线粒体解偶联蛋白2基因启动子-866G﹥A突变与二型糖尿病脑卒中遗传易感相关性的研究
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摘要
脑卒中(stroke),又称中风或脑血管意外,是一组突然起病,以局灶性神经功能缺失为共同特征的急性脑血管疾病。缺血性脑卒中约占所有卒中的70%,因其高发病率、高致残率、高死亡率,且短期内复发率高,严重危害病人的生活质量。脑卒中引起的神经功能严重损伤使患者死亡率明显增加,而存活者也会产生严重的神经功能障碍。高血糖是缺血性脑病发病的独立危险因素,同时也是导致局部或广泛缺血区预后更差的危险因素。其原因有：急性血糖漂移,发作性低血糖及低血糖后的反应性高血糖加重脑细胞损伤；胰岛素生物活性作用下降,使脑细胞利用葡萄糖能力下降,即使有较高的颅内循环血糖水平,脑细胞亦不能获得足够的能量。同时,缺血区域由于无氧代谢引起缺血区域酸中毒,梗死灶扩大；缺血本身应激反应,神经内分泌系统激活,下丘脑-垂体-肾上腺素代谢产物(皮质醇、儿茶酚胺、胰高血糖素)急剧上升,加重胰岛素抵抗。糖尿病患者并发缺血性脑卒中的原因主要有易感基因、高凝状态、高血糖、脂质代谢紊乱、激素调节失常等,寻找脑卒中发生发展的相关基因,对脑卒中的发生进行有效的预测,从而减轻患者神经功能的损伤,是近年来脑血管疾病临床研究的热点。
1997年线粒体解偶联蛋白2(uncoupling protein-2, UCP-2)基因首次被克隆定位于人类染色体11q13,该区域与高胰岛素血症和肥胖相连锁,其生理作用是消除线粒体膜电位,使物质氧化与磷酸化解偶联,从而抑制二磷酸腺苷(Adenosine diphosphate, ADP)合成。大量的动物实验和临床研究发现,UCP-2基因在体内广泛分布并且在体内体外均具有保护组织器官抗氧化和减少活性氧产生的作用。UCP-2是p细胞胰岛素分泌的一个重要的负向调节因子,作用机制可能是UCP-2通过氧化磷酸化解偶联,致ATP合成减少,ATP/ADP比值降低,使ATP敏感性K+通道(K+-ATP通道)去极化而开放,进而通过Na+-K+交换,β细胞外Na+增加、K+减少,胞内Na+减少、K+增加,使电压门控性钙通道开放,Ca2+内流,β细胞中含胰岛素的分泌颗粒与膜融合,通过胞吐作用将胰岛素释放,UCP-2表达增多可使胰岛素分泌减少。因此,UCP-2基因可能是偶联肥胖、胰岛p细胞功能障碍和二型糖尿病的关键基因。近年许多研究结果表明：UCP-2在脑卒中的发展过程中具有神经保护作用。脑卒中发生时,UCP-2通过降低线粒体膜电位、调节钙超载、降低ROS产量等作用,从而减少神经细胞的死亡。同时,随着对UCP-2研究的深入,不断有报道证实UCP-2基因启动子区-866G>A突变是一个功能性突变位点,与糖尿病、胰岛素抵抗、冠脉综合征、血脂异常等有关,但该突变位点与脑卒中的发生、发展及预后是否相关,该相关性是否独立于脑卒中其他易感因素,目前尚不清楚。
本文第一章中,我们选择了404例二型糖尿病伴有脑卒中的患者及440例单纯二型糖尿病患者,通过TaqMan MGB (minor grove binder)中通量探针基因检测技术确定基因型并且对所有病例进行4年随访,观察脑卒中的新发、复发及死亡率,结果发现无论是在基线状态下还是在随访中,携带A等位基因的女性患者较之GG野生型女性患者脑卒中的发生风险加大,且该相关性独立于脑卒中的其他风险因素,但在男性受试者中并不存在差异。
本文第二、第三章在前期的研究结果上继续观察脑卒中患者的复发、预后与UCP-2基因启动子区-866G>A基因型的相关性,并且探讨该相关性的可能发生机制,用多元logistic回归模型等方法计算各不同基因型与脑卒中预后的交互作用。结果表明携带A等位基因的男性患者较之携带GG野生型的患者,增加脑卒中复发及死亡的风险。但是A等位基因并不是卒中复发的独立危险因素。同时,我们发现携带A等位基因的患者对氯吡格雷的反应性较之GG野生型的患者降低,具体的机制仍待进一步探讨。
综上所述,本研究首先发现UCP-2基因启动子区-866G>A突变与国人女性患者二型糖尿病脑卒中的发生具有遗传易感相关性,并且此相关性独立于脑卒中的其他风险因素。随后,实验发现四年随访过程中,UCP-2基因该位点突变并不是国人二型糖尿病脑卒中复发的独立危险因素。但是,携带A等位基因的患者对氯吡格雷的反应性较之GG野生型的患者显著降低。本研究表明UCP-2基因启动子区-866G>A突变与国人二型糖尿病脑卒中的发生发展相关,对于脑卒中的发病前预测等具有潜在的临床价值。
第一部分UCP-2基因-866G>A变异与二型糖尿病脑卒中发生的遗传易感相关性研究
目的：探讨UCP-2基因启动子-866G>A突变与二型糖尿病合并脑卒中发生风险的相关性。
方法：对844例二型糖尿病患者(伴有脑卒中组404例,不伴脑卒中组440例)进行为期4年的前瞻性队列研究,提取所有受试者的基因组全血DNA,用TaqMan MGB探针对UCP-2基因启动子-866G>A进行基因分型,分析不同基因型与二型糖尿病合并脑卒中发生风险的关联性。
结果：无论在受试者入组时还是在4年随访过程中,携带A等位基因的二型糖尿病女性患者脑卒中发生风险显著高于GG (P<0.05)野生型,但男性患者三种基因型之间未见统计学差异。
结论：UCP-2基因启动子-866G>A变异增加国人女性二型糖尿病并发脑卒中的风险。
第二部分UCP-2基因-866G>A变异与二型糖尿病脑卒中的预后遗传易感相关性的研究
目的：探讨UCP-2基因启动子-866G>A突变与二型糖尿病脑卒中复发风险的相关性。
方法：入组二型糖尿病初发脑卒中未进行溶栓治疗的患者进行为期4年的前瞻性研究,观察终点事件为脑卒中复发、短暂性缺血发作、死亡。提取所有受试者的基因组全血DNA,用TaqMan MGB探针对UCP-2基因启动子-866G>A进行基因分型,分析不同基因型与二型糖尿病合并脑卒中复发风险的关联性。
结果：发生与未发生终点事件的患者各基因型分布并无明显差异。携带A等位基因男性受试者与GG野生型相比会增加脑卒中复发风险(P<0.05),但并不是脑卒中复发的独立危险因素,年龄、肥胖等风险因素与脑卒中的生存率也相关。
结论：携带A等位基因的二型糖尿病患者(XA突变型)与GG(P<0.05)野生型相比,男性患者有增加脑卒中复发的风险,但不是其独立危险因素。女性患者并不存在相关性。二型糖尿病和脑卒中的预后均受遗传和环境等多种因素影响,单一一个基因的多态性也许未能改变其预后。
第三部分UCP-2基因-866G>A变异与二型糖尿病脑卒中遗传易感相关性的机制探讨
目的：探讨UCP-2基因启动子-866G>A突变与二型糖尿病合并脑卒中遗传易感相关性的可能机制。
方法：对第二部分入组的二型糖尿病合并脑卒中患者服用氯吡格雷进行脑卒中复发预防,使用血小板功能分析系统(PFA-100)测定血小板聚集率,同时提取所有受试者的基因组全血DNA,对UCP-2基因启动子-866G>A进行基因分型,分析不同基因型与氯吡格雷低反应性发生的关联。
结果：UCP-2基因启动子-866G>A突变携带A等位基因的患者对于氯吡格雷的反应性下降,无论用ADP还是肾上腺素作为诱导剂测定血小板聚集率,携带A等位基因的患者发生氯吡格雷抵抗的几率远远大于GG野生型,结果具有统计学差异。
结论：携带A等位基因的二型糖尿病患者(GA/AA)与GG野生型相比,A等位基因与患者对氯吡格雷低反应性产生存在明显相关,我们推测A等位基因可能与氯吡格雷抵抗的产生有关从而对二型糖尿病脑卒中的复发及预后产生影响。
综上所述,本研究工作的主要创新之处在于：
1.A等位基因与卒中的发生具有遗传易感相关性本课题首次对UCP-2基因启动子-866G>A突变与二型糖尿病脑卒中患者卒中的发生、发展、预后的遗传易感相关性进行探讨,通过4年前瞻性随访研究,发现A等位基因能增加国人女性二型糖尿病脑卒中的风险；
2.A等位基因可能通过增加氯吡格雷抵抗的产生影响二型糖尿病脑卒中的复发及预后在上述基础上,本课题首次发现UCP-2基因启动子-866G>A突变与氯吡格雷的低反应性存在明显相关,A等位基因可能与氯吡格雷抵抗的产生有关从而对二型糖尿病脑卒中的复发及预后产生影响。
Stroke, also called cerebrovascular accident, constitutes a significant human health hazard because of its high incidence, morbidity and mortality. In the past ten years, clinical trials aiming to figure out suitable neuroprotectants against the debilitating effects of stroke have met with no success. Identifying novel neuroprotectants which can reverse the effects against stroke is becoming a challenge to both clinicians and scientists. Ischemic stroke is the most common stroke category which accounted to70%of stroke. The lingering effects of ischemic stroke are very serious, resulting in patient death, and most of survivors suffer nerve function disorder. The consequence of stroke is often enhanced by risk factors such as diabetes, which increases the incidence of stroke in the ischemic stroke by4to12folds particularly. Acute hyperglycemia and diabetes could aggravate brain damage, because the transient focal or forebrain ischemia by both glutamate excitotoxicity and increased reactive oxygen species (ROS) generation. Additionally, the excessive glucose supply is suggested to upregulate the glucose transporters levels and△Ψm, which might be detrimental to the brain cells. The results of these above risk factors are the extension of core region or conversion of penumbra into the core in a short time. The reasons that diabetic patients may associate with ischemic stroke including susceptibility genes, hypercoagulable state, high blood sugar, lipid metabolism disorders, hormone regulation disorders.So finding the related genes in ischemic stroke can predict the happening of ischemic stroke and decrease the damage of nerve function to become the focus question of research in ischemic stroke.
