胰安肽（Aglycin）治疗2型糖尿病的分子机制研究

T2D is an important risk factor to threaten human health, and its incidence is rapidly increasing in the worldwide. So far, there is no really medicine to treat it. We have isolated and characterized a novel peptide Aglycin from porcine intestine. Aglycin is consisted of 37 amino acids, and contains the special cystine knot structure in the molecule, which is capable to resist hydrolysis of proteases in the digestive tract. By oral administration,Aglycin depressed fasting blood glucose of T2D mice significantly,and the glucose tolerance was significantly improved.During acute toxicological tests, no animal was killed. Compared with the normal group,all of the biochemical markers of experimental group had no significant difference.However,the molecular mechanisms and molecular pharmacology of aglycin to treat T2D is unclear.This project aims to ：1）Dissect the mechanisms by which aglycin could treat T2D at multiple levels; 2)Confirm the distribution and position,the target cells and proteins of aglycin in vivo; 3)Reveal the time and space law of aglycin to be storaged,to be transferred and to be transported in a single living cell by using the femtosecond laser photon excitation scanning microscopy imaging system and high-resolution small animal imaging system. Provides conclusive theoretical basis and technical support for the pre-clinical studies of aglycin.

2型糖尿病（T2D）危害人类健康，发病率逐年上升，发病机理尚未彻底阐明，无有效治疗药物。在研究胃肠多肽激素与T2D关系时，我们自猪小肠分离鉴定出胰安肽（Aglycin）。它由37个氨基酸组成，三对二硫键形成胱氨酸结结构,耐消化道酶解。前期研究证实口服胰安肽可显著降低T2D小鼠空腹血糖，改善胰岛素敏感性，使糖耐量趋向正常。急性毒理研究表明受试动物所有生化指标与正常组均无显著性差异。然而胰安肽治疗2型糖尿病的分子机理及其分子药理尚不清楚。本项目拟在分子、细胞和活体动物水平上系统揭示胰安肽治疗2型糖尿病的精细机制；并利用飞秒激光光子激发扫描显微成像系统和高分辨小动物活体成像系统，检测Aglycin在体内的分布与定位情况、作用的靶细胞以及相互作用的蛋白。揭示胰安肽在单个活细胞内储存、转移和运输的时空规律，为胰安肽的临床前研究提供确凿的理论依据和技术支撑。

2 型糖尿病（ T2DM）危害人类健康，发病率逐年上升，发病机理尚未彻底阐明，无有效治疗药物。前期研究证实口服胰安肽可显著降低 T2D 小鼠空腹血糖，改善胰岛素敏感性，使糖耐量趋向正常，然而胰安肽治疗 2 型糖尿病的分子机理及其分子药理尚不清楚。本项目研究结果表明，Aglycin通过促进胰岛β细胞增殖并抑制细胞凋亡和去分化，在T2DM动物模型中表现出了良好的治疗效果，并通过激活胰岛素受体和相应的转录因子信号通路来发挥作用。在长期的Aglycin治疗后，T2DM小鼠的胰岛素敏感性、葡萄糖耐受能力和炎症因子水平有明显改善。这些结果体现了Aglycin在改善糖脂毒性中对胰岛β细胞的保护作用。因此，Aglycin可以通过补充内源性胰岛β细胞来作为一种预防和治疗糖尿病的新型药物进行开发和深入研究。