硫辛酸對(duì)糖尿病及其慢性并發(fā)癥的作用機(jī)制研究進(jìn)展

呂　川，王　冠(綜述)，王秋月(審校)

(1.中國(guó)醫(yī)科大學(xué)附屬第一醫(yī)院內(nèi)分泌科，沈陽(yáng) 110001； 2.中國(guó)醫(yī)科大學(xué)七年制，沈陽(yáng) 110001)

硫辛酸對(duì)糖尿病及其慢性并發(fā)癥的作用機(jī)制研究進(jìn)展

呂川1△，王冠2(綜述)，王秋月1※(審校)

(1.中國(guó)醫(yī)科大學(xué)附屬第一醫(yī)院內(nèi)分泌科，沈陽(yáng) 110001； 2.中國(guó)醫(yī)科大學(xué)七年制，沈陽(yáng) 110001)

摘要：糖尿病及糖尿病腎病患病率的快速增長(zhǎng)，給家庭及社會(huì)造成了極大的負(fù)擔(dān)。由于缺乏有效的治療方法，目前臨床上只能防止糖尿病腎病的發(fā)生、進(jìn)展，或腎臟替代治療。硫辛酸具有強(qiáng)大的抗氧化效應(yīng)，并通過下丘腦及外周組織腺苷酸活化蛋白激酶(AMPK)信號(hào)通路調(diào)節(jié)機(jī)體能量代謝，因而對(duì)糖尿病及其慢性并發(fā)癥發(fā)揮保護(hù)作用。硫辛酸可通過增強(qiáng)組織細(xì)胞AMPK活性進(jìn)而抑制雷帕霉素靶蛋白信號(hào)通路，對(duì)細(xì)胞生長(zhǎng)和蛋白質(zhì)合成發(fā)揮調(diào)節(jié)作用。該文就硫辛酸對(duì)糖尿病及其慢性并發(fā)癥的作用機(jī)制研究進(jìn)展予以綜述。

關(guān)鍵詞：糖尿病；糖尿病腎臟疾病；硫辛酸

硫辛酸是一種天然存在的化合物，又稱為1,2-二硫戊環(huán)-3-戊酸；硫辛酸包含有2個(gè)氧化或還原的硫醇基團(tuán),其氧化形式被稱為A硫辛酸或硫辛酸，而二氫硫辛酸是指還原形式的硫辛酸；2種形式的硫辛酸都是強(qiáng)效抗氧化劑，其功能包括：①減少活性氧產(chǎn)生；②再生外源和內(nèi)源性抗氧化劑(如維生素C和E、谷胱甘肽)；③螯合金屬離子；④修復(fù)氧化的蛋白質(zhì)；⑤調(diào)控基因轉(zhuǎn)錄；⑥抑制核因子κB的激活[1]。硫辛酸這一系列細(xì)胞和分子功能，使其在應(yīng)用于營(yíng)養(yǎng)保健和疾病治療方面，被廣泛關(guān)注?，F(xiàn)就硫辛酸在改善糖尿病及其慢性并發(fā)癥作用機(jī)制的研究進(jìn)展予以綜述。