Recent reports on the uncoupling protein-2(UCP-2) appears it has nerve protection on ischemic stroke. The functional structure of UCP-2is a homodimer composed of309amino-acid residues. It is present on chromosomes11and7in the human and mouse, respectively. The primary function of UCPs in the mitochondria is translocation of protons, which are pumped out against concentration gradient during the flow of electrons through respiratory chain complexes Ⅰ-Ⅳ. The proton electrochemical gradient, the△Ψm, established by these protons is used to synthesize adenosine triphosphate (ATP) by FOF1-ATPase (complex V). However, the consumption of oxygen during electron transport chain (ETC) may not be completely used to concomitant ATP generation because of proton leak through UCPs, and the resultant energy of the△Ψm is dissipated as heat. The protons may be directly transported by UCPs or indirectly through a process called fatty acid cycling across the IMM. The exact mechanism of proton transport although is not clear, however, both processes suggested may uncouple the oxidation from ATP synthesis. When ischemic stroke happened, uncoupling protein-2can decrease the mitochondrial membrane potential, regulate the calcium overload, decrease the ROS production. By that means, UCP-2protects the nerve cells. Now more and more investigations confirm UCP-2-866G>A SNP is a functional polymorphism. A series of clinical studies showed associations of this polymorphism with several phenotypes related to obesity, diabetes, insulin sensitivity, insulin secretion, and dyslipidemia. But is this SNP related in ischemic stroke and is the genetic predisposition independent from other susceptible factor? These questions now have no answer. Therefore, we focused on investigation of those questions.
In the first chapter, a total of844patients were selected.404cases with cerebral thrombosis (T2DM+IS),440cases without ischemic stroke (T2DM) in4-years follow up, UCP-2gene polymorphism was confirmed by TaqMan MGB probe method, then compared genotype and allele gene frequency. We found IS incidence, recurrence and death rate, the assay suggested that XA(AA+GA) of genotype frequencies polymorphism of UCP-2increase the risk of ischemic stroke in women but not in men.
In the second and third chapter, we based on the results and continued to follow-up the patients with IS recurrence, discussing the relationship between prognosis and UCP-2gene promoter-866G>A gene type and the relevance of possible mechanism with multiple logistic regression model calculate each different genotype. We found that the patients carrying A alleles had no different recurrent rate of IS than carrying GG wild type, but carrying A alleles the patients had lower clopidogrel reactive than GG wild type of patients, the exact mechanism was still being discussed further.
In conclusion, the present study first found that UCP-2gene-866G>A polymorphism can increase the risk of ischemic stroke in Chinese diabetic women. This effect was independent of effects of other risk factors, such as age, arterial hypertension and obesity. Later, we found that during the four years follow-up, UCP-2gene mutations and the stroke of the recurrence were not obviously related, but, carrying A alleles of the patients had lower clopidogrel reactive than GG wild type of patients, the results were significantly different. This research showed that UCP-2gene promoter area-866G>A mutation had relationship with Chinese type two diabetes stroke occurrence and development. This research was good for stroke clinical and forecast.
Part Ⅰ Association between mitochondrial uncoupling protein2gene-866G>A polymorphism and diabetic patients with ischemic stroke
Objective:To investigate the association of uncoupling protein2(UCP-2) gene-866G>A polymorphism on diabetic patients with cerebral thrombosis.
Methods:A total of844patients were selected404cases with cerebral thrombosis(T2DM+IS),440cases without ischemic stroke(T2DM), UCP-2gene polymorphism was confirmed by TaqMan MGB probe method, then compared genotype and allele gene frequency.
Results:The assay suggested that XA (AA+GA) of genotype frequencies polymorphism of UCP-2increase the risk of ischemic stroke in women but not in men.
Conclusion:UCP-2-866G>A polymorphism can increase the risk of ischemic stroke in Chinese diabetic women.
Part Ⅱ Effects of uncoupling protein2-866G/A polymorphism on prognosis in Chinese type2diabetic patients with ischemic stroke
Objective:The purpose of this study was to assess the effects of-866G>A polymorphism of mitochondrial uncoupling protein2(UCP-2) on prognosis in patients with type2diabetic companied by ischemic stroke.
Methods:A total of405Chinese patients with T2DM and stroke were assessed in a4-year follow-up case-control study. The primary end point was a composite of stroke and TIA (transient ischemic attack), the secondary end point was death. The-866G>A polymorphism in UCP-2was genotyped by TaqMan MGB probe method.
Results:The-866G>A SNP in UCP-2was not significantly associated with recurrence of diabetic ischemic stroke (P=0.57).
Conclusion:There was no relationship between-866G>A variant of UCP-2in type2diabetes and the risk of developing stroke as shown by our4-year follow-up study.
Part Ⅲ The mechanism of-866G/A polymorphism on prognosis in Chinese type2diabetic patients with ischemic stroke
Objective:The purpose of this study was to assess the mechanism of-866G>A polymorphism on prognosis in ischemic stroke in Chinese type2diabetic patients.
Methods:405patients enrolled in part II studies were measured in response to antiplatelet therapy with the Platelet Function Analyzer-100by means of collagen/adenosine diphosphate (CADP) and collagen/epinephrine (CEPI) cartridges.
Results:For A allel carrying patients in comparison with GG genotype a significant trend toward non-full response to antiplatelet therapy in the CADP and CEPI test was observed (P<0.0001).
Conclusion:The A allele was associated with increased risk of clopidogrel resistance.
In summary, our present study has the following new concerns:
1. The A allele of the-866G>A variant of UCP-2was associated with increased risk of IS In a4-year prospective study, we first found the A allele was associated with increased risk of IS in Chinese diabetic women with type2diabetes. This association was independent of other common IS risk factors.
2. The A allele was associated with increased risk of clopidogrel resistance There were no exactly relationship between-866G>A variant of UCP-2in type2diabetes and the risk of developing stroke as shown by our4-year follow-up study. But the A allele was associated with increased risk of clopidogrel resistance.
