Histone deacetylase 3-selective inhibitor RGFP966 ameliorates impaired glucose tolerance through beta-cell protection
Histone deacetylase 3-selective inhibitor RGFP966 ameliorates impaired glucose tolerance through beta-cell protection
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组蛋白脱乙酰酶 3 选择性抑制剂 RGFP966 通过 β 细胞保护改善糖耐量受损
DOI：
10.1016/j.taap.2020.115189
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发表时间：
2020
影响因子：
3.8
通讯作者：
Shen Zhufang
中科院分区：
文献类型：
--
作者：
Lei Lei;Bai Guoliang;Wang Xing;Liu Shuainan;Xia Jie;Wu Song;Huan Yi;Shen Zhufang
组蛋白去乙酰化酶3（HDAC 3）的药理学抑制对糖尿病的潜在治疗作用是近年来的研究热点。RGFP 966作为一种高选择性HDAC 3抑制剂，其在糖尿病治疗中可能的作用和机制尚待阐明。在这项研究中，使用低剂量链脲佐菌素（STZ）诱导的糖尿病前期小鼠来测试RGFP 966对血糖和胰岛素的调节能力。我们从正常C57 BL/6 J小鼠和患有自发性2型糖尿病的KKAymice中分离胰岛，以确定RGFP 966对葡萄糖刺激的胰岛素分泌的效力。采用棕榈酸钠（sodium palmitate，PA）诱导的NIT-1胰岛β细胞，观察RGFP 966对胰岛β细胞凋亡的保护作用。结果显示，给予糖尿病前期小鼠RGFP 966不仅显著降低高血糖，促进I相胰岛素分泌，改善胰岛形态，而且在高血糖钳夹试验中增加葡萄糖输注速率（GIR）。当在体外处理时，RGFP 966增强正常C57 BL/6 J小鼠和糖尿病KKAymice的胰岛中的胰岛素分泌和合成。此外，它部分减弱PA诱导的NIT-1细胞凋亡。因此，我们的研究表明，RGFP 966可能通过选择性抑制HDAC 3，可能成为一种新的潜在的预防和治疗糖尿病的候选药物。
The potential therapeutic effect of histone deacetylase 3 (HDAC3) pharmacologic inhibition on diabetes has been focused recently. RGFP966, as a highly-selective HDAC3 inhibitor, its possible roles and underlying mechanism in the treatment of diabetes needs to be clarified. In this study, low-dose streptozotocin (STZ)-induced pre-diabetic mice were used to test the regulatory ability of RGFP966 in blood glucose and insulin. We isolated the islets both from normal C57BL/6 J mice and KKAymice with spontaneous type 2 diabetes to determine the potency of RGFP966 on glucose-stimulated insulin secretion. NIT-1 pancreatic β-cells induced by sodium palmitate (PA) were applied to identify the protective effects of RGFP966 against β-cell apoptosis. The results showed that administration of RGFP966 in the pre-diabetic mice not only significantly reduced hyperglycemia, promoted phase I insulin secretion, improved morphology of islets, but also increased glucose infusion rate (GIR) during hyperglycemic clamp test. When treatedin vitro, RGFP966 enhanced insulin secretion and synthesis in islets of normal C57BL/6J mice and diabetic KKAymice. In addition, it partially attenuated PA-induced apoptosis in NIT-1 cells. Therefore, our research suggests that RGFP966, probably through selective inhibition of HDAC3, might serve as a novel potential preventive and therapeutic candidate for diabetes.