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2型糖尿病合并動(dòng)脈粥樣硬化的發(fā)病機(jī)制、臨床診斷與治療

石維

(南京醫(yī)科大學(xué)附屬無(wú)錫市人民醫(yī)院內(nèi)分泌科，江蘇無(wú)錫214023)

〔關(guān)鍵詞〕2型糖尿病；動(dòng)脈粥樣硬化；炎癥反應(yīng)；糖代謝；脂代謝

全世界2型糖尿病(T2MD)發(fā)生率越來(lái)越高，嚴(yán)格的血糖控制能顯著改善糖尿病微血管病變，但對(duì)大血管病變的影響甚微。糖尿病大血管病變是T2DM患者致殘、致死的主要影響因素。動(dòng)脈粥樣硬化(AS)作為糖尿病的并發(fā)癥隨著病情的進(jìn)展會(huì)發(fā)生心肌梗死 、腦卒中等疾病〔1,2〕。據(jù)報(bào)道，T2MD首次心肌梗死的發(fā)生率是非T2DM患者的2~4倍〔2〕，腦卒中和外周動(dòng)脈疾病的發(fā)生率亦可升高2~4倍〔3,4〕。但許多患者在AS的初始階段沒(méi)有明顯癥狀。因此，探討T2DM合并AS患者的形成機(jī)制及其發(fā)生、發(fā)展而致各種并發(fā)癥的產(chǎn)生原因，可進(jìn)一步地對(duì)T2DM合并AS患者進(jìn)行有效的病情診斷并根據(jù)患者的不同情況進(jìn)行個(gè)體化的預(yù)防和治療。

1T2DM合并AS的斑塊形成機(jī)制

在T2DM患者中AS與攝糖過(guò)多、胰島素抵抗(IR)、糖尿病耐受等有關(guān)〔5〕。除了糖代謝異常，引起AS的主要因素還包括脂質(zhì)代謝紊亂和內(nèi)皮細(xì)胞功能受損。T2DM合并AS形成早期，空腹甘油三酯(TG)、載脂蛋白(Apo)B、 ApoB/ApoA1 比例顯著升高，而ApoA1、高密度脂蛋白膽固醇(HDL-C)和總膽固醇(TC)/HDL比例沒(méi)有差異性；這些患者用胰島素治療無(wú)助于ApoB水平的降低〔6〕。Apo的異常伴隨著脂質(zhì)紊亂，ApoB攜帶的脂蛋白升高，而ApoA攜帶的脂蛋白降低，這使T2DM患者血液中的TG水平較高，而HDL-C水平則較低，從而產(chǎn)生慢性炎癥，氧化壓力加大，啟動(dòng)AS形成〔7,8〕，盡管此時(shí)低密度脂蛋白膽固醇(LDL-C)水平可在正常范圍內(nèi)，但LDL-C會(huì)轉(zhuǎn)變成小的，致密動(dòng)脈粥樣LDL-C顆?！?〕，且LDL-C的糖化程度增加，糖化的LDL-C會(huì)快速被巨噬細(xì)胞攝入〔9〕，通過(guò)巨噬細(xì)胞內(nèi)化使LDL-C氧化〔10〕。胰島素增多癥是已知的AS高危因素，胰島素增多癥可能也是通過(guò)巨噬泡細(xì)胞的作用促進(jìn)AS形成〔11〕?；罨木奘杉?xì)胞釋放相關(guān)趨化因子、細(xì)胞因子，激發(fā)一系列炎癥反應(yīng)。

隨著動(dòng)脈壁中脂質(zhì)的累積，血管內(nèi)皮細(xì)胞功能出現(xiàn)異常，而高血糖癥則抑制內(nèi)皮一氧化氮(NO)的生產(chǎn)〔12〕，或促進(jìn)其降解〔13〕，引起內(nèi)皮細(xì)胞功能缺損。內(nèi)皮細(xì)胞功能異常引起血管緊張度升高、促凝血和促炎癥因子升高，激活免疫細(xì)胞，引起血細(xì)胞滲進(jìn)動(dòng)脈內(nèi)膜，并形成AS斑塊，AS斑塊的形成，使血栓形成的風(fēng)險(xiǎn)增加〔14〕。前述多種原因使細(xì)胞和細(xì)胞外基質(zhì)聚積，刺激內(nèi)膜增厚。隨后發(fā)生脂質(zhì)沉積，薄的纖維帽覆蓋在大的粥樣斑塊脂質(zhì)核心上，這構(gòu)成了AS軟斑，而在后期進(jìn)展為鈣化斑塊。個(gè)體間的異質(zhì)性也使AS的發(fā)生具有差異性，而這種差異可能在患者出生時(shí)就產(chǎn)生。胚胎發(fā)育過(guò)程中，印跡基因，如印記母源表達(dá)轉(zhuǎn)錄、胰島素樣生長(zhǎng)因子(IGF)2發(fā)生表觀遺傳紊亂，可致個(gè)體不可避免地發(fā)生T2DM〔15〕。這就大大增加了AS的發(fā)生。這將促使未來(lái)研究者和醫(yī)務(wù)工作者對(duì)T2DM易感人群的異質(zhì)性進(jìn)行遺傳學(xué)水平的研究，從基因水平、生活方式等各方面綜合分析，找到不同患者AS發(fā)生的不同成因，從而進(jìn)行更為精準(zhǔn)的診斷，合理的治療。