1997年线粒体解偶联蛋白2(uncoupling protein-2, UCP-2)基因首次被克隆定位于人类染色体11q13,该区域与高胰岛素血症和肥胖相连锁,其生理作用是消除线粒体膜电位,使物质氧化与磷酸化解偶联,从而抑制二磷酸腺苷(Adenosine diphosphate, ADP)合成。大量的动物实验和临床研究发现,UCP-2基因在体内广泛分布并且在体内体外均具有保护组织器官抗氧化和减少活性氧产生的作用。UCP-2是p细胞胰岛素分泌的一个重要的负向调节因子,作用机制可能是UCP-2通过氧化磷酸化解偶联,致ATP合成减少,ATP/ADP比值降低,使ATP敏感性K+通道(K+-ATP通道)去极化而开放,进而通过Na+-K+交换,β细胞外Na+增加、K+减少,胞内Na+减少、K+增加,使电压门控性钙通道开放,Ca2+内流,β细胞中含胰岛素的分泌颗粒与膜融合,通过胞吐作用将胰岛素释放,UCP-2表达增多可使胰岛素分泌减少。因此,UCP-2基因可能是偶联肥胖、胰岛p细胞功能障碍和二型糖尿病的关键基因。近年许多研究结果表明：UCP-2在脑卒中的发展过程中具有神经保护作用。脑卒中发生时,UCP-2通过降低线粒体膜电位、调节钙超载、降低ROS产量等作用,从而减少神经细胞的死亡。同时,随着对UCP-2研究的深入,不断有报道证实UCP-2基因启动子区-866G>A突变是一个功能性突变位点,与糖尿病、胰岛素抵抗、冠脉综合征、血脂异常等有关,但该突变位点与脑卒中的发生、发展及预后是否相关,该相关性是否独立于脑卒中其他易感因素,目前尚不清楚。
本文第一章中,我们选择了404例二型糖尿病伴有脑卒中的患者及440例单纯二型糖尿病患者,通过TaqMan MGB (minor grove binder)中通量探针基因检测技术确定基因型并且对所有病例进行4年随访,观察脑卒中的新发、复发及死亡率,结果发现无论是在基线状态下还是在随访中,携带A等位基因的女性患者较之GG野生型女性患者脑卒中的发生风险加大,且该相关性独立于脑卒中的其他风险因素,但在男性受试者中并不存在差异。
本文第二、第三章在前期的研究结果上继续观察脑卒中患者的复发、预后与UCP-2基因启动子区-866G>A基因型的相关性,并且探讨该相关性的可能发生机制,用多元logistic回归模型等方法计算各不同基因型与脑卒中预后的交互作用。结果表明携带A等位基因的男性患者较之携带GG野生型的患者,增加脑卒中复发及死亡的风险。但是A等位基因并不是卒中复发的独立危险因素。同时,我们发现携带A等位基因的患者对氯吡格雷的反应性较之GG野生型的患者降低,具体的机制仍待进一步探讨。
综上所述,本研究首先发现UCP-2基因启动子区-866G>A突变与国人女性患者二型糖尿病脑卒中的发生具有遗传易感相关性,并且此相关性独立于脑卒中的其他风险因素。随后,实验发现四年随访过程中,UCP-2基因该位点突变并不是国人二型糖尿病脑卒中复发的独立危险因素。但是,携带A等位基因的患者对氯吡格雷的反应性较之GG野生型的患者显著降低。本研究表明UCP-2基因启动子区-866G>A突变与国人二型糖尿病脑卒中的发生发展相关,对于脑卒中的发病前预测等具有潜在的临床价值。
第一部分UCP-2基因-866G>A变异与二型糖尿病脑卒中发生的遗传易感相关性研究
目的：探讨UCP-2基因启动子-866G>A突变与二型糖尿病合并脑卒中发生风险的相关性。
方法：对844例二型糖尿病患者(伴有脑卒中组404例,不伴脑卒中组440例)进行为期4年的前瞻性队列研究,提取所有受试者的基因组全血DNA,用TaqMan MGB探针对UCP-2基因启动子-866G>A进行基因分型,分析不同基因型与二型糖尿病合并脑卒中发生风险的关联性。
结果：无论在受试者入组时还是在4年随访过程中,携带A等位基因的二型糖尿病女性患者脑卒中发生风险显著高于GG (P<0.05)野生型,但男性患者三种基因型之间未见统计学差异。
结论：UCP-2基因启动子-866G>A变异增加国人女性二型糖尿病并发脑卒中的风险。
第二部分UCP-2基因-866G>A变异与二型糖尿病脑卒中的预后遗传易感相关性的研究
目的：探讨UCP-2基因启动子-866G>A突变与二型糖尿病脑卒中复发风险的相关性。
方法：入组二型糖尿病初发脑卒中未进行溶栓治疗的患者进行为期4年的前瞻性研究,观察终点事件为脑卒中复发、短暂性缺血发作、死亡。提取所有受试者的基因组全血DNA,用TaqMan MGB探针对UCP-2基因启动子-866G>A进行基因分型,分析不同基因型与二型糖尿病合并脑卒中复发风险的关联性。
结果：发生与未发生终点事件的患者各基因型分布并无明显差异。携带A等位基因男性受试者与GG野生型相比会增加脑卒中复发风险(P<0.05),但并不是脑卒中复发的独立危险因素,年龄、肥胖等风险因素与脑卒中的生存率也相关。
结论：携带A等位基因的二型糖尿病患者(XA突变型)与GG(P<0.05)野生型相比,男性患者有增加脑卒中复发的风险,但不是其独立危险因素。女性患者并不存在相关性。二型糖尿病和脑卒中的预后均受遗传和环境等多种因素影响,单一一个基因的多态性也许未能改变其预后。
第三部分UCP-2基因-866G>A变异与二型糖尿病脑卒中遗传易感相关性的机制探讨
目的：探讨UCP-2基因启动子-866G>A突变与二型糖尿病合并脑卒中遗传易感相关性的可能机制。
方法：对第二部分入组的二型糖尿病合并脑卒中患者服用氯吡格雷进行脑卒中复发预防,使用血小板功能分析系统(PFA-100)测定血小板聚集率,同时提取所有受试者的基因组全血DNA,对UCP-2基因启动子-866G>A进行基因分型,分析不同基因型与氯吡格雷低反应性发生的关联。
结果：UCP-2基因启动子-866G>A突变携带A等位基因的患者对于氯吡格雷的反应性下降,无论用ADP还是肾上腺素作为诱导剂测定血小板聚集率,携带A等位基因的患者发生氯吡格雷抵抗的几率远远大于GG野生型,结果具有统计学差异。
结论：携带A等位基因的二型糖尿病患者(GA/AA)与GG野生型相比,A等位基因与患者对氯吡格雷低反应性产生存在明显相关,我们推测A等位基因可能与氯吡格雷抵抗的产生有关从而对二型糖尿病脑卒中的复发及预后产生影响。
综上所述,本研究工作的主要创新之处在于：
1.A等位基因与卒中的发生具有遗传易感相关性本课题首次对UCP-2基因启动子-866G>A突变与二型糖尿病脑卒中患者卒中的发生、发展、预后的遗传易感相关性进行探讨,通过4年前瞻性随访研究,发现A等位基因能增加国人女性二型糖尿病脑卒中的风险；
2.A等位基因可能通过增加氯吡格雷抵抗的产生影响二型糖尿病脑卒中的复发及预后在上述基础上,本课题首次发现UCP-2基因启动子-866G>A突变与氯吡格雷的低反应性存在明显相关,A等位基因可能与氯吡格雷抵抗的产生有关从而对二型糖尿病脑卒中的复发及预后产生影响。
Stroke, also called cerebrovascular accident, constitutes a significant human health hazard because of its high incidence, morbidity and mortality. In the past ten years, clinical trials aiming to figure out suitable neuroprotectants against the debilitating effects of stroke have met with no success. Identifying novel neuroprotectants which can reverse the effects against stroke is becoming a challenge to both clinicians and scientists. Ischemic stroke is the most common stroke category which accounted to70%of stroke. The lingering effects of ischemic stroke are very serious, resulting in patient death, and most of survivors suffer nerve function disorder. The consequence of stroke is often enhanced by risk factors such as diabetes, which increases the incidence of stroke in the ischemic stroke by4to12folds particularly. Acute hyperglycemia and diabetes could aggravate brain damage, because the transient focal or forebrain ischemia by both glutamate excitotoxicity and increased reactive oxygen species (ROS) generation. Additionally, the excessive glucose supply is suggested to upregulate the glucose transporters levels and△Ψm, which might be detrimental to the brain cells. The results of these above risk factors are the extension of core region or conversion of penumbra into the core in a short time. The reasons that diabetic patients may associate with ischemic stroke including susceptibility genes, hypercoagulable state, high blood sugar, lipid metabolism disorders, hormone regulation disorders.So finding the related genes in ischemic stroke can predict the happening of ischemic stroke and decrease the damage of nerve function to become the focus question of research in ischemic stroke.
