譚明典，鄧曉蓓，張芳，丁文軍

中國科學(xué)院大學(xué)生命科學(xué)學(xué)院 環(huán)境與健康實(shí)驗(yàn)室， 北京 100049

我國現(xiàn)已成為全球糖尿病人數(shù)最多的地區(qū)[1]，成年人發(fā)病率達(dá)到了9.7%[2]。其中2型糖尿病占到90%以上。目前，1型糖尿病的發(fā)病與自身免疫紊亂、遺傳因素、環(huán)境因素等其他因素相關(guān)。誘發(fā)2型糖尿病的原因主要有：遺傳因素、環(huán)境因素、肥胖、高糖和脂毒性、炎癥反應(yīng)和氧化應(yīng)激等，導(dǎo)致β細(xì)胞功能紊亂和胰島素抵抗[3]。

我國大氣顆粒物污染對健康的影響已日益受到公眾關(guān)注和政府重視。大量流行病學(xué)和臨床研究表明，大氣細(xì)顆粒物(PM2.5，空氣動(dòng)力學(xué)直徑<2.5 μm的大氣顆粒物)污染嚴(yán)重危害人體健康，導(dǎo)致呼吸、心血管、內(nèi)分泌等系統(tǒng)的發(fā)病率上升。并且，細(xì)顆粒物的組成成分和濃度與疾病發(fā)生密切相關(guān)[4-8]。毒理學(xué)研究也顯示，顆粒物中金屬元素、脂多糖、多環(huán)芳烴、醌類化合物等組分誘導(dǎo)體內(nèi)活性氧(ROS)生成[9]和炎癥反應(yīng)[10, 11]，引起組織和細(xì)胞的氧化損傷[9, 12, 13]和內(nèi)質(zhì)網(wǎng)(ER)應(yīng)激，激活細(xì)胞轉(zhuǎn)錄因子參與一系列信號通路，引起細(xì)胞凋亡和壞死等生物效應(yīng)及疾病[9]。目前發(fā)現(xiàn)，大氣顆粒物污染也與糖尿病并發(fā)癥的發(fā)病率相關(guān)[14]。

1 細(xì)顆粒物與糖尿病

流行病學(xué)調(diào)查結(jié)果顯示，長期PM2.5暴露可誘發(fā)糖尿病。Sun等發(fā)現(xiàn)北京市PM2.5濃度升高與2型糖尿病發(fā)病率增加呈正相關(guān)[15]。Chen等的研究結(jié)果也表明，PM2.5年平均濃度每升高10 μg·m-3，2型糖尿病發(fā)病的危險(xiǎn)度將增加1.11[16]。空氣污染與糖尿病急性并發(fā)癥、昏迷和酮癥酸中毒相關(guān)[14]。Pearson等發(fā)現(xiàn)，PM2.5日平均濃度每增加10 μg·m-3，2型糖尿病發(fā)病率增加1%[17]。短期亞急性暴露低濃度PM2.5導(dǎo)致人體胰島素抵抗[18]。

糖尿病、高血壓患者和肥胖人群暴露于高濃度PM2.5后，機(jī)體的C-反應(yīng)蛋白(CRP)、白介素-6(IL-6)、白細(xì)胞數(shù)量等炎癥水平明顯高于正常人群[19]。2型糖尿病患者外周血中血管內(nèi)皮細(xì)胞粘附因子(VCAM-1)的濃度隨著PM暴露水平增加而升高[20]。PM2.5日平均濃度每增加10 μg·m-3，2型糖尿病患者血液中IL-6、TNF-α水平分別升高20.2%和13.1%[19]。

