大气细颗粒物与糖尿病

谭明典，邓晓蓓，张芳，丁文军

中国科学院大学生命科学学院 环境与健康实验室， 北京 100049

我国现已成为全球糖尿病人数最多的地区[1]，成年人发病率达到了9.7%[2]。其中2型糖尿病占到90%以上。目前，1型糖尿病的发病与自身免疫紊乱、遗传因素、环境因素等其他因素相关。诱发2型糖尿病的原因主要有：遗传因素、环境因素、肥胖、高糖和脂毒性、炎症反应和氧化应激等，导致β细胞功能紊乱和胰岛素抵抗[3]。

我国大气颗粒物污染对健康的影响已日益受到公众关注和政府重视。大量流行病学和临床研究表明，大气细颗粒物(PM2.5，空气动力学直径<2.5 μm的大气颗粒物)污染严重危害人体健康，导致呼吸、心血管、内分泌等系统的发病率上升。并且，细颗粒物的组成成分和浓度与疾病发生密切相关[4-8]。毒理学研究也显示，颗粒物中金属元素、脂多糖、多环芳烃、醌类化合物等组分诱导体内活性氧(ROS)生成[9]和炎症反应[10, 11]，引起组织和细胞的氧化损伤[9, 12, 13]和内质网(ER)应激，激活细胞转录因子参与一系列信号通路，引起细胞凋亡和坏死等生物效应及疾病[9]。目前发现，大气颗粒物污染也与糖尿病并发症的发病率相关[14]。

1 细颗粒物与糖尿病

流行病学调查结果显示，长期PM2.5暴露可诱发糖尿病。Sun等发现北京市PM2.5浓度升高与2型糖尿病发病率增加呈正相关[15]。Chen等的研究结果也表明，PM2.5年平均浓度每升高10 μg·m-3，2型糖尿病发病的危险度将增加1.11[16]。空气污染与糖尿病急性并发症、昏迷和酮症酸中毒相关[14]。Pearson等发现，PM2.5日平均浓度每增加10 μg·m-3，2型糖尿病发病率增加1%[17]。短期亚急性暴露低浓度PM2.5导致人体胰岛素抵抗[18]。

糖尿病、高血压患者和肥胖人群暴露于高浓度PM2.5后，机体的C-反应蛋白(CRP)、白介素-6(IL-6)、白细胞数量等炎症水平明显高于正常人群[19]。2型糖尿病患者外周血中血管内皮细胞粘附因子(VCAM-1)的浓度随着PM暴露水平增加而升高[20]。PM2.5日平均浓度每增加10 μg·m-3，2型糖尿病患者血液中IL-6、TNF-α水平分别升高20.2%和13.1%[19]。

动物实验研究也发现，肥胖ICR小鼠暴露于15 μg·m-3PM2.510周后，肥胖小鼠的血糖水平、脂肪组织炎症因子(TNF-ɑ、Nos2、IL-6)均明显升高，抗炎症因子(IL-10、Mgl-1、PPARγ)的表达水平下调，并出现胰岛素抵抗和内脏脂肪增多症状[21]。近期研究表明，当用PM2.5暴露处理C57BL/6小鼠10周后，小鼠肝细胞的c-jun氨基末端激酶(JNK)、核因子κB(NF-κB)、Toll样受体4(TLR4)等炎症信号通路激活，并出现非酒精性脂肪肝、肝脏葡萄糖代谢紊乱以及胰岛素抵抗等症状[8, 22, 23]。PM2.5暴露明显引起高脂饲料(HFD)组小鼠胰岛素和葡萄糖代谢失衡和炎症反应[15]，也引起糖尿病小鼠骨骼肌中ROS产物增加，并诱发胰岛素抵抗[24]。此外，ApoE-/-小鼠长期暴露PM2.5和过渡金属元素Ni后，出现空腹血糖升高、线粒体损伤、炎症反应和胰岛素抵抗[25]。PM2.5长期暴露导致小鼠白色脂肪组织内脂滴的生成和沉积[26]，引起受体识别的低密度脂蛋白氧化和脂质受体功能紊乱[18, 27]。