Recent reports on the uncoupling protein-2(UCP-2) appears it has nerve protection on ischemic stroke. The functional structure of UCP-2is a homodimer composed of309amino-acid residues. It is present on chromosomes11and7in the human and mouse, respectively. The primary function of UCPs in the mitochondria is translocation of protons, which are pumped out against concentration gradient during the flow of electrons through respiratory chain complexes Ⅰ-Ⅳ. The proton electrochemical gradient, the△Ψm, established by these protons is used to synthesize adenosine triphosphate (ATP) by FOF1-ATPase (complex V). However, the consumption of oxygen during electron transport chain (ETC) may not be completely used to concomitant ATP generation because of proton leak through UCPs, and the resultant energy of the△Ψm is dissipated as heat. The protons may be directly transported by UCPs or indirectly through a process called fatty acid cycling across the IMM. The exact mechanism of proton transport although is not clear, however, both processes suggested may uncouple the oxidation from ATP synthesis. When ischemic stroke happened, uncoupling protein-2can decrease the mitochondrial membrane potential, regulate the calcium overload, decrease the ROS production. By that means, UCP-2protects the nerve cells. Now more and more investigations confirm UCP-2-866G>A SNP is a functional polymorphism. A series of clinical studies showed associations of this polymorphism with several phenotypes related to obesity, diabetes, insulin sensitivity, insulin secretion, and dyslipidemia. But is this SNP related in ischemic stroke and is the genetic predisposition independent from other susceptible factor? These questions now have no answer. Therefore, we focused on investigation of those questions.
In the first chapter, a total of844patients were selected.404cases with cerebral thrombosis (T2DM+IS),440cases without ischemic stroke (T2DM) in4-years follow up, UCP-2gene polymorphism was confirmed by TaqMan MGB probe method, then compared genotype and allele gene frequency. We found IS incidence, recurrence and death rate, the assay suggested that XA(AA+GA) of genotype frequencies polymorphism of UCP-2increase the risk of ischemic stroke in women but not in men.
In the second and third chapter, we based on the results and continued to follow-up the patients with IS recurrence, discussing the relationship between prognosis and UCP-2gene promoter-866G>A gene type and the relevance of possible mechanism with multiple logistic regression model calculate each different genotype. We found that the patients carrying A alleles had no different recurrent rate of IS than carrying GG wild type, but carrying A alleles the patients had lower clopidogrel reactive than GG wild type of patients, the exact mechanism was still being discussed further.
In conclusion, the present study first found that UCP-2gene-866G>A polymorphism can increase the risk of ischemic stroke in Chinese diabetic women. This effect was independent of effects of other risk factors, such as age, arterial hypertension and obesity. Later, we found that during the four years follow-up, UCP-2gene mutations and the stroke of the recurrence were not obviously related, but, carrying A alleles of the patients had lower clopidogrel reactive than GG wild type of patients, the results were significantly different. This research showed that UCP-2gene promoter area-866G>A mutation had relationship with Chinese type two diabetes stroke occurrence and development. This research was good for stroke clinical and forecast.
Part Ⅰ Association between mitochondrial uncoupling protein2gene-866G>A polymorphism and diabetic patients with ischemic stroke
Objective:To investigate the association of uncoupling protein2(UCP-2) gene-866G>A polymorphism on diabetic patients with cerebral thrombosis.
Methods:A total of844patients were selected404cases with cerebral thrombosis(T2DM+IS),440cases without ischemic stroke(T2DM), UCP-2gene polymorphism was confirmed by TaqMan MGB probe method, then compared genotype and allele gene frequency.
Results:The assay suggested that XA (AA+GA) of genotype frequencies polymorphism of UCP-2increase the risk of ischemic stroke in women but not in men.
Conclusion:UCP-2-866G>A polymorphism can increase the risk of ischemic stroke in Chinese diabetic women.
Part Ⅱ Effects of uncoupling protein2-866G/A polymorphism on prognosis in Chinese type2diabetic patients with ischemic stroke
Objective:The purpose of this study was to assess the effects of-866G>A polymorphism of mitochondrial uncoupling protein2(UCP-2) on prognosis in patients with type2diabetic companied by ischemic stroke.
Methods:A total of405Chinese patients with T2DM and stroke were assessed in a4-year follow-up case-control study. The primary end point was a composite of stroke and TIA (transient ischemic attack), the secondary end point was death. The-866G>A polymorphism in UCP-2was genotyped by TaqMan MGB probe method.
Results:The-866G>A SNP in UCP-2was not significantly associated with recurrence of diabetic ischemic stroke (P=0.57).
Conclusion:There was no relationship between-866G>A variant of UCP-2in type2diabetes and the risk of developing stroke as shown by our4-year follow-up study.
Part Ⅲ The mechanism of-866G/A polymorphism on prognosis in Chinese type2diabetic patients with ischemic stroke
Objective:The purpose of this study was to assess the mechanism of-866G>A polymorphism on prognosis in ischemic stroke in Chinese type2diabetic patients.
Methods:405patients enrolled in part II studies were measured in response to antiplatelet therapy with the Platelet Function Analyzer-100by means of collagen/adenosine diphosphate (CADP) and collagen/epinephrine (CEPI) cartridges.
Results:For A allel carrying patients in comparison with GG genotype a significant trend toward non-full response to antiplatelet therapy in the CADP and CEPI test was observed (P<0.0001).
Conclusion:The A allele was associated with increased risk of clopidogrel resistance.
In summary, our present study has the following new concerns:
1. The A allele of the-866G>A variant of UCP-2was associated with increased risk of IS In a4-year prospective study, we first found the A allele was associated with increased risk of IS in Chinese diabetic women with type2diabetes. This association was independent of other common IS risk factors.
2. The A allele was associated with increased risk of clopidogrel resistance There were no exactly relationship between-866G>A variant of UCP-2in type2diabetes and the risk of developing stroke as shown by our4-year follow-up study. But the A allele was associated with increased risk of clopidogrel resistance.
引文
1.谭志学.聚焦2007-2008年全国糖尿病流行病学调查.药品评价2009,6(1)：4
2. Fleury C, Neverova M, Collins S, et al. Uncoupling protein 2:a novel gene linked to obesity and hyperinsulinemia. Nat Genet 1997,15(3):269-72
3. Boss O, Samec S, Paoloni-Giacobino A, et al. Uncoupling protein 3:a new member of the mitochondrial carrier family with tissue specific expression. FEBS Lett 1997,408(1):39-42
4. Maclellan JD, Gerrits MF, Gowing A, et al. Physiological increases in uncoupling protein 2 augment fatty acid oxidation and decrease reactive oxygen species p roduction without uncoupling respiration in muscle cells. Diabetes 2005,54(8): 2343-2350
5. Wei CF, Chen LL, WangBP, et al. Effect of fenofibrate on the expression of uncoupling protein 3 gene in skeletal muscle of diabetic rats fed with high fat diet. Chin Pharm acol Bull 2007,23(3):399-402