1硫辛酸改善活性氧類誘導(dǎo)的血管內(nèi)皮細(xì)胞功能紊亂

硫辛酸在糖尿病發(fā)病機(jī)制的多個(gè)方面都有潛在的防治意義。研究發(fā)現(xiàn)，活性氧類誘導(dǎo)的血管功能障礙是糖尿病的主要特點(diǎn)之一，活性氧類的積聚狀態(tài)與一氧化氮介導(dǎo)的內(nèi)皮依賴性血管舒張功能受損密切相關(guān)[2]。糖尿病時(shí)氧化應(yīng)激導(dǎo)致蛋白激酶C激活，對(duì)基因表達(dá)產(chǎn)生多種影響，包括內(nèi)皮型一氧化氮合酶表達(dá)下降和內(nèi)皮素、血管內(nèi)皮生長(zhǎng)因子、纖溶酶原激活物抑制劑1、轉(zhuǎn)化生長(zhǎng)因子β、煙酰胺腺嘌呤二核苷酸氧化酶、核因子κB等表達(dá)增強(qiáng)，其中，核因子κB表達(dá)增加又導(dǎo)致脈管系統(tǒng)中的促炎基因活化[3]。硫辛酸可以改善血漿的氧化還原狀態(tài)，并且能改善內(nèi)皮依賴性血管舒張功能[4]。胰島素受體酪氨酸激酶、磷脂酰肌醇3-激酶、蛋白激酶B(protein kinase B,PKB/Akt)是胰島素信號(hào)通路關(guān)鍵組分，與血管內(nèi)皮細(xì)胞一氧化氮合成相關(guān)；Akt誘導(dǎo)的內(nèi)皮型一氧化氮合酶磷酸化，對(duì)于胰島素激活A(yù)kt信號(hào)通路十分必要[5]。在一項(xiàng)應(yīng)用挪威大鼠的老化研究中，硫辛酸通過激活A(yù)kt，在一定程度上恢復(fù)了老化大鼠內(nèi)皮依賴性一氧化氮合酶的活性[6]。硫辛酸還可增加缺血再灌注損傷小鼠腦血管內(nèi)皮細(xì)胞Akt磷酸化[7]。這些研究表明，硫辛酸對(duì)血管內(nèi)皮功能的保護(hù)作用，與其提高一氧化氮合酶活性和增加一氧化氮的生物利用度有關(guān)。

非對(duì)稱二甲基精氨酸(asymmetric dimethylarginine，ADMA)是一種內(nèi)源性一氧化氮合酶抑制劑，由蛋白質(zhì)與L-精氨酸在蛋白質(zhì)精氨酸甲基轉(zhuǎn)移酶催化作用下發(fā)生甲基化反應(yīng)而生成；ADMA通過二甲基精氨酸二甲基氨基水解酶(dimethylarginine dimethylaminohydrolase，DDAH)代謝后經(jīng)腎臟排泄，該酶對(duì)氧化應(yīng)激敏感[8]。DDAH在腎臟、胰腺、腦、肝、肺，血管內(nèi)皮中均有表達(dá)，而ADMA可導(dǎo)致內(nèi)皮細(xì)胞功能紊亂[9]、增加全身血管阻力和動(dòng)脈血壓[10]。ADMA水平升高是包括2型糖尿病在內(nèi)不同人群心腦血管疾病的預(yù)測(cè)因子，也是不良心腦血管事件的病因之一[11-12]。DDAH活性下降導(dǎo)致ADMA分解減少，是糖尿病內(nèi)皮依賴性血管舒張功能障礙的重要機(jī)制之一[13]。在腎功能正?；蚪K末期腎臟病的糖尿病患者，硫辛酸均能有效降低ADMA水平[8,14]。另外，在培養(yǎng)的內(nèi)皮細(xì)胞，硫辛酸通過增加內(nèi)皮細(xì)胞DDAH的表達(dá)及活性，并通過促進(jìn)信號(hào)轉(zhuǎn)導(dǎo)及轉(zhuǎn)錄活化子3(signal transducer and activator of transcription 3,STAT3)磷酸化，降低培養(yǎng)上清液中ADMA的水平[15]。

