哺乳动物雷帕霉素靶蛋白（mTOR）介导膜联蛋白A1（Annexin A1）调控衰老相关胰岛β细胞功能下降的研究

It is important topic to prevent the development of T2DM with aging. Our previous research found that beta cells function and expression of ANXA1 protein both declined in islets with aging. ANXA1 expression is related positively with the activation of mTOR pathway. These results suggested that ANXA1 protein in islet might be an aging-related protein mediated by mTOR pathway. mTOR is an important signal molecule, which can inhibit autophagy and promote protein translation. We had proved that autophagy in islet beta cells decreased during the process of aging, which induced accumulation of harmful macromolecular protein and impaired mitochondria. Endoplasmic reticulum function will be restored and glucose metabolic stability will be maintained in beta cells when Protein translation is inhibited appropriately. We inferred that high expression of ANXA1 in old individual would activate mTOR pathway and regulate autophagy and protein translation, and then promote aging and dysfunction of beta cells. It’s not clear that how GLP-1 improve beta cell dysfunction in patients with type 2 diabetes. We found that GLP-1 could enhance autophagy of beta cells. So we speculated that GLP-1 might inhibit ANXA1 expression, activate autophagy and delay aging of beta cells.

探讨衰老相关胰岛β细胞功能降低的发病机制，预防糖尿病发生，是当今社会必须引起重视的命题。课题组发现，衰老过程中胰岛β细胞衰老、功能降低，胰岛内ANXA1蛋白表达升高；且β细胞内ANXA1表达与mTOR活化正相关；提示胰岛β细胞内ANXA1可能是由mTOR介导的一种衰老相关蛋白。mTOR是抑制细胞自噬、促进蛋白翻译的重要信号分子。课题组已经证明衰老引起胰岛β细胞自噬功能下降，β细胞内有害大分子积聚、线粒体损伤加重，导致β细胞衰老、功能下降；适当抑制β细胞蛋白翻译，利于保护内质网功能，维持糖代谢稳定。提示衰老过程中ANXA1高表达可能激活mTOR，调控下游自噬及蛋白翻译相关细胞活动，从而加重β细胞衰老及功能降低。GLP-1药物在2型糖尿病治疗中可改善胰岛β细胞功能的机制尚不明确。课题组发现，GLP-1增强胰岛β细胞自噬功能。推测，GLP-1通过抑制ANXA1从而激活β细胞自噬、延缓β细胞衰老。

哺乳动物雷帕霉素靶蛋白（mTOR）是抑制细胞自噬、促进蛋白翻译的重要信号分子。课题组发现，衰老过程中胰岛β细胞衰老，mTOR蛋白活性增强，自噬相关蛋白如Atg8/LC3表达下降，受自噬途径降解的有害大分子物质p62积聚增加，蛋白翻译相关蛋白s6k1表达增加，胰岛素分泌功能降低；提示衰老导致胰岛自噬功能减弱、蛋白质翻译增多失调，从而导致β细胞功能受损，逐渐出现糖代谢紊乱。mTOR抑制剂雷帕霉素是已知可延长老年鼠寿命的药物。本课题发现雷帕霉素和利拉鲁肽均可以抑制mTOR活性，改善胰岛分泌胰岛素的功能，保护自噬功能、适当抑制蛋白质翻译，从而保护线粒体及内质网功能，延缓β细胞衰老，改善糖代谢紊乱；且利拉鲁肽可抑制大鼠胰岛内膜联蛋白A1(ANXA1)的表达。ANXA1在老年大鼠胰岛中表达升高，抑制其在β细胞株内的表达后，mTOR表达活性减弱，调控胰岛β细胞自噬和蛋白质翻译。综合以上，考虑ANXA1参与利拉鲁肽调控大鼠胰岛内mTOR活性，影响mTOR信号下游的自噬和蛋白质翻译功能，进而影响β细胞的衰老及分泌胰岛素的功能。这为远期预防衰老相关胰岛功能受损及糖尿病发生的研究提供了基础资料。