2 致病作用机制

大气颗粒物导致的健康损害主要由细胞氧化损伤和炎症反应所引起的。大气颗粒物诱导的氧化应激，巨噬细胞分化[28]、DNA和线粒体损伤[23, 29, 30]，抑制肝脏糖代谢相关酶活性，促进炎症因子释放[31, 32]，上调与炎症应答通路[33, 34]相关的JNK、NF-κB和TLR4表达水平。有研究发现，炎症应答通路与胰岛素抵抗之间密切相关[35]。此外，PM2.5降低肝糖原合成水平，破坏血糖和胰岛素稳态，抑制胰岛素受体底物-1(IRS-1)介导信号通路的激活，下调肝脏PPARγ和PPARα蛋白的表达水平[22]，并引起免疫功能紊乱或细胞毒性[22, 36-38]。大气颗粒物介导的炎症反应激活JNK通路，引起细胞功能紊乱或细胞凋亡。同时，炎症因子进一步引起ROS水平升高。大气颗粒物中的多环芳烃化合物(PAHs)可以持续激活DNA损伤的信号通路[39]。当用颗粒物中提取的含碳有机物处理HepG2细胞后，细胞8-羟基脱氧鸟苷(8-OHdG)和NF-κB p65蛋白水平均升高，该结果与ROS诱导的DNA损伤相关[40]。下面主要从氧化应激、炎症因子、糖脂毒性和其他方面探讨大气颗粒物的致病机制。

2.1 氧化应激对胰岛β细胞功能的影响

研究表明，氧化应激激活Iκ激酶β(IKKβ)后引起NF-κB水平升高[58, 59]，诱导β细胞凋亡。此外，氧化应激还激活胰岛β细胞的JNK、p38丝裂原活化蛋白激酶(p38 MAPK)和蛋白激酶C(PKC)[48]。P38 MPAK通过蛋白激酶D(PKD)抑制PKD1磷酸化，降低胰岛素的分泌水平，进一步调控β细胞的存活率和胰岛素的分泌。研究表明，P38δ敲除小鼠的葡萄糖耐量和胰岛β细胞分泌胰岛素水平升高，高脂饲料诱导的胰岛素抵抗明显改善，氧化应激诱导的β细胞凋亡水平降低[60]。以上也表明，P38δ是调控葡萄糖稳态平衡的重要调节因素之一。

核因子E2相关因子2(Nrf2)与抗氧化反应元件(antioxidant responsive element, ARE)结合后，调节抗氧化蛋白的表达[61, 62]。Nrf2/ARE信号通路已作为重要的抗氧化应激信号通路，在调节细胞氧化还原平衡中起到重要作用。此外，Nrf2参与过氧化物酶体增殖物激活受体γ(PPARγ)和PI3K/Akt调节的抗氧化酶活性[63]。动物实验也发现，Nrf2对Nrf2-KO小鼠的肥胖、胰岛素抵抗和葡萄糖耐量方面具有一定的保护作用[64]

FoxO1是β细胞中表达的FoxO家族主要的转录因子，也是生长因子信号的主要介导物，调控β细胞增殖和氧化应激应答[65, 66]、胰岛素分泌水平，抑制由游离脂肪酸(FFAs)激活的葡萄糖代谢[67-69]。此外，激活β细胞PI3K/Akt信号可以抑制FoxO活性[70, 71]，引起胰高血糖素样肽(GLP-1)介导的细胞增殖和抗氧化水平升高。

2.2 炎症因子对胰岛β细胞功能的影响

炎症反应是诱导胰岛素抵抗的原因之一[35]。PM2.5暴露降低与高密度脂蛋白(HDL-c)相关的抗炎能力[72]，导致炎症反应增强。在细颗粒物长期暴露下，在各时间点暴露组小鼠的血糖浓度均明显升高，葡萄糖耐量受损，肝脏、肌肉和脂肪组织胰岛素抵抗，以及系统性炎症和肺组织中招募巨噬细胞[73]。巨噬细胞通过分泌的细胞因子(如IL-1、IFN-γ和TNF-α等)激活NF-κB和STAT-1，尤其是IL-1β激活NF-κB可诱导胰岛β细胞凋亡[74]、NO和趋化因子产生，造成内质网损伤[75]。IL-1β持续激活JNK后，损伤胰岛β细胞[76, 77]，抑制JNK通路可降低β细胞的氧化损伤[78, 79]。此外，游离脂肪酸(FFA)也可通过氧化/内质网应激或PKC[80, 81]直接激活IKKβ和JNK；氧化应激也可能激活PKC，且PKC也能通过NADPH氧化酶诱导氧化应激[82]。另有研究显示，TLR2缺陷性可以保护高脂食物诱导的β细胞功能紊乱[83]；炎症激酶和PKC激活诱导β细胞的功能紊乱和凋亡，影响β细胞的胰岛素信号通路[84]，而且PM2.5暴露引起Akt磷酸化的表达下降[21]，最终引起胰岛素抵抗。

