2i TA-1887-treated and control mice. We also compare effects of SGLT2i TA-1887 with those of lowering blood glucose levels via insulin treatment. Untreated db/db mice showed remarkable weight loss, or cachexia, while TA-1887-treated mice did not but rather continued to gain weight at later time points and decreased mortality. TA-1887 treatment prevented pancreatic beta cell death, enhanced preservation of beta cell mass and endogenous insulin secretion, and increased insulin sensitivity. Moreover, TA-1887 treatment attenuated inflammation, oxidative stress, and cellular senescence, especially in visceral white adipose tissue, and antagonized endothelial dysfunction. Insulin treatment of db/db mice also prevented weight loss and antagonized inflammation and oxidative stress. However, insulin treatment had less potent effects on survival and prevention of cellular senescence and endothelial dysfunction than did TA-1887 treatment. SGLT2i treatment prevents diabetic cachexia and death by preserving function of beta cells and insulin target organs and attenuating complications. SGLT2i treatment may be a promising therapeutic strategy for type 2 diabetes patients with morbid obesity and severe insulin resistance. Sodium-glucose cotransporter 2 inhibitor (SGLT2i) has a favorable effect on mortality of diabetic subjects, but the mechanism stays unclear. Taichi Sugizaki at Kumamoto University examined SGLT2i effects in severe diabetic obese mice, and discovered that they showed prolonged survival without pathological weight loss, or cachexia. As with SGLT2i, Insulin also prevented cachexia, improved pancreatic beta cell function, insulin sensitivity and some organ damages. However, what makes SGLT2i important was to suppress cellular aging or vessel inflammation, while insulin accelerated those developments, which may lead to a result that SGLT2i has contributed to prolonged survival more than insulin. SGLT2i demonstrates an association with survival period upon maintaining good condition of pancreatic beta cells and insulin target organs, providing insight into strategies for treatment of severe diabetes.