6. Richard D, Rivest R, HuangQ, et al. Distribution of the uncoupling protein 2 mRNA in the mouse brain. J Comp Neurol 1998,397(4):549-560
7. Mattiasson G, Shamloo M, Gido G, et al. Uncoupling protein 2 prevents neuronal death and diminishes brain dysfunction after stroke and brain trauma. Nature Med 2003,9(8):1062-1068
8. Stuart JA, HarperJA, BrindleKM, et al. Physiological level so fmam malian uncoupling protein 2 do not uncouple yeast mitochondria. JBiolChem 2001, 276(21):18633-18639
9. Chan CB, De Leo D, Joseph JW, et al. Increased uncoupling protein level sin beta cells are associated with impaired glucose stimulated insulin secretion: mechanism ofaction. Diabetes 2001,50(6):1302-1310
10. Karen L, Furie, Scott E, et al. Uncoupling protein-2:a novel gene linked to obesity and hyperinsu linemia. Nat Genet 1997,15(3):269-272
11. Li LX, Skorpen F, EgebergK, et al. Uncoupling protein 2 participate sin cellular defense against oxidative stressing clonal beta cells. Biochem Biophys Res Commun 2001,282(1):273-277
12. Barazzoni R, Nair KS. Changes in uncoupling protein 2 and expression in ageing rat skeletal muscle, liver, and heart. Am JPhysiol Endocrinol Metab 2001,280(3): 413-419
13. Arsenijevic D, Onuma H, Pecqueur C, et al. Disruption of the uncoupling protein 2 gene in micereveal sarolein immunity and reactive oxygens pecies production. Nat Genet 2000,26(4):435-439
14. Hjentnes N, Fernstrom M, Zierath JR, et al. Regulation of UCP2 and UCP3 by muscle disuse and physical activity in subjects. Diabetologia 1999,42(5): 826-830
15. O'Rahilly S. Uncoupling protein2:Adiposity angel and diabetes devil? Nat Med 2001,7(7):770-772
16. Klingenberg M, Echtay KS. Uncoupling proteins:the issues from abio chemist point of view. Biochim Biophys Acta 2001,1504(1):128-143
17. Gnanalingham MG, Mostyn A, Forhead AJ, et al. Increased uncoupling protein2 mRNA abundance and gluco corticoidactionin adipose tissue in the sheep fetus during lategestationis dependent on plasma cortisol and triiodothyronine. J Physiol 2005,567(1):283-292
18. Sullivan PG, Springer JE, Hall ED, et al. Mitochondrial uncoupling as a therapeutic target following neuronal injury. J Bioenerg Biomembr 2004,36(4): 353-356
19. Blass JP. Brain metabolism and brain disease:is metabolic deficiency the proximate cause of Alzheimer dementia? JNeurosci Res 2001,66(5):851-856
20. Horvath TL, Diano S, Mivamoto S, et al. Uncoupling proteins 2 and 3 influence obesity and inflammation in transgenic mice. Int J Obes Relat Metab Disord 2003, 27(4):433-442
21. Chan SL, Liu D, Kvriazis GA, et al. Mitochondrial uncoupling protein 2: regulates calcium homeostasis and sensitivity to store depletion-induced apoptosis in neural cells. J Biol Chem 2006,281(49):37391-37403
22. Liu SS. Cooperation of a"reactive oxygen cycle"with the Q cycle and the proton cycle in the respiratory chain 2 superoxide generating and cycling mechanisms in mitochondria. JBioenerg Biomembr 1999,31(4):367-376
23. Andrews ZB, Horvath B, Barnstable CJ, et al. Uncoupling protein 2 is critical for nigral dopamine cell survival in a mouse model of Parkinson's disease. JNeurosci 2005,25(1):184-191
24. Echtay KS, Roussel D, Stepierre J, et al. Superoxide activates mitochondrial uncoupling proteins. Nature 2002,415(6857):96-99
25. Arsenijevic D, Onuma H, Pecqueur C, et al. Disruption of the uncoupling protein-2 gene in mice reveals a role in immunity and reactive oxygen species production. Nat Genet 2000,26:435-439
26. Blanc J, Alves-Guerra MC, Esposito B, et al. Protective role of uncoupling protein 2 in atherosclerosis. Circulation 2003,107:388-390
27. Lee KU, Lee IK, Han J, et al. Effects of recombinant adenovirus-mediated uncoupling protein 2 overexpression on endothelial function and apoptosis. Circ Res 2005,96:1200-1207
28. Arsenijevic D, Onuma H, Pecqueur C, et al. Disruption of the uncoupling protein-2 gene in mice reveals a role in immunity and reactive oxygen species production. Nat Genet 2000,26:435-439
29. Mattiasson G, Shamloo M, Gido G, Mathi K, et al. Uncoupling protein-2 prevents neuronal death and diminishes brain dysfunction after stroke and brain trauma. Nat Med 2003,9:1062-1068
30. Mattiasson G, Sullivan PG. The emerging functions of UCP-2 in health, disease, and therapeutics. Antioxid Redox Signal 2006,8:1-38
31. Ne'gre-Salvayre A, Hirtz C, Carrera G, et al. A role for uncoupling protein-2 as a regulator of mitochondrial hydrogen peroxide generation. FASEB J 1997,11:809 -815
32. Park JY, Park KG, Kim HJ, et al. The effects of the overexpression of recombinant uncoupling protein 2 on proliferation, migration and plasminogen activator inhibitor 1 expression in human vascular smooth muscle cells. Diabetologia 2005, 48:1022-1028
33. Marre M, Lievre M, Chatellier G, et al. Effects of low dose ramipril on cardiovascular and renal outcomes in patients with type 2 diabetes and raised excretion of urinary albumin:randomized, double blind, placebo controlled trial (the DIABHYCAR study). BMJ 2004,328:495-498
34. Blanc J, Alves-Guerra MC, Esposito B, et al. Protective role of uncoupling protein 2 in atherosclerosis. Circulation 2003,107:388-390
35. Lee KU, Lee IK, Han J, et al. Effects of recombinant adenovirus-mediated uncoupling protein 2 overexpression on endothelial function and apoptosis. Circ Res 2005,96:1200-1207
36. Negre-Salvayre A, Hirtz C, Carrera G, et al. A role for uncoupling protein-2 as a regulator of mitochondrial hydrogen peroxide generation. FASEB J1997,11:809-815
37. Chevillotte E, Giralt M, Miroux B, et al. Uncoupling protein-2 controls adiponectin gene expression in adipose tissue through the modulation of reactive oxygen species production. Diabetes 2007,56:1042-1050
38. Ouchi N, Kihara S, Arita Y, et al. Novel modulator for endothelial adhesion molecules:adipocytederived plasma protein adiponectin. Circulation 1999,100: 2473-2476
39. Ouchi N, Kihara S, Arita Y, Nishida M, et al. Adipocyte-derived plasma protein, adiponectin, suppresses lipid accumulation and class A scavenger receptor expression in human monocyte-derived macrophages. Circulation 2001,103: 1057-1063
40. Reis AF, Dubois-Laforgue D, Bellanne'-Chantelot C, et al. A polymorphism in the promoter of UCP2 gene modulates lipid levels in patients with type 2 diabetes. Mol Genet Metab 2004,82:339-344
41. Sesti G, Cardellini M, Marini MA, et al. A common polymorphism in the promoter of UCP2 contributes to the variation in insulin secretion in glucose-tolerant subjects. Diabetes 2003,52:1280-1283
42. Zee RY, Ridker PM, Chasman DI. Mitochondrial uncoupling protein gene cluster variation (UCP2-UCP3) and the risk of incident type 2 diabetes mellitus:The Women's Genome Health Study. Atherosclerosis 2010, Oct 20
43. Krempler F, Esterbauer H, Weitgasser R, et al. A functional polymorphism in the promoter of UCP2 enhances obesity risk but reduces type 2 diabetes risk in obese middle-aged humans. Diabetes 2002,51:3331-3335
44. Wang H, Chu WS, Lu T, et al. Uncoupling protein-2 polymorphisms in type 2 diabetes, obesity, and insulin secretion. Am J Physiol Endocrinol Metab 2004,86: E1-E7
45. Beitelshees AL, Finck BN, Leone TC, et al. Interaction between the UCP2-866 G>A polymorphism, diabetes, and beta-blocker use among patients with acute coronary syndromes. Pharmacogenet Genomics 2010,20(4):231-238
46. Heidari J, Akrami SM, Heshmat R, et al. Association study of the-866G/A UCP-2 gene promoter polymorphism with type 2 diabetes and obesity in a Tehran population:a case control study. Arch Iran Med 2010,13(5):384-390
1.谭志学.聚焦2007-2008年全国糖尿病流行病学调查.药品评价2009,6(1)：4.
