2型糖尿病合并動脈粥樣硬化的發病機制、臨床診斷與治療

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2型糖尿病合并動脈粥樣硬化的發病機制、臨床診斷與治療

石維

(南京醫科大學附屬無錫市人民醫院內分泌科，江蘇無錫214023)

〔關鍵詞〕2型糖尿病；動脈粥樣硬化；炎癥反應；糖代謝；脂代謝

全世界2型糖尿病(T2MD)發生率越來越高，嚴格的血糖控制能顯著改善糖尿病微血管病變，但對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。動脈粥樣硬化(AS)作為糖尿病的并發癥隨著病情的進展會發生心肌梗死 、腦卒中等疾病〔1,2〕。據報道，T2MD首次心肌梗死的發生率是非T2DM患者的2~4倍〔2〕，腦卒中和外周動脈疾病的發生率亦可升高2~4倍〔3,4〕。但許多患者在AS的初始階段沒有明顯癥狀。因此，探討T2DM合并AS患者的形成機制及其發生、發展而致各種并發癥的產生原因，可進一步地對T2DM合并AS患者進行有效的病情診斷并根據患者的不同情況進行個體化的預防和治療。

1T2DM合并AS的斑塊形成機制

在T2DM患者中AS與攝糖過多、胰島素抵抗(IR)、糖尿病耐受等有關〔5〕。除了糖代謝異常，引起AS的主要因素還包括脂質代謝紊亂和內皮細胞功能受損。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比例沒有差異性；這些患者用胰島素治療無助于ApoB水平的降低〔6〕。Apo的異常伴隨著脂質紊亂，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，從而產生慢性炎癥，氧化壓力加大，啟動AS形成〔7,8〕，盡管此時低密度脂蛋白膽固醇(LDL-C)水平可在正常范圍內，但LDL-C會轉變成小的，致密動脈粥樣LDL-C顆粒〔7〕，且LDL-C的糖化程度增加，糖化的LDL-C會快速被巨噬細胞攝入〔9〕，通過巨噬細胞內化使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巨噬泡細胞的作用促進AS形成〔11〕。活化的巨噬細胞釋放相關趨化因子、細胞因子，激發一系列炎癥反應。

隨著動脈壁中脂質的累積，血管內皮細胞功能出現異常，而高血糖癥則抑制內皮一氧化氮(NO)的生產〔12〕，或促進其降解〔13〕，引起內皮細胞功能缺損。內皮細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，激活免疫細胞，引起血細胞滲進動脈內膜，并形成AS斑塊，AS斑塊的形成，使血栓形成的風險增加〔14〕。前述多種原因使細胞和細胞外基質聚積，刺激內膜增厚。隨后發生脂質沉積，薄的纖維帽覆蓋在大的粥樣斑塊脂質核心上，這構成了AS軟斑，而在后期進展為鈣化斑塊。個體間的異質性也使AS的發生具有差異性，而這種差異可能在患者出生時就產生。胚胎發育過程中，印跡基因，如印記母源表達轉錄、胰島素樣生長因子(IGF)2發生表觀遺傳紊亂，可致個體不可避免地發生T2DM〔15〕。這就大大增加了AS的發生。這將促使未來研究者和醫務工作者對T2DM易感人群的異質性進行遺傳學水平的研究，從基因水平、生活方式等各方面綜合分析，找到不同患者AS發生的不同成因，從而進行更為精準的診斷，合理的治療。