2.3 糖脂毒性

PM2.5暴露引起机体血糖水平升高和脂质堆积[21, 73]，高血糖和高脂进一步诱导氧化应激，导致细胞内ROS水平升高[85]。而且，脂质也可引起血液循环系统相关氧化应激因子水平的增加[86]。长期高脂和高糖减少胰岛素分泌量，导致胰岛细胞功能紊乱[87]。研究发现，用高糖(11.1 mmol·L-1)培养仓鼠胰岛瘤HIT-T15细胞6个月后，细胞的胰岛素mRNA表达水平下降，胰岛素分泌量降低。相反，在低糖(0.8 mmol·L-1)条件下，细胞的胰岛素mRNA表达和胰岛素分泌量胰岛素均维持于正常状态[88]。另有研究发现，2型糖尿病患者的胰岛β细胞凋亡水平明显升高[89]。在糖毒性中，MafA是Maf bZIP(basic region leucine zipper)家族的转录因子之一，长期高糖(11.1mmol·L-1)培养的HIT-T15细胞的MafA结合和转录功能降低，导致胰岛素基因表达、MafA和PDX-1蛋白水平降低[90]。重组HIT-T15细胞内PDX-1的cDNA可部分增加高糖培养细胞的胰岛素启动子活性[91]。而且，抗氧化剂NAC升高高糖培养HIT-T15细胞中MafA蛋白的表达水平[90]。

在高脂高糖条件下，β细胞易发生凋亡，该作用可能与Bax、caspase-2、NO和UCP-2(Uncoupling protein 2)水平升高相关[92, 93]。游离脂肪酸通过JNK激活和IRS-1丝氨酸磷酸化，影响ER的钙离子调控[94]，抑制胰岛素信号通路，调节氧化调控蛋白150(ORP150，保护细胞免受ER应激损伤)的水平。高浓度FFAs引起胰岛素敏感性降低[95]。大鼠注射葡萄糖和脂肪乳剂后，其胰岛素基因的表达水平降低[96]。当FFAs水平下降时，胰岛素的分泌水平升高[97, 98]。

2.4 其 他

成人发病型糖尿病(MODY)由pdx-1基因变异所引起[99, 100]，PDX-1在胰岛β细胞发育和功能中起到重要作用[49, 101]。PDX-1下调严重影响胰岛素生成，导致β细胞功能紊乱和糖尿病[102]。MafA在葡萄糖调节胰岛素基因表达和介导其他基因(如PDX-1)表达中具有重要作用[49, 103, 104]。FoxO1和PDX-1与MafA启动子结合后，介导MafA转录[49]，β细胞中，脂质和前炎症因子下调MafA和胰岛素基因的表达[101, 105-107]，用腺病毒转染PDX-1和MafA可明显增加内源性胰岛素mRNA水平约93%[108]。因此，MafA可能是治疗β细胞紊乱的潜在靶点[101]。

总体而言，PM2.5诱导的氧化应激和炎症反应在糖尿病的发生发展中具有一定的生物学作用(图1)。

图1 PM2.5诱导的氧化应激在糖尿病发生发展的作用机制ARE：抗氧化反应元件，GSH：谷胱甘肽，IKK-β：Iκ激酶β，JNK：氨基末端激酶，NF-κB：核因子κB，Nrf2：核因子E2相关因子2，p38 MAPK：p38丝裂原活化蛋白激酶，PDX-1：胰腺十二指肠同源异型盒1，PKD：蛋白激酶D，PM2.5：细颗粒物，ROS：活性氧，TLR4：Toll样受体4 Fig. 1 The mechanesim of PM2.5-induced oxidative stress on development of diabetes mellitusARE: Antioxidant responsive element, GSH: Glutathione, IKK-β: Inhibitor of nuclear factor kappa-B kinase, JNK: c-Jun N-terminal kinases, NF-κB: Nuclear factor kappa B, Nrf2: Nuclea factor erythroid-2-related factor 2, p38 MAPK: P38 Mitogen-activated protein kinases, PDX-1: Pancreatic and duodenal homeobox 1(Insulin promoter factor 1), PKD: Protein kinase D, PM2.5: Fine particulate matter, ROS: Reactive oxygen species, TLR4: Toll-like receptor 4

3 研究展望

目前，有关大气细颗粒物组成成分(金属元素、离子和有机化合物等)引起胰腺β细胞损伤的研究报道甚少，其生物学作用机制有待于深入研究。

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