2. Kissela BM, Khoury J, Kleindorfer D, et al. Epidemiology of ischemic st roke in patient s with diabetes:the greater Cincinnati/Northern Kentucky Stroke Study. Diabetes Care 2005,28:355
3.向红丁.住院病例高血压与糖尿病慢性并发症患病率的研究.中华流行病学杂志2008,24(9)：819
4. Murphy MP. Development of lipophilic cation as therapies for disorders due to mitochondrial dysfunction. Expert opin Biol Ther 2008(6):753-764
5. Fleury C, Neverova M, Collins S, et al. Uncoupling protein-2:a novel gene linked to obesity and hyperinsu linemia. Nat Genet 1997,15(3):269-272
6. Echtay KS, Roussel D, St-Pierre J, et al. Superoxide activates mitochondrial uncoupling proteins. Nature 2002,415(6867):96-99
7. Pecqueur C, Alves-Guerra MC, Gelly C, et al. Uncoupling protein 2, in vivo distribution, induction upon oxidative stress, and evidence for translantional regulation. Biol Chem 2001,276(12):8705-8712
8. Chan CB, De Leo D, Joseph JW, et al. Increased uncoupling protein-2 levels in beta-cells are associated with impaired glucose-stimulated insulin secretion: mechanism of action. Diabetes 2001,50(6):1302-1310
9. Joseph JW, Koshkin V, Zhang CY, et al. Uncoupling protein 2 knockout mice have enhanced insulin secretory capacity after a high-fat diet. Diabetes 2002,51(11): 3211-3219
10. Li L, Prabhakaran K, Zhang X, et al. PPARalpha mediated unregulation of uncoupling protein-2 switches cyanide induced apoptosis in primary cortical cells. Toxicol Sci 2006,93(1):136-145
11. Liu S S. Cooperation of a"reactive oxygen cycle"with the Q cycle and the proton cycle in the respiratory chain superoxide generating and cycling mechanisms in mitochondria. JBioenerg Biomem-br 1999,31(4):367-376
12. Andrews ZB, Horvath B, Barnstable CJ, et al. Uncoupling protein-2 is critical for nigral dopamine cell survival in a mouse model of Parkinson's disease. J Neurosci 2005,25(1):184-191
13. Mattiasson G, Shamloo M, Gido G, et al. Uncoupling protein 2 revents neuronal death and diminishes brain dysfunction after stroke and brain trauma. NatureMed 2003,9(8):1062-1068
14. Sasahara M, Nishi M, Kawashima H, et al. Uncoupling protein 2 promoter polymorphism -866G/A affects its expression in beta-cells and modulates clinical profiles of Japanese type 2 diabetic patients. Diabetes 2004,53:482-485
15. Reis AF, Dubois-Laforgue D, Bellanne'-Chantelot C, et al. A polymorphism in the promoter of UCP2 gene modulates lipid levels in patients with type 2 diabetes. Mol Genet Metab 2004,82:339-344
16. Sesti G, Cardellini M, Marini MA, et al. A common polymorphism in the promoter of UCP2 contributes to the variation in insulin secretion in glucose-tolerant subjects. Diabetes 2003,52:1280-1283
17. Zee RY, Ridker PM, Chasman DI. Mitochondrial uncoupling protein gene cluster variation (UCP2-UCP3) and the risk of incident type 2 diabetes mellitus:The Women's Genome Health Study. Atherosclerosis 2010, Oct 20
18. Krempler F, Esterbauer H, Weitgasser R, et al. A functional polymorphism in the promoter of UCP-2 enhances obesity risk but reduces type 2 diabetes risk in obese middle-aged humans. Diabetes 2002,51:3331-3335
19. Wang H, Chu WS, Lu T, et al. Uncoupling protein-2 polymorphisms in type 2 diabetes, obesity, and insulin secretion. Am J Physiol Endocrinol Metab 2004,86: E1-E7
20. Beitelshees AL, Finck BN, Leone TC, et al. Interaction between the UCP-2-866 G>A polymorphism, diabetes, and beta-blocker use among patients with acute coronary syndromes. Pharmacogenet Genomics 2010,20(4):231-238
21. Heidari J, Akrami SM, Heshmat R, et al. Association study of the-866G/A UCP-2 gene promoter polymorphism with type 2 diabetes and obesity in a Tehran population:a case control study. Arch Iran Med 2010,13(5):384-390
22. Marre M, Lievre M, Chatellier G, et al. Effects of low dose ramipril on cardiovascular and renal outcomes in patients with type 2 diabetes and raised excretion of urinary albumin:randomized, double blind, placebo controlled trial (the DIABHYCAR study).BMJ2004,328:495
23. Nadir Cheurfa, Danie' le, Dubois-Laforgue, et al. The Common-866G>A Variant in the Promoter of UCP-2 Is Associated With Decreased Risk of Coronary Artery Disease in Type 2 Diabetic Men. Diabetes 2008,8(57):1063-1068
24. Fleury C, Neverova M, Collins S, et al. Uncoupling protein 2:anovel gene linked to obesity and hyper insulinemia. Nat Genet 1997,15(3):269-272
25. Enerback S, Jacobsson A, Simpson EM, et al. Mice lacking mitochondrial uncoupling protein are cold-sensitive but not obese. Nature 1997,387:90-94
26. Krauss S, Zhang CY, Lowell BB. A significant portion of mitochondrial proton leak in intact thymocytes depends on expression of UCP-2. Proc Natl Acad Sci USA 2002,99:118-122
27. Tomlinson DR, Gardiner NJ. Glucose neurotoxicity. Nat Rev Neurosci 2008,9: 36-45
28. Lukovits TG, Mazzone TM, Gorelick TM, et al. Diabetesmellitus and cerebrovascular isease. Neuroep idemiology 1999,18 (1):1-14
29. Maragos WF, Korde AS. Mitochondrial uncoupling as a potential therapeutic target in acute central nervous system injury. J Neurochem 2004,91:257-262
30. Arsenijevic D, Onuma H, Pecqueur C, et al. Disruption of the uncoupling protein-2 gene in mice reveals a role in immunity and reactive oxygen species production. Nat Genet 2000,26:435-439
31. Mattiasson G, Shamloo M, Gido G, Mathi K, et al. Uncoupling protein-2 prevents neuronal death and diminishes brain dysfunction after stroke and brain trauma. Nat Med 2003,9:1062-1068
32. Mattiasson G, Sullivan PG. The emerging functions of UCP-2 in health, disease, and therapeutics. Antioxid Redox Signal 2006,8:1-38
33. Sasahara M, Nishi M, Kawashima H, et al. Uncoupling protein 2 promoter polymorphism-866G/A affects its expression in beta-cells and modulates clinical profiles of Japanese type 2 diabetic patients. Diabetes 2004,53:482-485
34. Reis AF, Dubois-Laforgue D, Bellanne'-Chantelot C, et al. A polymorphism in the promoter of UCP-2 gene modulates lipid levels in patients with type 2 diabetes. Mol Genet Metab 2004,82:339-344
35. Sesti G, Cardellini M, Marini MA, et al. A common polymorphism in the promoter of UCP-2 contributes to the variation in insulin secretion in glucose-tolerant subjects. Diabetes 2003,52:1280-1283
36. Esterbauer H, Schneitler C, Oberkofler H, et al. A common polymorphism in the promoter of UCP-2 is associated withdecreased risk of obesity in middle-aged humans. Nat Genet 2001,28:178-183
1. Enerback S, Jacobsson A, Simpson EM, et al. Mice lacking mitochondrial uncoupling protein are cold-sensitive but not obese. Nature 1997,387:90-94
2. Krauss S, Zhang C.Y., Lowell B.B. A significant portion of mitochondrial proton leak in intact thymocytes depends on expression of UCP-2. Proc Natl Acad Sci USA 2002,99:118-122
3. Tomlinson DR, Gardiner NJ. Glucose neurotoxicity. Nat Rev Neurosci 2008,9: 36-45
4. Lukovits TG, Mazzone TM, Gorelick TM, et al. Diabetesmellitus and cerebrovascular isease. Neuroep idemiology 1999,18(1):1-14
5. Maragos WF, Korde AS. Mitochondrial uncoupling as a potential therapeutic target in acute central nervous system injury. JNeurochem 2004,91:257-262
6. Arsenijevic D, Onuma H, Pecqueur C, et al. Disruption of the uncoupling protein-2 gene in mice reveals a role in immunity and reactive oxygen species production. Nat Genet 2000,26:435-439
7. Mattiasson G, Shamloo M, Gido G, Mathi K, et al. Uncoupling protein-2 prevents neuronal death and diminishes brain dysfunction after stroke and brain trauma. Nat Med 2003,9:1062-1068
8. Mattiasson G, Sullivan PG. The emerging functions of UCP-2 in health, disease, and therapeutics. Antioxid Redox Signal 2006,8:1-38
9. Sasahara M, Nishi M, Kawashima H, et al. Uncoupling protein 2 promoter polymorphism -866G/A affects its expression in beta-cells and modulates clinical profiles of Japanese type 2 diabetic patients. Diabetes 2004,53:482-485
10. Reis AF, Dubois-Laforgue D, Bellanne'-Chantelot C, et al. A polymorphism in the promoter of UCP-2 gene modulates lipid levels in patients with type 2 diabetes. Mol Genet Metab 2004,82:339-344
11. Sesti G, Cardellini M, Marini MA, et al. A common polymorphism in the promoter of UCP-2 contributes to the variation in insulin secretion in glucose-tolerant subjects. Diabetes 2003,52:1280-1283
12. Esterbauer H, Schneitler C, Oberkofler H, et al. A common polymorphism in the promoter of UCP-2 is associated withdecreased risk of obesity in middle-aged humans. Nat Genet 2001,28:178-183
13. Krempler F, Esterbauer H, Weitgasser R, et al. A functional polymorphism in the promoter of UCP-2 enhances obesity risk but reduces type 2 diabetes risk in obese middle-aged humans. Diabetes 2002,51:3331-3335
