A novel SIRT1 activator E6155 improves insulin sensitivity in type 2 diabetic KKA(y) mice.
A novel SIRT1 activator E6155 improves insulin sensitivity in type 2 diabetic KKA(y) mice.
复制标题
新型 SIRT1 激活剂 E6155 可改善糖尿病 KKA(y) 型小鼠的胰岛素敏感性
DOI：
10.1016/j.bbrc.2018.03.034
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发表时间：
2018-04-06
影响因子：
3.1
通讯作者：
Si S
中科院分区：
文献类型：
--
作者：
Liu P;Feng T;Zuo X;Wang X;Luo J;Li N;Han X;Zhu N;Xu S;Xu Y;Jin ZG;Si S
沉默信息调节因子1（SIRT1）是一种依赖烟酰胺腺嘌呤二核苷酸（NAD+）的蛋白质去乙酰化酶，在调控能量代谢、应激反应和衰老过程中发挥着关键作用。因此，增强SIRT1活性可能是治疗糖尿病等代谢性疾病的一种潜在治疗策略。然而，截至目前，SIRT1的药理学激活剂仍较为匮乏。在本研究中，通过优化的高通量筛选，我们发现了一种哌嗪1,4 - 二酰胺化合物E6155，它是SIRT1的一种新型小分子激活剂。我们进一步发现，E6155通过提高SIRT1去乙酰化酶活性，显著上调了培养的小鼠肝细胞和骨骼肌细胞对葡萄糖的摄取。在2型糖尿病KKAy小鼠中，E6155处理显著降低了空腹血糖水平。此外，E6155改善了口服葡萄糖耐量和胰岛素耐量。正常血糖钳夹实验和胰岛素抵抗指数的稳态模型评估表明，E6155改善了糖尿病小鼠的胰岛素抵抗并提高了胰岛素敏感性。从作用机制上看，我们观察到E6155的抗糖尿病作用与SIRT1依赖的LKB1/AMPK和IRS1/AKT信号通路激活有关。总之，我们的研究结果确定E6155是一种新型SIRT1激活剂，并表明E6155可能是治疗胰岛素抵抗和糖尿病的一种有前景的候选药物。
Sirtuin 1 (SIRT1) is an NAD+-dependent protein deacetylase that plays a critical role in controlling energy metabolism, stress response and aging. Hence, enhancing SIRT1 activity could be a potential therapeutic strategy to treat metabolic diseases such as diabetes. However, pharmacological activators for SIRT1 are scarce to date. In this study, using the optimized high throughput screening, we identified E6155, a piperazine 1, 4- diamide compound, as a new small molecular activator of SIRT1. We further found that E6155 significantly upregulated glucose uptake in cultured mouse liver cells and skeletal muscle cells through increasing SIRT1 deacetylase activity. In type 2 diabetic KKAy mice, E6155 treatment markedly decreased the level of fasting glucose. Moreover, E6155 improved oral glucose tolerance and insulin tolerance. Euglycemic clamp and the homeostasis model assessment of insulin resistance index showed that E6155 ameliorated the insulin resistance and increased insulin sensitivity in diabetic mice. Mechanistically, we observed that the antidiabetic effects of E6155 were involved in SIRT1 dependent activation of LKB1/AMPK and IRS1/AKT pathways. In conclusion, our findings identified E6155 as a novel SIRT1 activator and suggested that E6155 could be a promising drug candidate for treating insulin resistance and diabetes.
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影响因子：
64.8
作者：
Wood, JG;Rogina, B;Sinclair, D
通讯作者：
Sinclair, D
DOI：
10.1016/j.apsb.2017.04.010
发表时间：
2017-07
期刊：
Acta pharmaceutica Sinica. B
影响因子：
--
作者：
Liu Q;Liu S;Gao L;Sun S;Huan Y;Li C;Wang Y;Guo N;Shen Z
通讯作者：
Shen Z
影响因子：
4.8
作者：
Lan, Fan;Cacicedo, Jose M.;Ido, Yasuo
通讯作者：
Ido, Yasuo
影响因子：
15.9
作者：
Ruderman, Neil B.;Carling, David;Cacicedo, Jose M.
通讯作者：
Cacicedo, Jose M.
影响因子：
64.5
作者：
Knight, Zachary A.;Gonzalez, Beatriz;Shokat, Kevan M.
通讯作者：
Shokat, Kevan M.