2型糖尿病合并动脉粥样硬化的发病机制、临床诊断与治疗



2型糖尿病合并动脉粥样硬化的发病机制、临床诊断与治疗

石维

(南京医科大学附属无锡市人民医院内分泌科，江苏无锡214023)

〔关键词〕2型糖尿病；动脉粥样硬化；炎症反应；糖代谢；脂代谢

全世界2型糖尿病(T2MD)发生率越来越高，严格的血糖控制能显著改善糖尿病微血管病变，但对大血管病变的影响甚微。糖尿病大血管病变是T2DM患者致残、致死的主要影响因素。动脉粥样硬化(AS)作为糖尿病的并发症随着病情的进展会发生心肌梗死 、脑卒中等疾病〔1,2〕。据报道，T2MD首次心肌梗死的发生率是非T2DM患者的2~4倍〔2〕，脑卒中和外周动脉疾病的发生率亦可升高2~4倍〔3,4〕。但许多患者在AS的初始阶段没有明显症状。因此，探讨T2DM合并AS患者的形成机制及其发生、发展而致各种并发症的产生原因，可进一步地对T2DM合并AS患者进行有效的病情诊断并根据患者的不同情况进行个体化的预防和治疗。

1T2DM合并AS的斑块形成机制

在T2DM患者中AS与摄糖过多、胰岛素抵抗(IR)、糖尿病耐受等有关〔5〕。除了糖代谢异常，引起AS的主要因素还包括脂质代谢紊乱和内皮细胞功能受损。T2DM合并AS形成早期，空腹甘油三酯(TG)、载脂蛋白(Apo)B、 ApoB/ApoA1 比例显著升高，而ApoA1、高密度脂蛋白胆固醇(HDL-C)和总胆固醇(TC)/HDL比例没有差异性；这些患者用胰岛素治疗无助于ApoB水平的降低〔6〕。Apo的异常伴随着脂质紊乱，ApoB携带的脂蛋白升高，而ApoA携带的脂蛋白降低，这使T2DM患者血液中的TG水平较高，而HDL-C水平则较低，从而产生慢性炎症，氧化压力加大，启动AS形成〔7,8〕，尽管此时低密度脂蛋白胆固醇(LDL-C)水平可在正常范围内，但LDL-C会转变成小的，致密动脉粥样LDL-C颗粒〔7〕，且LDL-C的糖化程度增加，糖化的LDL-C会快速被巨噬细胞摄入〔9〕，通过巨噬细胞内化使LDL-C氧化〔10〕。胰岛素增多症是已知的AS高危因素，胰岛素增多症可能也是通过巨噬泡细胞的作用促进AS形成〔11〕。活化的巨噬细胞释放相关趋化因子、细胞因子，激发一系列炎症反应。

随着动脉壁中脂质的累积，血管内皮细胞功能出现异常，而高血糖症则抑制内皮一氧化氮(NO)的生产〔12〕，或促进其降解〔13〕，引起内皮细胞功能缺损。内皮细胞功能异常引起血管紧张度升高、促凝血和促炎症因子升高，激活免疫细胞，引起血细胞渗进动脉内膜，并形成AS斑块，AS斑块的形成，使血栓形成的风险增加〔14〕。前述多种原因使细胞和细胞外基质聚积，刺激内膜增厚。随后发生脂质沉积，薄的纤维帽覆盖在大的粥样斑块脂质核心上，这构成了AS软斑，而在后期进展为钙化斑块。个体间的异质性也使AS的发生具有差异性，而这种差异可能在患者出生时就产生。胚胎发育过程中，印迹基因，如印记母源表达转录、胰岛素样生长因子(IGF)2发生表观遗传紊乱，可致个体不可避免地发生T2DM〔15〕。这就大大增加了AS的发生。这将促使未来研究者和医务工作者对T2DM易感人群的异质性进行遗传学水平的研究，从基因水平、生活方式等各方面综合分析，找到不同患者AS发生的不同成因，从而进行更为精准的诊断，合理的治疗。

