2型糖尿病患者血管内皮细胞功能异常及其机理研究

糖尿病(DM)大血管病变一直是T2DM患者早死及致残的首要原因，多种因素参与了这一病理过程，其中血管内皮细胞(EC)功能异常在其中扮演了至关重要的角色。血管内皮是一个复杂的内分泌器官，它对于动脉粥样硬化(AS)的发生起到”第一道防线”的生理防御作用。近年来大量研究结果表明，血管EC功能异常在DM前期就已经存在，     

甲状腺疾病与糖尿病

甲状腺疾病常合并糖尿病（DM），其临床表现呈多样化，甲状腺疾病可使DM恶化，也可使DM好转，在甲状腺功能亢进（甲亢）治疗过程中还可出现低血糖昏迷，甚至死亡，甲亢者葡萄糖耐量异常的发病机制可能涉及肠道葡萄糖吸收，胰岛素抵抗，胰岛B细胞分泌等方面，甲状腺疾病与DM有着内在联系，两者在自身免疫及分子生物学方面的联系有待进一步研究。     

南昌地区2型糖尿病家系患者及一级亲胰岛素抵抗与体重指数等多因素相关性研究

2型糖尿病（T2DM）的发生有明显家族聚集倾向。国外报道T2DM患者的后代约30％～40％将患T2DM。大多数T2DM患者在其病程中存在胰岛素抵抗（IR）和胰岛细胞功能异常与不足两方面的问题，但哪一项是首要发病机制则尚有争议，他们是遗传缺陷和环境因素共同作用的结果。本组在对T2DM的家系调查中研究了部分DM患者及其一级亲：包括正常糖耐量（NGT），糖耐量异常（IGT）／空腹血糖受损（IFG），及新发现DM者，胰岛素抵抗（IR）及其与年龄、血压（BP）、体重指数（BMI）、腰臀比（WHR）、血脂、血糖（BG）、胰岛素（INS）等参数的关系，以探讨其临床意义。     

2型糖尿病合并甲状腺功能异常的临床分析

目的 探讨T2DM合并甲状腺疾病的患病情况及临床特点. 方法 回顾性分析420例住院T2DM患者甲状腺功能相关指标及临床资料. 结果 （1）T2DM患者甲状腺疾病患病率16.67％;甲状腺功能异常患病率15.71％.甲状腺功能异常患病率甲亢组3.57％,甲减组8.10％,低T3综合征组4.05％.甲减组中,亚临床甲减甲状腺功能异常患病率（4.52％）最高,女性甲状腺疾病及甲状腺功能异常的患病率均高于男性（P＜0.05）.（2）与T2DM组相比,T2DM合并甲状腺疾病组病程及胰岛素泵治疗时间增加,C-P120min水平降低;两组UAlb 30～299 mg/24 h差异有统计学意义（P＜0.01）.（3）甲亢组DPN患病率最高,低T3组年龄最大,且合并冠心病史发生率最高（P＜0.05）. 结论 T2DM合并甲状腺疾病患病率较高,甲状腺功能异常表现形式多样,对T2DM患者进行早期甲状腺功能的筛查具有临床意义.     

糖尿病血管内皮细胞代谢改变的研究进展

血管内皮细胞功能障碍是糖尿病（DM）血管并发症的始动环节。高血糖所致的氧化应激水平升高、异常糖代谢途径激活、晚期糖基化终产物（AGEs）累积和蛋白激酶C（PKC）通路活化等代谢改变均可介导内皮细胞损伤。如何抑制内皮细胞异常代谢并改善内皮细胞功能一直是DM血管并发症的研究重点。本文主要就DM患者血管内皮细胞的代谢改变作一综述。     