14. Wang H, Chu WS, Lu T, et al. Uncoupling protein-2 polymorphisms in type 2 diabetes, obesity, and insulin secretion. Am JPhysiol Endocrinol Metab 2004,86: E1-E7
15. Le Fur S, Le Stunff C, Dos Santos C, et al. The common-866 G/A polymorphism in the promoter of uncoupling protein 2 is associated with increased carbohydrate and decreased lipid oxidation in juvenile obesity. Diabetes 2004,53:235-239
16. Oberkofler H, Iglseder B, Klein K, et al. Associations of the UCP-2 gene locus with asymptomatic carotid atherosclerosis in middle-aged women. Arterioscler Thromb Vasc Biol 2005,25(3):604-610
17. Marre M, Lievre M, Chatellier G, et al. Effects of low dose ramipril on cardiovascular and renal outcomes in patients with type 2 diabetes and raised excretion of urinary albumin:randomized, double blind, placebo controlled trial (the DIABHYCAR study). BMJ 2004,328:495
18. Zee RY, Ridker PM, Chasman DI. Mitochondrial uncoupling protein gene cluster variation (UCP2-UCP3) and the risk of incident type 2 diabetes mellitus:The Women's Genome Health Study. Atherosclerosis 2010, Oct 20
19. Krempler F, Esterbauer H, Weitgasser R, et al. A functional polymorphism in the promoter of UCP-2 enhances obesity risk but reduces type 2 diabetes risk in obese middle-aged humans. Diabetes 2002,51:3331-3335
20. Wang H, Chu WS, Lu T, et al. Uncoupling protein-2 polymorphisms in type 2 diabetes, obesity, and insulin secretion. Am J Physiol Endocrinol Metab 2004,86: E1-E7
21. Beitelshees AL, Finck BN, Leone TC, et al. Interaction between the UCP-2-866 G>A polymorphism, diabetes, and beta-blocker use among patients with acute coronary syndromes. Pharmacogenet Genomics 2010,20(4):231-238
22. Heidari J, Akrami SM, Heshmat R, et al. Association study of the-866G/A UCP-2 gene promoter polymorphism with type 2 diabetes and obesity in a Tehran population:a case control study. Arch Iran Med 2010,13(5):384-390
23. Marre M, Lievre M, Chatellier G, et al. Effects of low dose ramipril on cardiovascular and renal outcomes in patients with type 2 diabetes and raised excretion of urinary albumin:randomized, double blind, placebo controlled trial (the DIABHYCAR study).BMJ 2004,328:495
24. Nadir Cheurfa, Danie'le, Dubois-Laforgue, et al. The Common -866G>A Variant in the Promoter of UCP-2 Is Associated With Decreased Risk of Coronary Artery Disease in Type 2 Diabetic Men. Diabetes 2008,8(57):1063-1068
1. Enerback S, Jacobsson A, Simpson EM,.et al. Mice lacking mitochondrial uncoupling protein are cold-sensitive but not obese. Nature 1997,387:90-94
2. Krauss S, Zhang C.Y., Lowell B.B. A significant portion of mitochondrial proton leak in intact thymocytes depends on expression of UCP-2. Proc Natl Acad Sci USA 2002,99:118-122
3. Tomlinson DR., Gardiner NJ. Glucose neurotoxicity. Nat Rev Neurosci 2008,9: 36-45
4. Lukovits TG, Mazzone TM, Gorelick TM, et al. Diabetesmellitus and cerebrovascular isease. Neuroepidemiology 1999,18 (1):1-14
5. Maragos WF, Korde AS. Mitochondrial uncoupling as a potential therapeutic target in acute central nervous system injury. JNeurochem 2004,91:257-262
6. Arsenijevic D, Onuma H, Pecqueur C, et al. Disruption of the uncoupling protein-2 gene in mice reveals a role in immunity and reactive oxygen species production. Nat Genet 2000,26:435-439
7. Mattiasson G, Shamloo M, Gido G, Mathi K. et al. Uncoupling protein-2 prevents neuronal death and diminishes brain dysfunction after stroke and brain trauma. Nat Med'2003,9:1062-1068
8. Mattiasson G, Sullivan PG. The emerging functions of UCP-2 in health, disease, and therapeutics. Antioxid Redox Signal 2006,8:1-38
9. Sasahara M, Nishi M, Kawashima H, et al. Uncoupling protein 2 promoter polymorphism-866G/A affects its expression in beta-cells and modulates clinical profiles of Japanese type 2 diabetic patients. Diabetes 2004,53:482-485
10. Reis AF, Dubois-Laforgue D, Bellanne'-Chantelot C, et al. A polymorphism in the promoter of UCP-2 gene modulates lipid levels in patients with type 2 diabetes. Mol Genet Metab 2004,82:339-344
11. Sesti G, Cardellini M, Marini MA, et al. A common polymorphism in the promoter of UCP-2 contributes to the variation in insulin secretion in glucose-tolerant subjects. Diabetes 2003,52:1280-1283
12. Esterbauer H, Schneitler C, Oberkofler H, et al. A common polymorphism in the promoter of UCP-2 is associated withdecreased risk of obesity in middle-aged humans. Nat Genet 2001,28:178-183
13. Krempler F, Esterbauer H, Weitgasser R, et al. A functional polymorphism in the promoter of UCP-2 enhances obesity risk but reduces type 2 diabetes risk in obese middle-aged humans. Diabetes 2002,51:3331-3335
14. Wang H, Chu WS, Lu T, et al. Uncoupling protein-2 polymorphisms in type 2 diabetes, obesity, and insulin secretion. Am JPhysiol Endocrinol Metab 2004,86: E1-E7
15. Le Fur S, Le Stunff C, Dos Santos C, et al. The common-866 G/A polymorphism in the promoter of uncoupling protein 2 is associated with increased carbohydrate and decreased lipid oxidation in juvenile obesity. Diabetes 2004,53:235-239
16. Oberkofler H, Iglseder B, Klein K, et al. Associations of the UCP-2 gene locus with asymptomatic carotid atherosclerosis in middle-aged women. Arterioscler Thromb Vasc Biol 2005,25(3):604-610
17. Marre M, Lievre M, Chatellier G, et al. Effects of low dose ramipril on cardiovascular and renal outcomes in patients with type 2 diabetes and raised excretion of urinary albumin:randomised, double blind, placebo controlled trial (the DIABHYCAR study).BMJ2004,328:495
18. Zee RY, Ridker PM, Chasman DI. Mitochondrial uncoupling protein gene cluster variation (UCP-2-UCP3) and the risk of incident type 2 diabetes mellitus:The Women's Genome Health Study. Atherosclerosis,2010, Oct 20
19. Krempler F, Esterbauer H, Weitgasser R, et al. A functional polymorphism in the promoter of UCP-2 enhances obesity risk but reduces type 2 diabetes risk in obese middle-aged humans. Diabetes 2002,51:3331-3335
20. Wang H, Chu WS, Lu T, et al. Uncoupling protein-2 polymorphisms in type 2 diabetes, obesity, and insulin secretion. Am J Physiol Endocrinol Metab 2004,86: E1-E7
21. Beitelshees AL, Finck BN, Leone TC, et al. Interaction between the UCP-2-866 G>A polymorphism, diabetes, and beta-blocker use among patients with acute coronary syndromes. Pharmacogenet Genomics 2010,20(4):231-238
22. Heidari J, Akrami SM, Heshmat R, et al. Association study of the -866G/A UCP-2 gene promoter polymorphism with type 2 diabetes and obesity in a Tehran population:a case control study. Arch Iran Med 2010,13(5):384-390
23. Marre M, Lievre M, Chatellier G, et al. Effects of low dose ramipril on cardiovascular and renal outcomes in patients with type 2 diabetes and raised excretion of urinary albumin:randomized, double blind, placebo controlled trial (the DIABHYCAR study). BMJ2004,328:495
24. Nadir Cheurfa, Daniele, Dubois-Laforgue, et al. The Common-866G>A Variant in the Promoter of UCP-2 Is Associated With Decreased Risk of Coronary Artery Disease in Type 2 Diabetic Men. Diabetes 2008,8(57):1063-1068
25. Frere C, Cuisset T, Morange PE. Effect of cytochrome p450 polymorphisms on platelet reactivity after treatment with clopidogrel in acute coronary syndrome. Am J Cardiol 2008,101:1088-1093
26. Gurbel PA, Bliden KP, Hiatt BL, et al. Clopidogrel for coronary stenting:response variability, drug resistance, and the effect of pretreatment platelet reactivily. Circulation 2003,107:2908-2913
27. Wenaweser P, Dorffler-Melly J, Imboden K, et al. Stent thrombosis is associated with an impaired response to anti-platelet therapy. J Coil Cardiol 2005,45: 1748-1752
1. Fleury C, Neverova M, Collins S, et al. Uncoup ling protein2:a novel gene linked to obesity and hyperinsulinemia. Nat Genet 1997,15 (3):269-272
2. Boss O, Samec S, Paoloni-Giacobino A, et al. Uncoupling protein23:a new member of the mitochondrial carrier family with tissue specific expression. FEBS Lett 1997,408 (1):39-42
3. Mao W, Yu XX, Zhong A, et al. UCP4, a novel brain2specific mitochondrial p rotein that reducesmembrane potential in mammalian cells. FEBS Lett 1999,443 (3):326-330
4. Sanchis D, Fleury C, Chomiki N, et al. BMCP1, a novel mitochondrial carrierwith high expression in the central nervous system of humans and rodents, and resp iration uncoup ling activity in recombinant yeast. J B iol Chem 1998, 273(51):34611-34615
5. Richard D, Rivest R, Huang Q, et al. Distribution of the uncoupling p rotein 2 mRNA in the mouse brain. J Comp Neurol 1998,397(4):549-560
6. Kim2Han J S, Reichert S A, Quick K L, et al. BMCP1:a mito2chondrial uncoup ling protein in neuronswhich regulatesmitochondrial function and oxidant p roduction[J].JN eurochem,2001,79(3):658-68.