2T2DM合并AS患者相關(guān)的診斷指標(biāo)

傳統(tǒng)的T2DM診斷需要進(jìn)行空腹血糖(FPG)、口服糖耐量實(shí)驗(yàn)(OGTT)、糖化血紅蛋白(HbA1c)、IR等檢測(cè)。除了常規(guī)檢測(cè)，對(duì)糖代謝、脂質(zhì)代謝、炎癥因子相關(guān)參數(shù)的聯(lián)合檢測(cè)有助于更為客觀地對(duì)患者的病情進(jìn)行診斷。HbA1c升高和外周血管病變(PAD)的風(fēng)險(xiǎn)相關(guān)，若其水平很高，提示有PAD、心血管致死高發(fā)風(fēng)險(xiǎn)。HbA1c可測(cè)定睡眠呼吸異常程度，特別對(duì)于有嚴(yán)重睡眠呼吸異常的老年人、肥胖人〔16~18〕。若男性年輕人T2DM中HDL-C濃度下降，血管硬化程度升高，HDL-C可輔助評(píng)估心血管病發(fā)生風(fēng)險(xiǎn)〔19〕。AS進(jìn)程加劇時(shí)，CRP升高，此時(shí)提示心血管病發(fā)生風(fēng)險(xiǎn)，死亡風(fēng)險(xiǎn)。CRP>3 mg/L時(shí)心血管疾病有高發(fā)風(fēng)險(xiǎn)，對(duì)T2DM進(jìn)行監(jiān)測(cè)運(yùn)動(dòng)可降低CRP水平〔20,21〕。在無(wú)癥狀T2DM患者中，和肽素可以作為心血管疾病的檢測(cè)標(biāo)記物，但AS疾病程度與和肽素的相關(guān)性需要進(jìn)一步證實(shí)〔22〕。而血清Vaspin濃度和頸動(dòng)脈斑呈顯著負(fù)相關(guān)性〔23,24〕。在T2DM中sclerostin和頸動(dòng)脈內(nèi)膜中層厚度(CIMT)顯著負(fù)相關(guān)，clerostin可能有預(yù)防T2DM患者中血管并發(fā)癥進(jìn)程的作用，其機(jī)制可能是抑制β-catenin活性，從而防止血管細(xì)胞衰減〔25〕。腦卒中，心肌缺血及冠心病在T2DM中更高發(fā)，此時(shí)平均鈉尿肽水平升高〔26〕。中央動(dòng)脈波形(AVI)反映第1 次和第2 次中央動(dòng)脈波形差，以脈沖壓力的百分比表示，是全身性動(dòng)脈硬化的檢測(cè)指標(biāo)〔27,28〕。CIMT，可診斷早期AS，CIMT和周?chē)懿?PVD)的發(fā)生相關(guān)性強(qiáng)較，特別對(duì)于婦女，可有效預(yù)測(cè)心臟疾病和腦卒中的發(fā)生風(fēng)險(xiǎn)〔29,30〕。斑塊內(nèi)出血(PH)的發(fā)生和男性顯著相關(guān)，和女性無(wú)相關(guān)性，PH和斑塊的不穩(wěn)定性相關(guān)，可用于輔助診斷男性心腦管血疾病發(fā)生〔31〕。

CIMT檢測(cè)已被認(rèn)為是AS發(fā)生的預(yù)示指標(biāo)，但一些研究者并不認(rèn)同此觀點(diǎn)。頸動(dòng)脈和下肢動(dòng)脈是AS損害的常發(fā)區(qū)域〔32〕。Sosnowski等〔33〕發(fā)現(xiàn)下肢AS斑較頸動(dòng)脈斑更能反映冠狀動(dòng)脈AS的嚴(yán)重程度。頸動(dòng)脈斑可能反映T2DM總的斑塊情況，聯(lián)合兩者可提高T2DM合并AS損害的檢出率。