糖代谢异常对原发性高血压患者左心室功能的影响

目的 探讨糖代谢异常（impaired glucose metabolism,IGM）对原发性高血压（essential hypertension,EH）患者左心室收缩和舒张功能的影响。方法选取46例单纯EH（单纯EH组）及36例合并2型糖尿病（T2DM）的EH患者（合并T2DM组）,检测其血糖、血脂、血尿酸、纤维蛋白原等代谢参数,同时行心脏超声多普勒获取左心室收缩及舒张功能参数。对比2组患者的各项代谢参数及左心室收缩与舒张功能参数的差异,并对左心室功能异常的EH患者与无左心室功能异常的EH患者糖代谢状态进行分析。结果合并T2DM组患者体质量指数、空腹血糖、餐后2h血糖（PBG）、糖化血红蛋白（HbAlc）、三酰甘油、总胆固醇、低密度脂蛋白胆固醇、载脂蛋白B、尿酸及纤维蛋白原等水平均显著高于单纯EH组（P〈0．05或P〈O．01）。心脏超声多普勒检查结果显示,所有EH患者均未出现左心室收缩功能不全（左心室射血分数〈40％）,而合并T2DM组左心室舒张功能障碍发生率显著高于单纯EH组（P〈O．05）。进一步分析发现,左心室舒张功能障碍EH患者合并T2DM的发病率显著高于无左心室舒张功能障碍的EH患者,且出现左心室舒张功能障碍的EH患者空腹血糖及HbAlc水平均显著高于无左心室舒张功能障碍的EH患者（P均〈0．01）,但2者之间PBG的差异则无统计学意义（P〉0．05）。结论糖代谢异常可加重EH患者左心室功能不全,尤其是早期心脏舒张功能障碍;改善EH患者的糖代谢状态,可能有助于延缓其左心功能异常的出现。     

老年糖尿病患者胰岛素抵抗对内皮细胞功能的影响

目的 探讨老年2型糖尿病（T2DM）患者胰岛素抵抗（IR）对内皮细胞（EC）功能损伤的影响。方法 选择43例对照组（N组）、33例老年T2DM正常体重组（A1组）、43例老年T2DM超重组（A2组）、27例老年T2DM肥胖组（A3组）患者。测定空腹血糖（FBG），餐后2h血糖（PBG）、空腹胰岛素（FINS）、餐后2h胰岛素（PINS）、血浆一氧化氮（NO）等参数，测量身高、体重，计算体重指数（BMI）、应用稳态模式IR指数（HOMA-IR）作为IR指标，并对各组的这些指标进行对比分析。结果 与N组比较，DM各组的FBG、PBG、FINS均明显增高（P〈0．01），A1组A2组A3组，HOMA-IR逐渐增高，NO逐渐下降，经直线相关分析，A1组无相关性；A2组呈负相关（r=-0．4567，P〈0．05）；A3组呈显著负相关（r=0．5647，P〈0．01）。结论 老年DM患者存在着血管内皮功能的损害，高血糖及IR均为重要原因之一，但损伤机制可能完全不相同。     

高糖对血管内皮细胞蛋白激酶Cα和δ表达及功能的影响

以高糖培养的人脐静脉内皮细胞（HUVECs）研究显示,高糖可诱导血管内皮细胞（EC）功能紊乱,凋亡增加,NO浓度降低,可溶性细胞间黏附分子1水平增加;高糖可诱导HUVECs的蛋白激酶C（PKC）α及PKCδ表达位置转移,PKCδ表达增强,但对PKCα表达影响不明显。高糖所致EC功能异常,可能部分是通过PKCα及PKCδ途径来实现的。     

原发性高血压合并2型糖尿病患者的心律失常

背景 原发性高血压（EH）和2型糖尿病（T2DM）常易并发。已有研究证实了EH可致心律失常，但对于二者合并存在时心律失常发生状况及心脏结构和功能的变化特征，还未见报道。目的 研究EH合并T2DM患者心律失常的发生状况及其可能机制。方法住院患者168例，分为EH组、T2DM组、EH合并T2DM组及正常组，对4组患者的相关临床资料、24h动态心电图及超声心动图检查结果进行分析比较。结果1）EH合并T2DM组与EH组和T2DM组相比易发生心律失常（P〈0．05）。2）EH合并T2DM组左心房内径（LAD）、升主动脉内径（AO）、左心室内径（LVD）、室间隔厚度（IVS）、左心室质量（LVM）值、E／A比值异常例数和二尖瓣返流程度（MR）均高于EH组和DM组（P均〈0．05），EF值低于EH组和DM组（P〈0．05）。3）多元线性回归分析显示EH合并T2DM时，房性心律失常次数与LAD、IVS、MR正相关，与LVD负相关；室性心律失常次数与LVD、IVS、LVM正相关。4）Logistic回归分析显示年龄、疾病种类、高血压病程和LVM的升高是患者发生心律失常的风险因素。结论 EH合并T2DM时更易发生心律失常，且能明显加重患者左心室结构和功能损害。     