2硫辛酸調(diào)節(jié)組織腺苷酸活化蛋白激酶和過氧化物酶體增殖物激活受體α/γ表達(dá)活性

2.1硫辛酸通過AMPK信號(hào)調(diào)節(jié)中樞及外周組織細(xì)胞代謝及功能硫辛酸可應(yīng)用于糖尿病的防治，另一個(gè)重要原因是其可通過激活外周組織細(xì)胞腺苷酸活化蛋白激酶(adenosine 5′-monophosphate-activated protein kinase，AMPK)活性，調(diào)節(jié)機(jī)體代謝。AMPK是一個(gè)高度保守的絲氨酸/蘇氨酸蛋白激酶，作為細(xì)胞的能量傳感器，在細(xì)胞能量供應(yīng)不足或細(xì)胞內(nèi)腺苷單磷酸(adenosine monophosphate，AMP)/腺苷二磷酸(adenosine diphosphate，ADP)比例升高時(shí)被激活；某些細(xì)胞應(yīng)激(如缺氧、氧化應(yīng)激、低血糖、運(yùn)動(dòng))以及營(yíng)養(yǎng)匱乏，可導(dǎo)致AMP/ATP比值升高，使AMPK磷酸化增加，抑制耗能的生物合成通路并促進(jìn)分解代謝[16]。AMPK還能調(diào)節(jié)與能量代謝有關(guān)特定基因的轉(zhuǎn)錄，進(jìn)而持久控制代謝反應(yīng)[17]。硫辛酸可增強(qiáng)肝臟AMPK活性，研究表明，增強(qiáng)肝臟AMPK活性可防止糖尿病小鼠的高血糖；AMPK激活的降糖作用可能與下調(diào)糖異生基因(如磷酸烯醇式丙酮酸激酶和葡萄糖-6-磷酸酶)表達(dá)、減少肝細(xì)胞葡萄糖輸出有關(guān)[18]。骨骼肌是細(xì)胞能量代謝的主要調(diào)節(jié)器官，骨骼肌AMPK激活可增加葡萄糖的攝取和脂肪酸氧化；激活的AMPK可刺激葡萄糖轉(zhuǎn)運(yùn)體4以胰島素依賴性的方式易位到質(zhì)膜，并通過促進(jìn)肌細(xì)胞增強(qiáng)因子2(myocyte enhancer factor-2，MEF-2)與葡萄糖轉(zhuǎn)運(yùn)體4基因啟動(dòng)子結(jié)合以增加葡萄糖轉(zhuǎn)運(yùn)體4的表達(dá)[19]。AMPK磷酸化激活和乙酰輔酶A羧化酶失活使丙二酰輔酶A下降、骨骼肌內(nèi)三酰甘油積聚減少，從而改善胰島素敏感性；乙酰輔酶A羧化酶是丙二酰輔酶A生物合成過程中一個(gè)重要的限速酶，而丙二酰輔酶A又是脂肪酸生物合成的重要前體和線粒體脂肪酸氧化的有效抑制劑，丙二酰輔酶A的水平下降使脂肪酸合成減少和氧化增加[20]。骨骼肌三酰甘油積聚可引起肥胖和2型糖尿病相關(guān)的胰島素抵抗[21]。易患糖尿病的Long Evans Tokushima肥胖大鼠肌肉AMPK活性下降，硫辛酸治療增加了大鼠和胰島素刺激條件下肌肉的葡萄糖利用，同時(shí)硫辛酸增加了骨骼肌AMPK活性和脂肪酸的氧化,骨骼肌AMPK基因沉默可以抵消硫辛酸的這一作用[22]。這些結(jié)果表明，硫辛酸可通過激活骨骼肌AMPK和減少三酰甘油積聚，而提高胰島素敏感性。AMPK在下丘腦組織也有表達(dá)，并且參與調(diào)節(jié)食欲[23]。下丘腦AMPK激活導(dǎo)致攝食和體質(zhì)量增加，而下丘腦AMPK活性的降低有利于瘦素對(duì)食欲的抑制；研究證實(shí)，應(yīng)用硫辛酸治療的肥胖大鼠下丘腦AMPK活性下降、攝食減少、能量消耗增加，體質(zhì)量明顯下降，血清脂聯(lián)素和瘦素水平均明顯降低[24]。這說(shuō)明下丘腦AMPK參與調(diào)節(jié)食欲，硫辛酸可通過抑制下丘腦AMPK活性，發(fā)揮抑制食欲、抗肥胖作用?；诓煌牟±砩頎顟B(tài)或藥物濃度，硫辛酸對(duì)胰島β細(xì)胞具有雙重作用，在2型糖尿病，氧化應(yīng)激促進(jìn)胰島β細(xì)胞凋亡，進(jìn)而減少胰島β細(xì)胞的數(shù)量，硫辛酸持續(xù)激活A(yù)MPK可導(dǎo)致線粒體氧自由基產(chǎn)生增加，并且激活線粒體凋亡通路[25]。但是,硫辛酸的作用呈劑量依賴性，在胰島細(xì)胞，硫辛酸濃度至少達(dá)到500 μmol/L才能明顯激活A(yù)MPK，明顯高于糖尿病神經(jīng)病變的治療濃度[26]；在氧化應(yīng)激狀態(tài)(如糖尿病)下，硫辛酸對(duì)胰島細(xì)胞發(fā)揮保護(hù)作用[27]。Lee等[28]研究發(fā)現(xiàn)，硫辛酸劑量依賴性地促進(jìn)大鼠胰島素瘤細(xì)胞凋亡；另一項(xiàng)相關(guān)的研究中，他們發(fā)現(xiàn)硫辛酸預(yù)處理降低了胰島β細(xì)胞活性氧的產(chǎn)生，線粒體膜去極化，抑制了c-Jun氨基端激酶激活。因此，雖然高濃度硫辛酸對(duì)胰島β細(xì)胞不利，但臨床治療劑量的硫辛酸對(duì)β細(xì)胞有保護(hù)作用。