2T2DM合并AS患者相关的诊断指标

传统的T2DM诊断需要进行空腹血糖(FPG)、口服糖耐量实验(OGTT)、糖化血红蛋白(HbA1c)、IR等检测。除了常规检测，对糖代谢、脂质代谢、炎症因子相关参数的联合检测有助于更为客观地对患者的病情进行诊断。HbA1c升高和外周血管病变(PAD)的风险相关，若其水平很高，提示有PAD、心血管致死高发风险。HbA1c可测定睡眠呼吸异常程度，特别对于有严重睡眠呼吸异常的老年人、肥胖人〔16~18〕。若男性年轻人T2DM中HDL-C浓度下降，血管硬化程度升高，HDL-C可辅助评估心血管病发生风险〔19〕。AS进程加剧时，CRP升高，此时提示心血管病发生风险，死亡风险。CRP>3 mg/L时心血管疾病有高发风险，对T2DM进行监测运动可降低CRP水平〔20,21〕。在无症状T2DM患者中，和肽素可以作为心血管疾病的检测标记物，但AS疾病程度与和肽素的相关性需要进一步证实〔22〕。而血清Vaspin浓度和颈动脉斑呈显著负相关性〔23,24〕。在T2DM中sclerostin和颈动脉内膜中层厚度(CIMT)显著负相关，clerostin可能有预防T2DM患者中血管并发症进程的作用，其机制可能是抑制β-catenin活性，从而防止血管细胞衰减〔25〕。脑卒中，心肌缺血及冠心病在T2DM中更高发，此时平均钠尿肽水平升高〔26〕。中央动脉波形(AVI)反映第1 次和第2 次中央动脉波形差，以脉冲压力的百分比表示，是全身性动脉硬化的检测指标〔27,28〕。CIMT，可诊断早期AS，CIMT和周围血管病(PVD)的发生相关性强较，特别对于妇女，可有效预测心脏疾病和脑卒中的发生风险〔29,30〕。斑块内出血(PH)的发生和男性显著相关，和女性无相关性，PH和斑块的不稳定性相关，可用于辅助诊断男性心脑管血疾病发生〔31〕。

CIMT检测已被认为是AS发生的预示指标，但一些研究者并不认同此观点。颈动脉和下肢动脉是AS损害的常发区域〔32〕。Sosnowski等〔33〕发现下肢AS斑较颈动脉斑更能反映冠状动脉AS的严重程度。颈动脉斑可能反映T2DM总的斑块情况，联合两者可提高T2DM合并AS损害的检出率。

上述检测项目是基于理化角度，但AS发生的起始在分子水平就发生了更早的变化。目前，对于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并发症的发生风险相关，Hp2-2和微血管〔34〕、巨血管〔35〕并发症相关，这类基因型患者心肌疾病的发生率〔35〕及心肌梗死风险更高〔36〕；与携带者相比，Hp 1-1纯合子T2DM患者到了老年，认知功能降低，心血管发生风险也升高〔37〕。因此，进一步需要研究的是基因型是否决定了AS的发生，还是AS推动了这类基因型患者的病程发展？基因水平的进步将直接引起对T2DM患者的治疗策略的调整。

3T2DM合并AS患者的治疗

针对T2DM合并AS的药物治疗能有效改善机体功能、延缓器质性病变。Thiazolidinediones在发挥抗炎反应的同时，还能改善胰岛素敏感性、延迟AS的形成和发展、降低PAD风险〔38，39〕。Metformin能降低Fibulin-1水平，改善内皮功能紊乱、细胞外基质修饰和积聚、钙化等生理病理反应；同时显著降低血清HbA1C水平，增强血管内皮细胞的功能〔40〕。Pioglitazone显著降低空腹胰岛素、HbA1C 和HOMA-IR，增强血管内皮功能，延迟AS进程，降低心血管疾病发生率〔41，42〕。Flavonoids和flavan-3-ols提高内皮细胞功能、逆转AS进程或斑块形成，降低心血管病发病风险，增加治疗存活率，同时可预防绝经妇女患CVD风险〔43，44〕。Dipeptidyl peptidase-4 (DPP-4)抑制剂saxagliptin和alogliptin防止肠血糖素激素和糖依赖性促胰岛肽的降解，提高摄糖控制效果；可增加NO的生物利用度，促进内皮细胞功能，降低炎症，即有效改善颈动脉AS〔38，45〕。Glucagon-like peptide-(GLP-1)受体激动剂exenatide、liraglutide和albiglutide，较内源性GLP-1有更长的半衰期，且对GLP-1受体的作用提升了1~5倍，可降低HbA1c、减轻体重，对于胰岛β细胞功能和脉管系统均有效应〔46〕。Dual PPAR-α/γ激动剂aleglitazar，对于脂质(PPAR-α效应)、胰岛素敏感性和糖摄取(PPAR-γ)有潜在的有利效应。临床二期表明，aleglitazar能显著降低HbA1c，并伴随TGs和LDL-C降低、HDL-C增高〔47,48〕。SGLT2 (Sodium-glucose cotransporter-2)抑制剂Sergliflozin和Dapagliflozin，通过抑制肾钠-糖协同转运蛋白而降低血糖浓度，可使体重下降，血压下降。但SGLT2抑制剂对于心血管病的效应目前未研究清楚〔49,50〕。Statin对脂质异常进行控制，可使LDL-C水平降低20%左右，而减少心血管发病率〔51〕。Dalcetrapib降低CETP (Cholesteryl ester transfer protein)活性，提高HDL-C水平，改善脂质紊乱，但需要临床三期实验进一步验证〔52〕。