糖尿病对老年高血压患者心脏结构和功能的影响

目的探讨糖尿病对老年高血压患者心脏结构和功能的影响。方法将351例60岁以上的住院患者分为3组，即单纯高血压（EH）组149例，高血压合并2型糖尿病（T2DM）组129例和对照组73例，依据超声心动图结果评价心脏的结构和功能。结果与单纯EH组比较，EH＋T2DM组的舒张末期左心室内径（LVD）、左室质量（LVM）、左室质量指数（LVW1）、收缩末期左心房内径（LA）、收缩末期升主动脉内径（AO）、射血分数（EF）、平均左室短轴缩短率（FS）、舒张晚期二尖瓣最大血流速度（A值）、左心室舒张早期二尖瓣最大血流速度（E值）／A值明显升高，EH＋T2DM组E／A小于0．8或大于1．6的例数大于EH组和对照组（P=0．03）；EH＋T2DM组的房颤发生率大于对照组（P=0．012）。结论糖尿病对老年高血斥患者心脏结构、收缩和舒张功能均有一定的影响，高血糖可加重老年高血压患者心脏结构和功能的异常。     

Nitric oxide-mediated coronary flow regulation in patients with coronary artery disease: recent advances

Nitric oxide (NO) formed via endothelial NO synthase (eNOS) plays crucial roles in the regulation of coronary blood flow through vasodilatation and decreased vascular resistance, and in inhibition of platelet aggregation and adhesion, leading to the prevention of coronary circulatory failure, thrombosis, and atherosclerosis. Endothelial function is impaired by several pathogenic factors including smoking, chronic alcohol intake, hypercholesterolemia, obesity, hyperglycemia, and hypertension. The mechanisms underlying endothelial dysfunction include reduced NO synthase (NOS) expression and activity, decreased NO bioavailability, and increased production of oxygen radicals and endogenous NOS inhibitors. Atrial fibrillation appears to be a risk factor for endothelial dysfunction. Endothelial dysfunction is an important predictor of coronary artery disease (CAD) in humans. Penile erectile dysfunction, associated with impaired bioavailability of NO produced by eNOS and neuronal NOS, is also considered to be highly predictive of ischemic heart disease. There is evidence suggesting an important role of nitrergic innervation in coronary blood flow regulation. Prophylactic and therapeutic measures to eliminate pathogenic factors inducing endothelial and nitrergic nerve dysfunction would be quite important in preventing the genesis and development of CAD.     

内皮细胞功能异常与动脉粥样硬化的研究进展

血管内皮细胞参与构成人体的生理屏障和维持人体内环境稳态,并且为适应内环境的动态变化及满足人体不同组织新陈代谢的需要,不同组织的内皮细胞具有功能差异性和组织特异性。心脏血管内皮细胞参与维持心脏内环境的稳定,当内皮细胞因高脂血症、高血糖、氧化应激、炎症反应及其他代谢因素发生功能障碍,会参与心血管疾病的病理生理过程,例如动脉粥样硬化、心肌缺血再灌注损伤和心室重塑。现综述血管内皮细胞的结构和功能,探讨血管剪切力对于内皮细胞的重要作用,分析内皮细胞功能障碍在动脉粥样硬化病理生理过程中的作用和针对内皮细胞功能障碍的治疗策略和方法。     

Endothelial dysfunction in (pre)diabetes: Characteristics, causative mechanisms and pathogenic role in type 2 diabetes

Endothelial dysfunction associated with diabetes and cardiovascular disease is characterized by changes in vasoregulation, enhanced generation of reactive oxygen intermediates, inflammatory activation, and altered barrier function. These endothelial alterations contribute to excess cardiovascular disease in diabetes, but may also play a role in the pathogenesis of diabetes, especially type 2. The mechanisms underlying endothelial dysfunction in diabetes differ between type 1 (T1D) and type 2 diabetes (T2D): hyperglycemia contributes to endothelial dysfunction in all individuals with diabetes, whereas the causative mechanisms in T2D also include impaired insulin signaling in endothelial cells, dyslipidemia and altered secretion of bioactive substances (adipokines) by adipose tissue. The close association of so-called perivascular adipose tissue with arteries and arterioles facilitates the exposure of vascular endothelium to adipokines, particularly if inflammation activates the adipose tissue. Glucose and adipokines activate specific intracellular signaling pathways in endothelium, which in concert result in endothelial dysfunction in diabetes. Here, we review the characteristics of endothelial dysfunction in diabetes, the causative mechanisms involved and the role of endothelial dysfunction(s) in the pathogenesis of T2D. Finally, we will discuss the therapeutic potential of endothelial dysfunction in T2D.     