動(dòng)物實(shí)驗(yàn)研究也發(fā)現(xiàn)，肥胖ICR小鼠暴露于15 μg·m-3PM2.510周后，肥胖小鼠的血糖水平、脂肪組織炎癥因子(TNF-ɑ、Nos2、IL-6)均明顯升高，抗炎癥因子(IL-10、Mgl-1、PPARγ)的表達(dá)水平下調(diào)，并出現(xiàn)胰島素抵抗和內(nèi)臟脂肪增多癥狀[21]。近期研究表明，當(dāng)用PM2.5暴露處理C57BL/6小鼠10周后，小鼠肝細(xì)胞的c-jun氨基末端激酶(JNK)、核因子κB(NF-κB)、Toll樣受體4(TLR4)等炎癥信號通路激活，并出現(xiàn)非酒精性脂肪肝、肝臟葡萄糖代謝紊亂以及胰島素抵抗等癥狀[8, 22, 23]。PM2.5暴露明顯引起高脂飼料(HFD)組小鼠胰島素和葡萄糖代謝失衡和炎癥反應(yīng)[15]，也引起糖尿病小鼠骨骼肌中ROS產(chǎn)物增加，并誘發(fā)胰島素抵抗[24]。此外，ApoE-/-小鼠長期暴露PM2.5和過渡金屬元素Ni后，出現(xiàn)空腹血糖升高、線粒體損傷、炎癥反應(yīng)和胰島素抵抗[25]。PM2.5長期暴露導(dǎo)致小鼠白色脂肪組織內(nèi)脂滴的生成和沉積[26]，引起受體識別的低密度脂蛋白氧化和脂質(zhì)受體功能紊亂[18, 27]。

2 致病作用機(jī)制

大氣顆粒物導(dǎo)致的健康損害主要由細(xì)胞氧化損傷和炎癥反應(yīng)所引起的。大氣顆粒物誘導(dǎo)的氧化應(yīng)激，巨噬細(xì)胞分化[28]、DNA和線粒體損傷[23, 29, 30]，抑制肝臟糖代謝相關(guān)酶活性，促進(jìn)炎癥因子釋放[31, 32]，上調(diào)與炎癥應(yīng)答通路[33, 34]相關(guān)的JNK、NF-κB和TLR4表達(dá)水平。有研究發(fā)現(xiàn)，炎癥應(yīng)答通路與胰島素抵抗之間密切相關(guān)[35]。此外，PM2.5降低肝糖原合成水平，破壞血糖和胰島素穩(wěn)態(tài)，抑制胰島素受體底物-1(IRS-1)介導(dǎo)信號通路的激活，下調(diào)肝臟PPARγ和PPARα蛋白的表達(dá)水平[22]，并引起免疫功能紊亂或細(xì)胞毒性[22, 36-38]。大氣顆粒物介導(dǎo)的炎癥反應(yīng)激活JNK通路，引起細(xì)胞功能紊亂或細(xì)胞凋亡。同時(shí)，炎癥因子進(jìn)一步引起ROS水平升高。大氣顆粒物中的多環(huán)芳烴化合物(PAHs)可以持續(xù)激活DNA損傷的信號通路[39]。當(dāng)用顆粒物中提取的含碳有機(jī)物處理HepG2細(xì)胞后，細(xì)胞8-羥基脫氧鳥苷(8-OHdG)和NF-κB p65蛋白水平均升高，該結(jié)果與ROS誘導(dǎo)的DNA損傷相關(guān)[40]。下面主要從氧化應(yīng)激、炎癥因子、糖脂毒性和其他方面探討大氣顆粒物的致病機(jī)制。

2.1 氧化應(yīng)激對胰島β細(xì)胞功能的影響

研究表明，氧化應(yīng)激激活I(lǐng)κ激酶β(IKKβ)后引起NF-κB水平升高[58, 59]，誘導(dǎo)β細(xì)胞凋亡。此外，氧化應(yīng)激還激活胰島β細(xì)胞的JNK、p38絲裂原活化蛋白激酶(p38 MAPK)和蛋白激酶C(PKC)[48]。P38 MPAK通過蛋白激酶D(PKD)抑制PKD1磷酸化，降低胰島素的分泌水平，進(jìn)一步調(diào)控β細(xì)胞的存活率和胰島素的分泌。研究表明，P38δ敲除小鼠的葡萄糖耐量和胰島β細(xì)胞分泌胰島素水平升高，高脂飼料誘導(dǎo)的胰島素抵抗明顯改善，氧化應(yīng)激誘導(dǎo)的β細(xì)胞凋亡水平降低[60]。以上也表明，P38δ是調(diào)控葡萄糖穩(wěn)態(tài)平衡的重要調(diào)節(jié)因素之一。

