摘要
胰岛β细胞是机体内唯一可以合成并分泌胰岛素的细胞,多种病理因素均可引起胰岛β细胞的损伤,保护胰岛β细胞治疗糖尿病的研究受到人们的日益重视。本文从增强胰岛β细胞功能,减少胰岛β细胞凋亡,增加胰岛β细胞体量和诱导细胞分化方面进行阐述,为糖尿病的治疗提供新的靶点及治疗策略。
糖尿病是以血液中葡萄糖水平升高为主要特征的代谢性疾病。随着生活水平不断提高,糖尿病发病率急剧上升。流行病学数据表明,2017年至2045年,糖尿病患者增长率将超过50%,糖尿病患者数预计达到6.93
胰岛素抵抗导致胰岛β细胞代偿性分泌更多胰岛素以维持机体正常的血糖水平,随病程延长,胰岛β细胞功能和数量逐渐下
胰岛β细胞是机体唯一可以合成并分泌胰岛素的细胞。促进胰岛素合成与分泌是增强胰岛β细胞功能的主要方式。
胃饥饿素(ghrelin)是生长激素促分泌素受体的内源性配体,它可以促进生长激素的分泌,并与能量代谢息息相关。Gray
胰岛内存在一定数量的先天性免疫细胞,其中巨噬细胞占80%左右。研究发现,胰岛内先天免疫细胞可调控胰岛β细胞功能,维持机体稳
除胰岛内驻留的先天免疫细胞对胰岛功能起调节作用外,肠道菌群对于调控胰岛功能具有重要的作用。研究发现,肠道菌来源的短链脂肪酸可激活迷走神经促进胰岛素分泌。Zhang
目前临床上使用的促胰岛素分泌剂包括磺酰脲类药物和格列奈类药物。磺酰脲类药物通过与胰岛β细胞膜上的磺酰脲受体(sulphonylurea receptor,SUR)结合,阻断与其偶联的ATP敏感钾通道(ATP-sensitive potassium channel,KATP),引起钙通道开放,使胞浆内钙离子浓度升高,从而刺激胰岛素分泌。格列奈类药物同样作用于胰岛β细胞膜上的KATP,但这两类药物仅适用于胰岛功能尚存的糖尿病患者。促胰岛素分泌剂的长期使用易导致胰岛β细胞凋
研究发现,胰高血糖素样肽-1(glucagon like peptide 1,GLP-1)作为肠促胰岛素激素,可促进胰岛素分泌,诱导胰岛β细胞增殖,从而抑制胰岛β细胞凋
1型糖尿病中,胰岛β细胞特异性抗原诱导T细胞分化成熟,诱发细胞因子如IL-1β,TNF-α和NO的分泌,从而促进胰岛β细胞凋
线粒体功能障碍可引起胰岛β细胞胰岛素分泌受阻,并可启动细胞凋亡程序。Zhang

Figure 1 Mechanisms of islet β cell apoptosis in type 2 diabetes
胰岛β细胞中内质网分布广泛,以维持正常的胰岛素分泌和释
持续的内质网应激可引发细胞启动凋亡程序,其中C/EBP同源蛋白(C/EBP homologous protein,CHOP)作为PERK信号通路下游的转录因子发挥促凋亡作用。糖尿病小鼠模型中,CHOP敲除可显著减少胰岛β细胞凋亡,CHOP过表达则降低抗凋亡蛋白Bcl-2的表达,升高活性氧水

Figure 2 Chemical structures of compound 9c and compound 13d
研究报道,1型和2型糖尿病均会引起胰岛β细胞数量减少和功能减退,且随着年龄增长,成人体内胰岛β细胞的增殖能力丧失,几乎不增
碳水化合物反应元件结合蛋白(carbohydrate response element binding protein,ChREBP)作为一种调控糖脂代谢的转录因子,可与碳水化合物反应元件结合,从而驱动靶基因的表达,同时也在胰岛中表达并参与胰岛β细胞的增殖过程。研究发现,ChREBP可增加核因子红细胞系-2相关因子2(nuclear factor erythroid 2 related factor 2,Nrf2)的表达和活性,发挥抗氧化作用并诱导线粒体生物发生,促进葡萄糖诱导的胰岛β细胞增

Figure 3 Pathways involved in islet β cell proliferation
研究发现肝脏分泌蛋白丝氨酸蛋白酶抑制剂B(serpin B1)促进胰岛β细胞增殖,在敲除serpin B1小鼠中胰岛β细胞增殖减慢,而在斑马鱼中过表达serpin B1引起胰岛β细胞增殖。在肝脏特异性敲除胰岛素受体引起胰岛素抵抗的小鼠模型中,敲除肝脏叉头框转录因子O1(forkhead box protein O1,FoxO1)可降低serpin B1的表达,从而抑制胰岛β细胞增
双底物特异性酪氨酸磷酸化调节激酶A(dual-specificity tyrosine-phosphorylation regulated kinase 1A,DYRK1A)是一种进化上高度保守的蛋白激酶。DYRK1A可通过磷酸化细胞周期相关蛋白如P21和Cyclin D1调控细胞的增殖和分化过程。Wang
诱导其他种类细胞分化为具有细胞功能且表达成熟胰岛β细胞标志基因NEUROD1,NKX6.1,PAX6,PDX1,MafA的胰岛β样细胞是增加胰岛β细胞体量和保护胰岛β细胞功能的另一重要方
在体外,Pagliuca
除多能干细胞外,其他来源的干细胞亦可诱导分化为胰岛β样细胞。2016年,实验发现糖尿病患者的表皮细胞可转分化成iPSC,再进一步分化为具有葡萄糖应答反应的胰岛β样细
随着对糖尿病研究的不断深入,胰岛β细胞的功能和体量在糖尿病的发生发展中的作用也逐渐受到关注。目前已发现许多新型天然产物可改善血糖水
在糖尿病治疗中,恢复胰岛β细胞体量和功能的策略日益受到关注。目前大量基础研究、药物筛选以及相关的干细胞疗法研究不断深入,同时取得了一定的成果,展现出良好的前景。但是,此策略是否能运用于临床,服务于糖尿病患者还需要多学科配合系统地展开研究。
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