双(α-呋喃甲酸)氧钒对胰岛beta细胞的保护作用及机制研究

Pancreatic beta-cell function impairment is one of key pathophysiological processes during the occurrence and development of type 2 diabetes mellitus (T2DM). Investigation on the preservation of islet beta cells attracts much innovational medicine research focuses to look for new treatments of T2DM currently. Recent reports found autophagy is essential for the maintenance of islet beta cell structure and function, which maybe is a must. The autophagy abnormal phenomena are closely related to beta cell function impairments. Therefore the effective intervention of beta cell autophagy is the new prevention strategy on T2DM mellitus and other metabolic diseases. Bis(alpha-furancarboxylato) -oxovanadium(IV)(BFOV) is the new organic complexes of vanadium, whose whole intellectual property rights belong to our research group thoroughly. Previous studies showed that the toxicity of BFOV is comparatively lower, while its hypoglycemic activity is better than or at least equal to bis(ethylmaltolato)oxovanadium(IV)(BEOV) under development overseas. BFOV can significantly improve the oral glucose tolerance and lipid metabolism disorders of STZ rats, KKay mice and other diabetic animal models as well. On these bases, our further research continues studying the effects of BFOV on the protection of islet cell function during two different stages, prediabetes and diabetes, using high fat diet induced insulin resistance mouse model and type 2 diabetic KKay mice. The mechanism of its action within the autophagy pathway is to be investigated at the cellular and molecular level, which will lay a sound experimental foundation on the clinical application and development of BFOV. A new theoretical treat routine of T2DM bound to be generalized based on it.

胰岛β细胞功能受损是2型糖尿病(T2DM)发生发展的关键病理生理过程，保护β细胞是目前寻找治疗T2DM创新药物的研究热点。新近研究发现，自噬对于维持胰岛β细胞的结构和功能是必不可少的，自噬异常与β细胞功能受损密切相关。因此有效干预β细胞自噬，是T2DM等代谢性疾病防治的新策略。双(α-呋喃甲酸)氧钒(BFOV)是本课题组设计合成的具有自主知识产权的新型有机钒配合物。前期研究表明,BFOV毒性小,降糖活性优于或等于国外正在研发的双(乙基麦芽酚)氧钒(BEOV)，可以明显改善STZ大鼠、KKay小鼠等糖尿病模型动物的葡萄糖耐量以及脂代谢紊乱。本研究利用高脂诱导的胰岛素抵抗小鼠和KKay小鼠,进一步研究BFOV对糖尿病前期以及糖尿病两种不同发展阶段的胰岛细胞的保护作用；并在细胞和分子水平探讨其在自噬通路的作用机制。为BFOV的临床应用和开发提供实验依据,也为糖尿病治疗策略提供新的理论依据。

双(α-呋喃甲酸)氧钒(BFOV)是本课题组设计合成的具有自主知识产权的新型有机钒配合物。前期研究表明，BFOV毒性较小，降糖活性优于或等于国外正在研发的双(乙基麦芽酚)氧钒(BEOV)，能明显改善1型和2型糖尿病动物的葡萄糖耐量以及脂代谢紊乱。本课题以BFOV为研究对象，较系统深入的研究了BFOV对胰岛的保护作用，并从自噬角度探讨其作用机制。结果表明BFOV可以降低高脂诱导的胰岛素抵抗小鼠(HF-C57)、ob/ob胰岛素抵抗小鼠和KKAy糖尿病小鼠的血糖、血脂水平，增加胰岛素敏感性，改善葡萄糖耐量。BFOV剂量依赖性地降低HF-C57小鼠、ob/ob小鼠和KKAy小鼠糖负荷后的胰岛素水平，组织病理学分析表明，BFOV可减少小鼠胰岛数量和减小胰岛体积，改善胰岛代偿性增生肥大，提示BFOV调节血糖可能是通过增加外周组织胰岛素敏感性而不是通过增加胰岛素的分泌量。高葡萄糖钳夹实验发现BFOV组在血糖稳态时呈剂量依赖性降低HF-C57小鼠的血清胰岛素水平，同时增加葡萄糖输注速率，提示BFOV可以改善高脂诱导的胰岛素抵抗小鼠β细胞的功能。体外研究发现，BFOV (6.25×10-7~2.5×10-6 mol/L) 能浓度依赖性地改善高糖高脂损伤胰岛β细胞NIT-1的细胞活力，减少高糖高脂诱导的细胞凋亡，逆转自噬抑制剂对高糖高脂NIT-1细胞进一步损伤。分子生物学结果显示，BFOV可上调NIT-1胰岛β细胞、HF-C57小鼠和KKAy小鼠胰腺组织Beclin-1 mRNA和/或蛋白的表达水平，下调P62蛋白的表达水平，进一步研究发现BFOV对自噬信号通路LC3、ATG12、ULK2、ATG7、mTOR等mRNA和蛋白均有不同程度的调节作用。以上体内外研究结果均提示，BFOV对胰岛β细胞有保护作用，此作用与调节自噬有关。该研究结果为钒类化合物的临床应用和开发提供了实验依据，也为糖尿病治疗策略提供了新的理论依据。