2.2硫辛酸通過激活過氧化物酶體增殖物激活受體(peroxisome proliferator activated receptor，PPAR)α/γ對(duì)糖尿病發(fā)揮保護(hù)作用硫辛酸還能通過PPARα/γ調(diào)節(jié)機(jī)體代謝，對(duì)糖尿病發(fā)揮保護(hù)作用。骨骼肌PPAR共激活蛋白1α過表達(dá)可增加線粒體呼吸和葡萄糖轉(zhuǎn)運(yùn)[29]；硫辛酸可通過增加PPAR共激活蛋白1α信使RNA的表達(dá)水平，改善葡萄糖穩(wěn)態(tài)[30]。研究表明，硫辛酸還可避免高糖誘導(dǎo)的PPAR-γ下降、高胰島素血癥、胰島素抵抗、收縮性高血壓和超氧化物的產(chǎn)生[31]。

3硫辛酸抑制糖化反應(yīng)

硫辛酸能應(yīng)用于糖尿病的治療，還與其抑制糖基化反應(yīng)有關(guān)。研究證實(shí)，糖尿病慢性并發(fā)癥的發(fā)生、發(fā)展涉及多種病理生理機(jī)制，包括蛋白質(zhì)糖化作用[32-33]；而硫辛酸能改善糖尿病相關(guān)的糖化作用[34]。這一保護(hù)作用并不依賴于其氧化還原狀態(tài)，硫辛酸和二氫硫辛酸均能有效防止血清白蛋白糖化，這可能與硫辛酸與血清白蛋白的非共價(jià)鍵疏水性結(jié)合有關(guān)[35]。

4硫辛酸與糖尿病神經(jīng)病變

目前，已知多種發(fā)病機(jī)制與糖尿病神經(jīng)病變有關(guān)，并且這些發(fā)病機(jī)制相互聯(lián)系，促進(jìn)糖尿病神經(jīng)病變的發(fā)生、發(fā)展。糖尿病神經(jīng)病變涉及的發(fā)病機(jī)制主要有：①通過多元醇通路導(dǎo)致山梨醇和果糖積累增加，山梨醇的合成過程會(huì)消耗肌醇和?；撬?，而牛磺酸是一種內(nèi)源性抗氧化劑，其減少可導(dǎo)致機(jī)體氧化防御能力下降；肌醇消耗則可能導(dǎo)致Na+-K+-ATP酶活性下降；②一氧化氮失活導(dǎo)致神經(jīng)內(nèi)膜微血管損傷和缺氧；③糖基化終產(chǎn)物積聚導(dǎo)致核因子κB激活；④同型半胱氨酸血癥；⑤神經(jīng)脂質(zhì)過氧化；⑥調(diào)節(jié)絲裂原活化蛋白激酶信號(hào)通路；⑦鈣穩(wěn)態(tài)失衡；⑧神經(jīng)營(yíng)養(yǎng)因子表達(dá)水平下降(如神經(jīng)生長(zhǎng)因子、神經(jīng)營(yíng)養(yǎng)素、胰島素樣生長(zhǎng)因子等)[36]。硫辛酸對(duì)上述機(jī)制均有直接或間接的調(diào)節(jié)作用。