不同患者用药效果具有差异性，随着T2MD合并AS形成的分子机制进一步阐明，药物的靶向治疗能够实现对不同患者进行个体化用药。分子机制对于药物与基因相互作用的研究，更有助于针对性地筛选治疗T2MD的药物，如metformin作用于SLC22A1、SLC22A2、SLC47A1、PRKAB2、PRKAA2、PRKAA1和STK11位点；此外，pioglitazone作用于PPARG2和PTPRD位点〔53〕。未来随着人类个体基因组测序、基因表达谱检测的普及、结合生物信息学技术，就有可能根据T2MD患者的缺陷基因进行有针对性的个体治疗。

对T2DM患者饮食、生活方式等方面进行指导有助于改善T2DM患者的AS相关症状。Horvath等〔54〕发现，T2DM患者单独摄入糖于粒细胞和单核细胞激活没有任何影响，而单独摄入脂或联合摄入糖和脂，在60~90 min内外周血CD11b、CD66细胞显著升高，因此脂质对于相关免疫细胞的激活可能有更强地、快速地促进作用，降低脂质摄入有助于更有效地预防T2DM合并AS发生，阻抑AS的发展进程。但对脂质单因素的控制不能全面改善患者的身体状况，需要采取一系列的措施才能使患者病情稳定。美国心脏协会推荐对伴有PAD的T2DM患者的AS的发生原因进行严格控制，以预防心血管疾病的发生。合理锻炼和戒烟已被证明是预防PAD发生的有效生活方式，对于未发生PAD的T2DM患者，根据胰岛素敏感性进行摄糖控制，能够有效降低PAD的发生率〔55〕。另根据心血管风险治疗指南〔56〕，对发生过脑卒中或心肌梗死伴颈动脉狭窄的T2DM患者每年进行4次体检，依据体检结果进行生活方式调整，将相关指标控制在一定范围内，如LDL-C<2.5 mmol/L、血压<140/90 mmHg、HbA1c<7%，同时测定CIMT观察血管壁厚度是否降低〔57〕，这些防预措施对于预防高体质指数(BMI)的T2DM患者的心血管疾病的发生十分重要。

4总结与展望

T2DM患者的血糖、脂质、炎症细胞等对全身或局部血管的理化、生物等作用，可使血管系统的功能损伤加重。随着AS的进一步发展，患者往往存在心脑血管系统隐患，继而发生严重的心肌梗死、脑卒中等急性疾病以及认知障碍等发展缓慢的疾病。相关生化指标以及颈动脉合并下肢动脉检测对以上疾病的预测起到积极作用。然而，目前的手段并不能实现对患者个体的系统性治疗。这涉及以下几个问题：在分子水平，T2DM合并AS患者的进程如何衍变，为何患者之间相关并发症的发生风险会有高低，调控各组织器官功能的信号因子作用在AS过程中如何调控的，为何疗效存在差异？阐明这些问题不仅需要追溯患者的生活习惯进行T2DM常规检测，还需要从遗传学的角度，如基因型检测、遗传印迹等表观遗传变化等方面进行研究，从而根据患者的不同情况进行更为精准的个体化治疗。

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〔2015-09-19修回〕

(编辑曹梦园)

〔中图分类号〕R587

〔文献标识码〕A

〔文章编号〕1005-9202(2016)07-1777-05；

doi：10.3969/j.issn.1005-9202.2016.07.108

第一作者：石维(1977-)，男，在读硕士，主治医师，主要从事脂肪肝与糖脂代谢研究。