上述檢測(cè)項(xiàng)目是基于理化角度，但AS發(fā)生的起始在分子水平就發(fā)生了更早的變化。目前，對(duì)于T2DM的研究已深入到基因水平的分析，如Hp(Haptoglobin)基因型Hp 1-1,1-2,或 2-2和T2DM并發(fā)癥的發(fā)生風(fēng)險(xiǎn)相關(guān)，Hp2-2和微血管〔34〕、巨血管〔35〕并發(fā)癥相關(guān)，這類(lèi)基因型患者心肌疾病的發(fā)生率〔35〕及心肌梗死風(fēng)險(xiǎn)更高〔36〕；與攜帶者相比，Hp 1-1純合子T2DM患者到了老年，認(rèn)知功能降低，心血管發(fā)生風(fēng)險(xiǎn)也升高〔37〕。因此，進(jìn)一步需要研究的是基因型是否決定了AS的發(fā)生，還是AS推動(dòng)了這類(lèi)基因型患者的病程發(fā)展？基因水平的進(jìn)步將直接引起對(duì)T2DM患者的治療策略的調(diào)整。

3T2DM合并AS患者的治療

針對(duì)T2DM合并AS的藥物治療能有效改善機(jī)體功能、延緩器質(zhì)性病變。Thiazolidinediones在發(fā)揮抗炎反應(yīng)的同時(shí)，還能改善胰島素敏感性、延遲AS的形成和發(fā)展、降低PAD風(fēng)險(xiǎn)〔38，39〕。Metformin能降低Fibulin-1水平，改善內(nèi)皮功能紊亂、細(xì)胞外基質(zhì)修飾和積聚、鈣化等生理病理反應(yīng)；同時(shí)顯著降低血清HbA1C水平，增強(qiáng)血管內(nèi)皮細(xì)胞的功能〔40〕。Pioglitazone顯著降低空腹胰島素、HbA1C 和HOMA-IR，增強(qiáng)血管內(nèi)皮功能，延遲AS進(jìn)程，降低心血管疾病發(fā)生率〔41，42〕。Flavonoids和flavan-3-ols提高內(nèi)皮細(xì)胞功能、逆轉(zhuǎn)AS進(jìn)程或斑塊形成，降低心血管病發(fā)病風(fēng)險(xiǎn)，增加治療存活率，同時(shí)可預(yù)防絕經(jīng)婦女患CVD風(fēng)險(xiǎn)〔43，44〕。Dipeptidyl peptidase-4 (DPP-4)抑制劑saxagliptin和alogliptin防止腸血糖素激素和糖依賴(lài)性促胰島肽的降解，提高攝糖控制效果；可增加NO的生物利用度，促進(jìn)內(nèi)皮細(xì)胞功能，降低炎癥，即有效改善頸動(dòng)脈AS〔38，45〕。Glucagon-like peptide-(GLP-1)受體激動(dòng)劑exenatide、liraglutide和albiglutide，較內(nèi)源性GLP-1有更長(zhǎng)的半衰期，且對(duì)GLP-1受體的作用提升了1~5倍，可降低HbA1c、減輕體重，對(duì)于胰島β細(xì)胞功能和脈管系統(tǒng)均有效應(yīng)〔46〕。Dual PPAR-α/γ激動(dòng)劑aleglitazar，對(duì)于脂質(zhì)(PPAR-α效應(yīng))、胰島素敏感性和糖攝取(PPAR-γ)有潛在的有利效應(yīng)。臨床二期表明，aleglitazar能顯著降低HbA1c，并伴隨TGs和LDL-C降低、HDL-C增高〔47,48〕。SGLT2 (Sodium-glucose cotransporter-2)抑制劑Sergliflozin和Dapagliflozin，通過(guò)抑制腎鈉-糖協(xié)同轉(zhuǎn)運(yùn)蛋白而降低血糖濃度，可使體重下降，血壓下降。但SGLT2抑制劑對(duì)于心血管病的效應(yīng)目前未研究清楚〔49,50〕。Statin對(duì)脂質(zhì)異常進(jìn)行控制，可使LDL-C水平降低20%左右，而減少心血管發(fā)病率〔51〕。Dalcetrapib降低CETP (Cholesteryl ester transfer protein)活性，提高HDL-C水平，改善脂質(zhì)紊亂，但需要臨床三期實(shí)驗(yàn)進(jìn)一步驗(yàn)證〔52〕。

不同患者用藥效果具有差異性，隨著T2MD合并AS形成的分子機(jī)制進(jìn)一步闡明，藥物的靶向治療能夠?qū)崿F(xiàn)對(duì)不同患者進(jìn)行個(gè)體化用藥。分子機(jī)制對(duì)于藥物與基因相互作用的研究，更有助于針對(duì)性地篩選治療T2MD的藥物，如metformin作用于SLC22A1、SLC22A2、SLC47A1、PRKAB2、PRKAA2、PRKAA1和STK11位點(diǎn)；此外，pioglitazone作用于PPARG2和PTPRD位點(diǎn)〔53〕。未來(lái)隨著人類(lèi)個(gè)體基因組測(cè)序、基因表達(dá)譜檢測(cè)的普及、結(jié)合生物信息學(xué)技術(shù)，就有可能根據(jù)T2MD患者的缺陷基因進(jìn)行有針對(duì)性的個(gè)體治療。