5硫辛酸與糖尿病腎病

硫辛酸在糖尿病腎病中的應(yīng)用仍處于實(shí)驗(yàn)階段，這些研究所涉及的機(jī)制有：①改善氧化應(yīng)激、抑制炎癥反應(yīng)[37-38]；②降低ADMA水平[14]；③保護(hù)線粒體功能和電壓依賴性陰離子通道[39]；④降低轉(zhuǎn)化生長(zhǎng)因子β、纖連蛋白的表達(dá)[40]；⑤抑制細(xì)胞外基質(zhì)積聚[41]。糖尿病時(shí)腎臟Akt活性增加，AMPK表達(dá)及活性下降，間接激活雷帕霉素靶蛋白復(fù)合物1(mammalian target of rapamycin complex 1，mTORC1)；mTORC1激活與糖尿病腎病腎小球肥大、細(xì)胞外基質(zhì)合成增加關(guān)系密切；應(yīng)用AMPK激活劑AICAR可顯著增加AMPK的活性，抑制高糖誘導(dǎo)的腎小球上皮細(xì)胞mTOR信號(hào)通路激活、細(xì)胞和腎臟肥大[42]。另外，硫辛酸通過增加大鼠骨骼肌鈣離子/鈣調(diào)素依賴的蛋白激酶β活性，使AMPK磷酸化激活，繼而抑制mTOR信號(hào)通路，有效防止了高糖誘導(dǎo)的骨骼肌蛋白質(zhì)合成增加和胰島素抵抗[43]。糖尿病腎病典型病理改變是腎小球硬化，其中系膜細(xì)胞增殖及過多的細(xì)胞外基質(zhì)積聚是腎小球硬化的使動(dòng)機(jī)制[44]。鈣離子/鈣調(diào)素依賴性蛋白激酶β作為AMPK的上游信號(hào)分子，在腎小球系膜細(xì)胞表達(dá)豐富，而mTORC1可通過其下游信號(hào)分子P70S6K調(diào)節(jié)細(xì)胞生長(zhǎng)，并通過4E-BPs調(diào)節(jié)細(xì)胞增殖[45]。由此推測(cè)，硫辛酸也可能在鈣離子/鈣調(diào)素依賴性蛋白激酶β介導(dǎo)下，通過增加腎小球系膜細(xì)胞AMPK活性，抑制mTORC1信號(hào)通路，改善高糖誘導(dǎo)的腎小球系膜細(xì)胞增殖，從而對(duì)早期糖尿病腎病發(fā)揮保護(hù)作用。

6硫辛酸與糖尿病視網(wǎng)膜病變

糖尿病視網(wǎng)膜病變作為糖尿病高度特異的嚴(yán)重并發(fā)癥，是導(dǎo)致成人失明的主要原因。最近的研究報(bào)告估計(jì)，大約30%初次確診為糖尿病的患者遭受視網(wǎng)膜病變困擾[46]。眼部各組織結(jié)構(gòu)均可受糖尿病影響，視網(wǎng)膜因富含毛細(xì)血管而更易受損。視網(wǎng)膜由多種細(xì)胞構(gòu)成，包括血管細(xì)胞、周細(xì)胞、內(nèi)皮細(xì)胞；小膠質(zhì)細(xì)胞、星形膠質(zhì)細(xì)胞、放射狀膠質(zhì)細(xì)胞；神經(jīng)元、感光細(xì)胞、雙極細(xì)胞、無(wú)長(zhǎng)突和神經(jīng)節(jié)細(xì)胞；巨噬細(xì)胞等。上述細(xì)胞結(jié)構(gòu)和功能異?？蓪?dǎo)致不同程度視網(wǎng)膜病變。高血糖誘發(fā)氧化應(yīng)激，促進(jìn)蛋白質(zhì)糖基化終產(chǎn)物和脂質(zhì)過氧化終產(chǎn)物生成，增加血管內(nèi)皮生長(zhǎng)因子表達(dá)，并激活多元醇通路、二酰甘油-蛋白激酶C、腎素-血管緊張素-醛固酮系統(tǒng)以及己糖胺通路，進(jìn)而損傷視網(wǎng)膜細(xì)胞結(jié)構(gòu)及功能[47]。硫辛酸可通過減少活性氧自由基的產(chǎn)生，改善氧化應(yīng)激，保護(hù)視網(wǎng)膜毛細(xì)血管的功能[48]。硫辛酸亦可通過減少糖尿病視網(wǎng)膜病變?cè)缙谝暰W(wǎng)膜毛細(xì)血管細(xì)胞凋亡，防止糖尿病視網(wǎng)膜病變的進(jìn)展[49]。硫辛酸還能降低血管內(nèi)皮細(xì)胞生長(zhǎng)因子、血管緊張素Ⅱ的表達(dá)，抑制結(jié)締組織生長(zhǎng)因子和轉(zhuǎn)化生長(zhǎng)因子β的作用，防止糖尿病視網(wǎng)膜新生血管形成和增生性病變[50]。