Mechanisms of Disease: endothelial dysfunction in insulin resistance and diabetes

Endothelial dysfunction is one manifestation of the many changes induced in the arterial wall by the metabolic abnormalities accompanying diabetes and insulin resistance. In type 1 diabetes, endothelial dysfunction is most consistently found in advanced stages of the disease. In other patients, it is associated with nondiabetic insulin resistance and probably precedes type 2 diabetes. In obesity and insulin resistance, increased secretion of proinflammatory cytokines and decreased secretion of adiponectin from adipose tissue, increased circulating levels of free fatty acids, and postprandial hyperglycemia can all alter gene expression and cell signaling in vascular endothelium, cause vascular insulin resistance, and change the release of endothelium-derived factors. In diabetes, sustained hyperglycemia causes increased intracellular concentrations of glucose metabolites in endothelial cells. These changes cause mitochondrial dysfunction, increased oxidative stress, and activation of protein kinase C. Dysfunctional endothelium displays activation of vascular NADPH oxidase, uncoupling of endothelial nitric oxide synthase, increased expression of endothelin 1, a changed balance between the production of vasodilator and vasoconstrictor prostanoids, and induction of adhesion molecules. This review describes how these and other changes influence endothelium-dependent vasodilation in patients with insulin resistance and diabetes. The clinical utility of endothelial function testing and future therapeutic targets is also discussed.     

The link between metabolic abnormalities and endothelial dysfunction in type 2 diabetes: an update

Despite abundant clinical evidence linking metabolic abnormalities to diabetic vasculopathy, the molecular basis of individual susceptibility to diabetic vascular complications is still largely undetermined. Endothelial dysfunction in diabetes-associated vascular complications is considered an early stage of vasculopathy and has attracted considerable research interests. Type 2 diabetes is characterized by metabolic abnormalities, such as hyperglycemia, excess liberation of free fatty acids (FFA), insulin resistance and hyperinsulinemia. These abnormalities exert pathological impact on endothelial function by attenuating endothelium-mediated vasomotor function, enhancing endothelial apoptosis, stimulating endothelium activation/endothelium–monocyte adhesion, promoting an atherogenic response and suppressing barrier function. There are multiple signaling pathways contributing to the adverse effects of glucotoxicity on endothelial function. Insulin maintains the normal balance for release of several factors with vasoactive properties. Abnormal insulin signaling in the endothelium does not affect the whole-body glucose metabolism, but impairs endothelial response to insulin and accelerates atherosclerosis. Excessive level of FFA is implicated in the pathogenesis of insulin resistance. FFA induces endothelial oxidative stress, apoptosis and inflammatory response, and inhibits insulin signaling. Although hyperglycemia, insulin resistance, hyperinsulinemia and dyslipidemia independently contribute to endothelial dysfunction via various distinct mechanisms, the mutual interactions may synergistically accelerate their adverse effects. Oxidative stress and inflammation are predicted to be among the first alterations which may trigger other downstream mediators in diabetes associated with endothelial dysfunction. These mechanisms may provide insights into potential therapeutic targets that can delay or reverse diabetic vasculopathy.     

Endothelial dysfunction: causes and consequences in patients with diabetes mellitus

Vascular endothelium plays a major role in maintaining cardiovascular homeostasis. Nitric oxide is the most powerful vasodilating compound. Diabetes disrupts endothelial integrity through an increased oxidative stress. Recent evidence indicates that there is a strong interaction between diabetes, the secretory proteins of adipocytes, called adipokines, and endothelium. Endothelial dysfunction may precede the development of overt DM, and a prolonged and repeated exposure to postprandial hyperglycemia may play an important role in the development of atherosclerosis, even in those who have normal fasting plasma glucose levels.     

Vascular endothelial dysfunction and pharmacological treatment

The endothelium exerts multiple actions involving regulation of vascular permeability and tone, coagulation and fibrinolysis, inflammatory and immunological reactions and cell growth. Alterations of one or more such actions may cause vascular endothelial dysfunction. Different risk factors such as hypercholesterolemia, homocystinemia, hyperglycemia, hypertension, smoking, inflammation, and aging contribute to the development of endothelial dysfunction. Mechanisms underlying endothelial dysfunction are multiple, including impaired endothelium-derived vasodilators, enhanced endothelium-derived vasoconstrictors, over production of reactive oxygen species and reactive nitrogen species, activation of inflammatory and immune reactions, and imbalance of coagulation and fibrinolysis. Endothelial dysfunction occurs in many cardiovascular diseases, which involves different mechanisms, depending on specific risk factors affecting the disease. Among these mechanisms, a reduction in nitric oxide (NO) bioavailability plays a central role in the development of endothelial dysfunction because NO exerts diverse physiological actions, including vasodilation, anti-inflammation, antiplatelet, antiproliferation and antimigration. Experimental and clinical studies have demonstrated that a variety of currently used or investigational drugs, such as angiotensin-converting enzyme inhibitors, angiotensin AT1 receptors blockers, angiotensin-(1-7), antioxidants, beta-blockers, calcium channel blockers, endothelial NO synthase enhancers, phosphodiesterase 5 inhibitors, sphingosine-1-phosphate and statins, exert endothelial protective effects. Due to the difference in mechanisms of action, these drugs need to be used according to specific mechanisms underlying endothelial dysfunction of the disease.     

