糖脂毒性导致的胰岛β细胞损伤与2型糖尿病发生发展密切相关。近年研究发现自噬对压力应激状态下胰岛β细胞生存与功能的维持十分重要。前期工作中我们发现富含A型低聚原花青素的桂皮提取物能够降低血糖、明显改善db/db小鼠的胰岛β细胞功能，其主要单体成分Cinnamtannin D1（CD-1）能够抵抗棕榈酸和H2O2诱导的胰岛β细胞损伤，并且这一保护作用与其自噬促进活性有关。本项目拟利用药理学和基因干预手段，在分子、细胞和动物水平系统研究CD-1通过促进自噬保护胰岛β细胞降低血糖的作用及分子机制，同时揭示自噬促进剂在氧化应激状态下提升受损线粒体降解效率、激活Keap1-Nrf2抗氧化信号通路，探讨自噬促进剂抵抗高糖高脂诱导的β细胞损伤的分子机制。本研究的顺利实施将为PCO类天然产物应用于糖尿病防治提供依据，为自噬促进剂用于β细胞保护的可行性提供理论支持。

Glucolipotoxicity-induced pancreatic β cell dysfunction is tightly associated with the development of type 2 diabetes mellitus (T2DM). Recent studies have shown that autophagy is crucial in the maintenance of islet homeostasis under stress response. In previous work, we had found the water extract of cinnamon riched in type A procyanidolic oligomers (PCO) could markedly reduce blood glucose and improve islets function in db/db mice. Meanwhile, The major bioactive constituent of cinnamon bark, Cinnamtannin D1(CD-1), protects pancreatic β cells from dysfunction induced by both palmitic acid and H2O2, which may tightly associated with its effect on autophagy induction. In this study, we will employ small molecule compounds and RNA interference to investigate the protective effect of CD-1 on pancreatic β-cell through autophagy induction under high glucose/ high FFA conditions, and to uncover the underlying mechanisms both in vitro and in vivo. In the same time, the role of autophagy enhancer in both promotion of impaired mitochondria clearance and activation of autophagy-dependent Keap1/Nrf2 antioxidative pathway under oxidative stress will also be examined to demonstrate the underlying molecular mechanisms of autophagy enhancer improving glucolipotoxicity-induced pancreatic β cell dysfunction. This study would provide support for the usage of PCO monomer in T2DM therapy and the potential application of autophagy enhancer in β-cell protection.