7小結(jié)

大量研究表明，硫辛酸對(duì)缺血再灌注損傷和神經(jīng)退行性疾病、代謝綜合征、糖尿病及其各種慢性并發(fā)癥等多種疾病有治療作用。隨機(jī)、雙盲、安慰劑對(duì)照試驗(yàn)均證明，硫辛酸可顯著改善糖尿病神經(jīng)病變的進(jìn)展。但是，硫辛酸對(duì)糖尿病腎病、糖尿病視網(wǎng)膜病變的治療作用仍缺乏足夠證據(jù)。mTOR信號(hào)通路激活與糖尿病腎臟肥大密切相關(guān)，近年來(lái)研究發(fā)現(xiàn)，硫辛酸對(duì)mTOR信號(hào)通路有調(diào)節(jié)作用。因此，針對(duì)糖尿病腎病這一病理生理機(jī)制，對(duì)恰當(dāng)?shù)牧蛐了嶂委焺┝亢蜁r(shí)間展開研究，可能為硫辛酸應(yīng)用于糖尿病腎病防治提供新的依據(jù)。

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Research Progress on the Effects and Mechanism of Lipoic Acid against Diabetes and Chronic Diabetic Complications

LVChuan1,WANGGuan2,WANGQiu-yue1.(1.DepartmentofEndocrinologyandMetabolism,theFirstAffiliatedHospital，ChinaMedicalUniversity，Shenyang110001，China； 2.ClinicalMedicineofSeven-yearEducation,ChinaMedicalUniversity,Shenyang110001，China)

Abstract：Rapid growth of diabetes and diabetic kidney disease exerts a great burden on family and society.Due to the lack of effective treatments for diabetic kidney disease,treatment relies on drugs that either reduces its progression or involves renal replacement therapies.Lipoic acid is a powerful antioxidant,which can regulate energy metabolism via adenosine 5′-monophosphate-activated protein kinase (AMPK) signaling in hypothalamus and peripheral tissues.Thus,lipoic acid has protective effects against diabetes and chronic diabetic complications by these diverse actions.Recently, lipoic acid has been shown to suppress mammalian target of rapamycin signaling in various tissues and cells by activating AMPK,thereby regulates cell growth and protein synthesis.Here is to make a review of the role and mechanisms of lipoic acid against diabetes and diabetic chronic complications.

Key words：Diabetes; Diabetic kidney disease; Lipoic acid

收稿日期：2014-07-17修回日期：2014-10-14編輯：鄭雪

基金項(xiàng)目：遼寧省科技攻關(guān)計(jì)劃項(xiàng)目(2011225017)；沈陽(yáng)市科技攻關(guān)計(jì)劃項(xiàng)目(F11-262-9-06)；遼寧省“百千萬(wàn)人才工程”資助項(xiàng)目(2011921037)

doi：10.3969/j.issn.1006-2084.2015.10.037

中圖分類號(hào)：R587.1

文獻(xiàn)標(biāo)識(shí)碼：A

文章編號(hào)：1006-2084(2015)10-1828-04