2T2DM合并AS患者相關的診斷指標

傳統的T2DM診斷需要進行空腹血糖(FPG)、口服糖耐量實驗(OGTT)、糖化血紅蛋白(HbA1c)、IR等檢測。除了常規檢測，對糖代謝、脂質代謝、炎癥因子相關參數的聯合檢測有助于更為客觀地對患者的病情進行診斷。HbA1c升高和外周血管病變(PAD)的風險相關，若其水平很高，提示有PAD、心血管致死高發風險。HbA1c可測定睡眠呼吸異常程度，特別對于有嚴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可輔助評估心血管病發生風險〔19〕。AS進程加劇時，CRP升高，此時提示心血管病發生風險，死亡風險。CRP>3 mg/L時心血管疾病有高發風險，對T2DM進行監測運動可降低CRP水平〔20,21〕。在無癥狀T2DM患者中，和肽素可以作為心血管疾病的檢測標記物，但AS疾病程度與和肽素的相關性需要進一步證實〔22〕。而血清Vaspin濃度和頸動脈斑呈顯著負相關性〔23,24〕。在T2DM中sclerostin和頸動脈內膜中層厚度(CIMT)顯著負相關，clerostin可能有預防T2DM患者中血管并發癥進程的作用，其機制可能是抑制β-catenin活性，從而防止血管細胞衰減〔25〕。腦卒中，心肌缺血及冠心病在T2DM中更高發，此時平均鈉尿肽水平升高〔26〕。中央動脈波形(AVI)反映第1 次和第2 次中央動脈波形差，以脈沖壓力的百分比表示，是全身性動脈硬化的檢測指標〔27,28〕。CIMT，可診斷早期AS，CIMT和周圍血管病(PVD)的發生相關性強較，特別對于婦女，可有效預測心臟疾病和腦卒中的發生風險〔29,30〕。斑塊內出血(PH)的發生和男性顯著相關，和女性無相關性，PH和斑塊的不穩定性相關，可用于輔助診斷男性心腦管血疾病發生〔31〕。

CIMT檢測已被認為是AS發生的預示指標，但一些研究者并不認同此觀點。頸動脈和下肢動脈是AS損害的常發區域〔32〕。Sosnowski等〔33〕發現下肢AS斑較頸動脈斑更能反映冠狀動脈AS的嚴重程度。頸動脈斑可能反映T2DM總的斑塊情況，聯合兩者可提高T2DM合并AS損害的檢出率。

上述檢測項目是基于理化角度，但AS發生的起始在分子水平就發生了更早的變化。目前，對于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并發癥的發生風險相關，Hp2-2和微血管〔34〕、巨血管〔35〕并發癥相關，這類基因型患者心肌疾病的發生率〔35〕及心肌梗死風險更高〔36〕；與攜帶者相比，Hp 1-1純合子T2DM患者到了老年，認知功能降低，心血管發生風險也升高〔37〕。因此，進一步需要研究的是基因型是否決定了AS的發生，還是AS推動了這類基因型患者的病程發展？基因水平的進步將直接引起對T2DM患者的治療策略的調整。

3T2DM合并AS患者的治療

針對T2DM合并AS的藥物治療能有效改善機體功能、延緩器質性病變。Thiazolidinediones在發揮抗炎反應的同時，還能改善胰島素敏感性、延遲AS的形成和發展、降低PAD風險〔38，39〕。Metformin能降低Fibulin-1水平，改善內皮功能紊亂、細胞外基質修飾和積聚、鈣化等生理病理反應；同時顯著降低血清HbA1C水平，增強血管內皮細胞的功能〔40〕。Pioglitazone顯著降低空腹胰島素、HbA1C 和HOMA-IR，增強血管內皮功能，延遲AS進程，降低心血管疾病發生率〔41，42〕。Flavonoids和flavan-3-ols提高內皮細胞功能、逆轉AS進程或斑塊形成，降低心血管病發病風險，增加治療存活率，同時可預防絕經婦女患CVD風險〔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，促進內皮細胞功能，降低炎癥，即有效改善頸動脈AS〔38，45〕。Glucagon-like peptide-(GLP-1)受體激動劑exenatide、liraglutide和albiglutide，較內源性GLP-1有更長的半衰期，且對GLP-1受體的作用提升了1~5倍，可降低HbA1c、減輕體重，對于胰島β細胞功能和脈管系統均有效應〔46〕。Dual PPAR-α/γ激動劑aleglitazar，對于脂質(PPAR-α效應)、胰島素敏感性和糖攝取(PPAR-γ)有潛在的有利效應。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，通過抑制腎鈉-糖協同轉運蛋白而降低血糖濃度，可使體重下降，血壓下降。但SGLT2抑制劑對于心血管病的效應目前未研究清楚〔49,50〕。Statin對脂質異常進行控制，可使LDL-C水平降低20%左右，而減少心血管發病率〔51〕。Dalcetrapib降低CETP (Cholesteryl ester transfer protein)活性，提高HDL-C水平，改善脂質紊亂，但需要臨床三期實驗進一步驗證〔52〕。