核因子E2相關(guān)因子2(Nrf2)與抗氧化反應(yīng)元件(antioxidant responsive element, ARE)結(jié)合后，調(diào)節(jié)抗氧化蛋白的表達(dá)[61, 62]。Nrf2/ARE信號通路已作為重要的抗氧化應(yīng)激信號通路，在調(diào)節(jié)細(xì)胞氧化還原平衡中起到重要作用。此外，Nrf2參與過氧化物酶體增殖物激活受體γ(PPARγ)和PI3K/Akt調(diào)節(jié)的抗氧化酶活性[63]。動(dòng)物實(shí)驗(yàn)也發(fā)現(xiàn)，Nrf2對Nrf2-KO小鼠的肥胖、胰島素抵抗和葡萄糖耐量方面具有一定的保護(hù)作用[64]

FoxO1是β細(xì)胞中表達(dá)的FoxO家族主要的轉(zhuǎn)錄因子，也是生長因子信號的主要介導(dǎo)物，調(diào)控β細(xì)胞增殖和氧化應(yīng)激應(yīng)答[65, 66]、胰島素分泌水平，抑制由游離脂肪酸(FFAs)激活的葡萄糖代謝[67-69]。此外，激活β細(xì)胞PI3K/Akt信號可以抑制FoxO活性[70, 71]，引起胰高血糖素樣肽(GLP-1)介導(dǎo)的細(xì)胞增殖和抗氧化水平升高。

2.2 炎癥因子對胰島β細(xì)胞功能的影響

炎癥反應(yīng)是誘導(dǎo)胰島素抵抗的原因之一[35]。PM2.5暴露降低與高密度脂蛋白(HDL-c)相關(guān)的抗炎能力[72]，導(dǎo)致炎癥反應(yīng)增強(qiáng)。在細(xì)顆粒物長期暴露下，在各時(shí)間點(diǎn)暴露組小鼠的血糖濃度均明顯升高，葡萄糖耐量受損，肝臟、肌肉和脂肪組織胰島素抵抗，以及系統(tǒng)性炎癥和肺組織中招募巨噬細(xì)胞[73]。巨噬細(xì)胞通過分泌的細(xì)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可誘導(dǎo)胰島β細(xì)胞凋亡[74]、NO和趨化因子產(chǎn)生，造成內(nèi)質(zhì)網(wǎng)損傷[75]。IL-1β持續(xù)激活JNK后，損傷胰島β細(xì)胞[76, 77]，抑制JNK通路可降低β細(xì)胞的氧化損傷[78, 79]。此外，游離脂肪酸(FFA)也可通過氧化/內(nèi)質(zhì)網(wǎng)應(yīng)激或PKC[80, 81]直接激活I(lǐng)KKβ和JNK；氧化應(yīng)激也可能激活PKC，且PKC也能通過NADPH氧化酶誘導(dǎo)氧化應(yīng)激[82]。另有研究顯示，TLR2缺陷性可以保護(hù)高脂食物誘導(dǎo)的β細(xì)胞功能紊亂[83]；炎癥激酶和PKC激活誘導(dǎo)β細(xì)胞的功能紊亂和凋亡，影響β細(xì)胞的胰島素信號通路[84]，而且PM2.5暴露引起Akt磷酸化的表達(dá)下降[21]，最終引起胰島素抵抗。