對(duì)T2DM患者飲食、生活方式等方面進(jìn)行指導(dǎo)有助于改善T2DM患者的AS相關(guān)癥狀。Horvath等〔54〕發(fā)現(xiàn)，T2DM患者單獨(dú)攝入糖于粒細(xì)胞和單核細(xì)胞激活沒(méi)有任何影響，而單獨(dú)攝入脂或聯(lián)合攝入糖和脂，在60~90 min內(nèi)外周血CD11b、CD66細(xì)胞顯著升高，因此脂質(zhì)對(duì)于相關(guān)免疫細(xì)胞的激活可能有更強(qiáng)地、快速地促進(jìn)作用，降低脂質(zhì)攝入有助于更有效地預(yù)防T2DM合并AS發(fā)生，阻抑AS的發(fā)展進(jìn)程。但對(duì)脂質(zhì)單因素的控制不能全面改善患者的身體狀況，需要采取一系列的措施才能使患者病情穩(wěn)定。美國(guó)心臟協(xié)會(huì)推薦對(duì)伴有PAD的T2DM患者的AS的發(fā)生原因進(jìn)行嚴(yán)格控制，以預(yù)防心血管疾病的發(fā)生。合理鍛煉和戒煙已被證明是預(yù)防PAD發(fā)生的有效生活方式，對(duì)于未發(fā)生PAD的T2DM患者，根據(jù)胰島素敏感性進(jìn)行攝糖控制，能夠有效降低PAD的發(fā)生率〔55〕。另根據(jù)心血管風(fēng)險(xiǎn)治療指南〔56〕，對(duì)發(fā)生過(guò)腦卒中或心肌梗死伴頸動(dòng)脈狹窄的T2DM患者每年進(jìn)行4次體檢，依據(jù)體檢結(jié)果進(jìn)行生活方式調(diào)整，將相關(guān)指標(biāo)控制在一定范圍內(nèi)，如LDL-C<2.5 mmol/L、血壓<140/90 mmHg、HbA1c<7%，同時(shí)測(cè)定CIMT觀察血管壁厚度是否降低〔57〕，這些防預(yù)措施對(duì)于預(yù)防高體質(zhì)指數(shù)(BMI)的T2DM患者的心血管疾病的發(fā)生十分重要。

4總結(jié)與展望

T2DM患者的血糖、脂質(zhì)、炎癥細(xì)胞等對(duì)全身或局部血管的理化、生物等作用，可使血管系統(tǒng)的功能損傷加重。隨著AS的進(jìn)一步發(fā)展，患者往往存在心腦血管系統(tǒng)隱患，繼而發(fā)生嚴(yán)重的心肌梗死、腦卒中等急性疾病以及認(rèn)知障礙等發(fā)展緩慢的疾病。相關(guān)生化指標(biāo)以及頸動(dòng)脈合并下肢動(dòng)脈檢測(cè)對(duì)以上疾病的預(yù)測(cè)起到積極作用。然而，目前的手段并不能實(shí)現(xiàn)對(duì)患者個(gè)體的系統(tǒng)性治療。這涉及以下幾個(gè)問(wèn)題：在分子水平，T2DM合并AS患者的進(jìn)程如何衍變，為何患者之間相關(guān)并發(fā)癥的發(fā)生風(fēng)險(xiǎn)會(huì)有高低，調(diào)控各組織器官功能的信號(hào)因子作用在AS過(guò)程中如何調(diào)控的，為何療效存在差異？闡明這些問(wèn)題不僅需要追溯患者的生活習(xí)慣進(jìn)行T2DM常規(guī)檢測(cè)，還需要從遺傳學(xué)的角度，如基因型檢測(cè)、遺傳印跡等表觀遺傳變化等方面進(jìn)行研究，從而根據(jù)患者的不同情況進(jìn)行更為精準(zhǔn)的個(gè)體化治療。

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〔2015-09-19修回〕

(編輯曹夢(mèng)園)

〔中圖分類(lèi)號(hào)〕R587

〔文獻(xiàn)標(biāo)識(shí)碼〕A

〔文章編號(hào)〕1005-9202(2016)07-1777-05；

doi：10.3969/j.issn.1005-9202.2016.07.108

第一作者：石維(1977-)，男，在讀碩士，主治醫(yī)師，主要從事脂肪肝與糖脂代謝研究。