不同患者用藥效果具有差異性，隨著T2MD合并AS形成的分子機制進一步闡明，藥物的靶向治療能夠實現對不同患者進行個體化用藥。分子機制對于藥物與基因相互作用的研究，更有助于針對性地篩選治療T2MD的藥物，如metformin作用于SLC22A1、SLC22A2、SLC47A1、PRKAB2、PRKAA2、PRKAA1和STK11位點；此外，pioglitazone作用于PPARG2和PTPRD位點〔53〕。未來隨著人類個體基因組測序、基因表達譜檢測的普及、結合生物信息學技術，就有可能根據T2MD患者的缺陷基因進行有針對性的個體治療。

對T2DM患者飲食、生活方式等方面進行指導有助于改善T2DM患者的AS相關癥狀。Horvath等〔54〕發現，T2DM患者單獨攝入糖于粒細胞和單核細胞激活沒有任何影響，而單獨攝入脂或聯合攝入糖和脂，在60~90 min內外周血CD11b、CD66細胞顯著升高，因此脂質對于相關免疫細胞的激活可能有更強地、快速地促進作用，降低脂質攝入有助于更有效地預防T2DM合并AS發生，阻抑AS的發展進程。但對脂質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定。美國心臟協會推薦對伴有PAD的T2DM患者的AS的發生原因進行嚴格控制，以預防心血管疾病的發生。合理鍛煉和戒煙已被證明是預防PAD發生的有效生活方式，對于未發生PAD的T2DM患者，根據胰島素敏感性進行攝糖控制，能夠有效降低PAD的發生率〔55〕。另根據心血管風險治療指南〔56〕，對發生過腦卒中或心肌梗死伴頸動脈狹窄的T2DM患者每年進行4次體檢，依據體檢結果進行生活方式調整，將相關指標控制在一定范圍內，如LDL-C<2.5 mmol/L、血壓<140/90 mmHg、HbA1c<7%，同時測定CIMT觀察血管壁厚度是否降低〔57〕，這些防預措施對于預防高體質指數(BMI)的T2DM患者的心血管疾病的發生十分重要。

4總結與展望

T2DM患者的血糖、脂質、炎癥細胞等對全身或局部血管的理化、生物等作用，可使血管系統的功能損傷加重。隨著AS的進一步發展，患者往往存在心腦血管系統隱患，繼而發生嚴重的心肌梗死、腦卒中等急性疾病以及認知障礙等發展緩慢的疾病。相關生化指標以及頸動脈合并下肢動脈檢測對以上疾病的預測起到積極作用。然而，目前的手段并不能實現對患者個體的系統性治療。這涉及以下幾個問題：在分子水平，T2DM合并AS患者的進程如何衍變，為何患者之間相關并發癥的發生風險會有高低，調控各組織器官功能的信號因子作用在AS過程中如何調控的，為何療效存在差異？闡明這些問題不僅需要追溯患者的生活習慣進行T2DM常規檢測，還需要從遺傳學的角度，如基因型檢測、遺傳印跡等表觀遺傳變化等方面進行研究，從而根據患者的不同情況進行更為精準的個體化治療。

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〔2015-09-19修回〕

(編輯曹夢園)

〔中圖分類號〕R587

〔文獻標識碼〕A

〔文章編號〕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，主治醫師，主要從事脂肪肝與糖脂代謝研究。