2.3 糖脂毒性

PM2.5暴露引起機(jī)體血糖水平升高和脂質(zhì)堆積[21, 73]，高血糖和高脂進(jìn)一步誘導(dǎo)氧化應(yīng)激，導(dǎo)致細(xì)胞內(nèi)ROS水平升高[85]。而且，脂質(zhì)也可引起血液循環(huán)系統(tǒng)相關(guān)氧化應(yīng)激因子水平的增加[86]。長期高脂和高糖減少胰島素分泌量，導(dǎo)致胰島細(xì)胞功能紊亂[87]。研究發(fā)現(xiàn)，用高糖(11.1 mmol·L-1)培養(yǎng)倉鼠胰島瘤HIT-T15細(xì)胞6個(gè)月后，細(xì)胞的胰島素mRNA表達(dá)水平下降，胰島素分泌量降低。相反，在低糖(0.8 mmol·L-1)條件下，細(xì)胞的胰島素mRNA表達(dá)和胰島素分泌量胰島素均維持于正常狀態(tài)[88]。另有研究發(fā)現(xiàn)，2型糖尿病患者的胰島β細(xì)胞凋亡水平明顯升高[89]。在糖毒性中，MafA是Maf bZIP(basic region leucine zipper)家族的轉(zhuǎn)錄因子之一，長期高糖(11.1mmol·L-1)培養(yǎng)的HIT-T15細(xì)胞的MafA結(jié)合和轉(zhuǎn)錄功能降低，導(dǎo)致胰島素基因表達(dá)、MafA和PDX-1蛋白水平降低[90]。重組HIT-T15細(xì)胞內(nèi)PDX-1的cDNA可部分增加高糖培養(yǎng)細(xì)胞的胰島素啟動(dòng)子活性[91]。而且，抗氧化劑NAC升高高糖培養(yǎng)HIT-T15細(xì)胞中MafA蛋白的表達(dá)水平[90]。

在高脂高糖條件下，β細(xì)胞易發(fā)生凋亡，該作用可能與Bax、caspase-2、NO和UCP-2(Uncoupling protein 2)水平升高相關(guān)[92, 93]。游離脂肪酸通過JNK激活和IRS-1絲氨酸磷酸化，影響ER的鈣離子調(diào)控[94]，抑制胰島素信號通路，調(diào)節(jié)氧化調(diào)控蛋白150(ORP150，保護(hù)細(xì)胞免受ER應(yīng)激損傷)的水平。高濃度FFAs引起胰島素敏感性降低[95]。大鼠注射葡萄糖和脂肪乳劑后，其胰島素基因的表達(dá)水平降低[96]。當(dāng)FFAs水平下降時(shí)，胰島素的分泌水平升高[97, 98]。

2.4 其 他

成人發(fā)病型糖尿病(MODY)由pdx-1基因變異所引起[99, 100]，PDX-1在胰島β細(xì)胞發(fā)育和功能中起到重要作用[49, 101]。PDX-1下調(diào)嚴(yán)重影響胰島素生成，導(dǎo)致β細(xì)胞功能紊亂和糖尿病[102]。MafA在葡萄糖調(diào)節(jié)胰島素基因表達(dá)和介導(dǎo)其他基因(如PDX-1)表達(dá)中具有重要作用[49, 103, 104]。FoxO1和PDX-1與MafA啟動(dòng)子結(jié)合后，介導(dǎo)MafA轉(zhuǎn)錄[49]，β細(xì)胞中，脂質(zhì)和前炎癥因子下調(diào)MafA和胰島素基因的表達(dá)[101, 105-107]，用腺病毒轉(zhuǎn)染PDX-1和MafA可明顯增加內(nèi)源性胰島素mRNA水平約93%[108]。因此，MafA可能是治療β細(xì)胞紊亂的潛在靶點(diǎn)[101]。

總體而言，PM2.5誘導(dǎo)的氧化應(yīng)激和炎癥反應(yīng)在糖尿病的發(fā)生發(fā)展中具有一定的生物學(xué)作用(圖1)。

圖1 PM2.5誘導(dǎo)的氧化應(yīng)激在糖尿病發(fā)生發(fā)展的作用機(jī)制ARE：抗氧化反應(yīng)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相關(guān)因子2，p38 MAPK：p38絲裂原活化蛋白激酶，PDX-1：胰腺十二指腸同源異型盒1，PKD：蛋白激酶D，PM2.5：細(xì)顆粒物，ROS：活性氧，TLR4：Toll樣受體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，有關(guān)大氣細(xì)顆粒物組成成分(金屬元素、離子和有機(jī)化合物等)引起胰腺β細(xì)胞損傷的研究報(bào)道甚少，其生物學(xué)作用機(jī)制有待于深入研究。

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