Endothelial dysfunction in impaired fasting glycemia, impaired glucose tolerance, and type 2 diabetes mellitus

The aim of this study was to evaluate whether abnormal endothelial function is present in early stages of diabetes, such as impaired glucose tolerance (IGT) and impaired fasting glucose (IFG). Endothelial function was assessed by measuring flow-mediated dilatation and nitrate-induced dilatation of the brachial artery using high-resolution ultrasound. Fasting serum lipid levels were determined, and glucose and insulin values in response to a 75-g oral glucose load were also measured. The results showed the following new findings: (1) compared with subjects with normal glucose tolerance, those with IFG and IGT had impaired flow-mediated dilatation, more remarkable in subjects with type 2 diabetes mellitus than those with IFG and IGT, and (2) flow-mediated dilatation was inversely and strongly related to the extent of hyperglycemia. In conclusion, endothelial dysfunction is present in subjects with IGT and IFG, indicating endothelial damage in these stages.     

A new ATP-sensitive potassium channel opener protects endothelial function in cultured aortic endothelial cells

OBJECTIVE: Endothelial dysfunction is an early risk factor for cardiovascular disease and hypertension. Mechanisms that participate in endothelial dysfunction include reduced nitric oxide (NO) generation and increased endothelin-1 (ET-1) generation. Endothelial ATP-sensitive potassium (K(ATP)) channels are responsible for maintaining the resting potential of endothelial cells and modulating the release of vasoactive compounds. We hypothesized that activation of endothelial K(ATP) channels might result in the protection against endothelial dysfunction. METHODS: Using cultured bovine or rat aortic endothelial cells, we examined the effects of a new K(ATP) channels opener, iptakalim, on the secretion of vasoactive substances. We also investigated its effects on the expression of adhesion molecules in metabolically disturbed cultured endothelial cells. RESULTS: In cultured aortic endothelial cells, iptakalim caused a concentration-dependent inhibition of ET-1 release and synthesis that correlated with reduced levels of mRNA for ET-1 and endothelin-converting enzyme. These effects of iptakalim were significantly inhibited by pretreatment with glibenclamide (a K(ATP) channel blocker) for 1 h. Similarly, iptakalim enhanced the release of NO in a concentration-dependent manner and increased basal levels of free intracellular calcium. Iptakalim at the concentrations of 100 and 1000 microM increased the activities of NO synthase (NOS) significantly. After the activity of NOS was blocked by L-N(omega)-nitro-arginine methyl ester (L-NAME), the inhibition of iptakalim on ET-1 release was abolished. In endothelial cell models of metabolic disturbance induced by low-density lipoprotein, homocysteine, or hyperglycemia, treatment with iptakalim could inhibit the overexpression of monocyte chemoattractant protein-1 (MCP-1), Intercellular adhesive molecule-1 (ICAM-1), and vascular cell adhesive molecule-1 (VCAM-1) mRNA. CONCLUSION: Iptakalim is a promising drug that could protect against endothelial dysfunction through activating K(ATP) channels in endothelial cells.     

Clinical aspects of endothelial dysfunction associated with human immunodeficiency virus infection and antiretroviral agents

Endothelial dysfunction is a critical initial step of atherogenesis that subsequently contributes to the progression and clinical manifestations of atherosclerosis. The use of human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) agents has been associated with increased cardiovascular events and worsening of multiple coronary heart disease risk factors including dys-lipidemia, insulin resistance, and endothelial dysfunction. Endothelial dysfunction may be caused by HIV infection itself as well as treatment-related effects of the antiretroviral agents used to treat HIV. The available evidence suggests that PIs may induce endothelial dysfunction via their effects on both lipid and glucose metabolism. Studies in healthy subjects confirm a role for reduced endothelial nitric oxide production in the endothelial dysfunction associated with the PI indinavir. Further work is needed to determine the relative tendencies of other antiretroviral agents to induce endothelial dysfunction, the physiologic mechanisms involved, and the contribution of the metabolic and body shape changes associated with HIV treatment-related lipodystrophy, and to establish effective interventions for endothelial dysfunction in HIV-infected patients.