7. Maclellan JD, Gerrits MF, Gowing A, et al. Physiological increases in uncoup ling p rotein 2 augment fatty acid oxidation and decrease reactive oxygen species production without uncoupling respiration in muscle cells. Diabetes 2005,54 (8): 2343-2350
8.魏翠凤,陈璐璐,王保平等。非诺贝特对高脂喂养的糖尿病大鼠骨骼肌UCP-3基因表达的影响。中国药理学通报2007,23(3)：399-402
9. Wei CF, Chen LL, Wang BP, et al. Effect of fenofibrate on the expression of uncoupling protein 3 gene in skeletal muscle of diabetic rats fed with high fat diet. Chin Pharm acol B ull 2007,23(3):399-402
10. Li L, Prabhakaran K, Zhang X, et al. PPARalpha mediated unregulation of uncoupling protein22 switches cyanide-induced apoptosis in primary cortical cells. Toxicol Sci 2006,93(1):136-145
11. Yamada S, Isojima Y, Yamatodani A, et al. Uncoupling protein influences dopamine secretion in PC12h cells. JNeurochem 2003,87(2):461-469
12. Chan SL, Liu D, Kvriazis GA, et al. Mitochondrial uncoupling protein2 regulates calcium homeostasis and sensitivity to store depletion-induced apop tosis in neural cells. J Biol Chem 2006,281(49):37391-37403
13. Liu SS. Cooperation of a"reactive oxygen cycle"with the Q cycle and the p roton cycle in the resp iratory chain2superoxide generating and cycling mechanisms in mitochondria. J Bioenerg Biomembr 1999,31(4):367-376
14. Andrews ZB, Horvath B, Barnstable CJ, et al. Uncoup ling p rotein-2 is critical for nigral dopamine cell survival in a mouse model of Parkinson's disease. J Neurosci 2005,25(1):184-191
15. Echtay KS, Roussel D, Stepierre J, et al. Superoxide activates mitochondrial uncoupling proteins. Nature 2002,415(6857):96-99
16. Echtay KS, Esteves TC, Pakay JL, et al. A signaling role for hydroxyl nonenal in regulation of mitochondrial uncoupling. EMBO J 2003,22(16):4103-4110
17. Krauss S, Zhang CY, Lowell BB. Themitochondrial uncoupling protein homologues. Nat Rev Mol Cell B iol 2005,6(3):248-261
18. Andrews ZB, Diano S, Horvath TL. Mitochondrial uncoupling proteins in the CNS:in support of function and survival. Nat Rev Neurosci 2005,6(11): 829-840
19. Diano S, Mattews RT, Patrylo P, et al. Uncoupling protein 2 prevents neuronal death including that occurring during seizures:a mechanism for p reconditioning. Endocrinology 2003,144(11):5014-5021
20. Sullivan PG, Rippy NA, Dorenbos K, et al. The ketogenic diet increases mitochondrial uncoupling protein levels and activity. Ann Neurol 2004,55(4): 576-580
21. Mattiasson G, Shamloo M, Gido G, et al. Uncoupling protein2 prevents neuronal death and diminishes brain dysfunction after stroke and brain trauma. Nature Med 2003,9(8):1062-1068
22. Sullivan PG, Springer JE, Hall ED, et al. Mitochondrial uncoupling as a therapeutic target following neuronal injury. J Bioenerg Biomembr 2004,36(4): 353-356
23. Blass JP. Brain metabolism and brain disease:is metabolic deficiency the proximate cause ofAlzheimer dementia?. JNeurosci Res 2001,66(5):851-856
24. Horvath TL, Diano S, Mivamoto S, et al. Uncoupling proteins2 and 3 influence obesity and inflammation in transgenic mice. Int J Obes Relat Metab Disord 2003,27(4):433-442
25. Fridell YW, Sanchez-Blanco A, Silvia BA, et al. Targeted expression of the human uncoupling protein 2 (hUCP-2) to adult neurons extends life span in the fly. Cell Metab 2005,1(2):145-152
26. Urhammer SA, Dalgaard LT, Sorensen TI, et al. Mutation analysis of the codingregion of the uncoupling protein2 gene inobese NIDDM patients:impact of a common amino acid polymorphism on jurenile and maturity onset forms of obesity and insulin resistance. Diabetologia 1997,40(10):1227-1230
27. Shiinoki T, Suehiro T, Ikeda Y, et al. Screening forvariants of the un coupling protein2 gene in Japanese patients with NIDDM. Metabolism 1999,48(5): 581-584
28. Yu X, Jacobs DRJ, Schreiner PJ, et al. The uncoupling protein Ala55Val polymorphismis associated with diabetes mellitus:the CARDIA study. Clin Chem 2005,51(8):1451-1456
29. Reis AF, Dubois-Laforgue D, Bellanne-Chantelot C, et al. A polymorphism in the promoter of UCP-2 gene modulates lipid levels in patients with type2 diabetes. Mol Genet Metab 2004,82(4):339-344
30. Vogler S, Goedde R, Miterski B, et al. Association of acommonpoly morphism in the promoter of UCP-2 with susceptibility to multiples clerosis. J Mol Med 2005,83(10):806-811
31. Kovacs P, Ma L, Hanson RL, et al. Genetic variation in UCP-2 (uncoupling protein-2) is associated with energymetabolism in Pima Indians. Diabetologia 2005,16(8):731-737
32. Maragos WF, Korde AS. Mitochondrial uncoupling as a potential therapeutic target in acute central nervous system injury. JNeurochem 2004,91:257-262
33. Arsenijevic D, Onuma H, Pecqueur C, et al. Disruption of the uncoupling protein-2 gene in mice reveals a role in immunity and reactive oxygen species production. Nat Genet 2000,26:435-439
2. Fleury C, Neverova M, Collins S, et al. Uncoupling protein 2:a novel gene linked to obesity and hyperinsulinemia. Nat Genet 1997,15(3):269-72
3. Boss O, Samec S, Paoloni-Giacobino A, et al. Uncoupling protein 3:a new member of the mitochondrial carrier family with tissue specific expression. FEBS Lett 1997,408(1):39-42
4. Maclellan JD, Gerrits MF, Gowing A, et al. Physiological increases in uncoupling protein 2 augment fatty acid oxidation and decrease reactive oxygen species p roduction without uncoupling respiration in muscle cells. Diabetes 2005,54(8): 2343-2350
5. Wei CF, Chen LL, WangBP, et al. Effect of fenofibrate on the expression of uncoupling protein 3 gene in skeletal muscle of diabetic rats fed with high fat diet. Chin Pharm acol Bull 2007,23(3):399-402
6. Richard D, Rivest R, HuangQ, et al. Distribution of the uncoupling protein 2 mRNA in the mouse brain. J Comp Neurol 1998,397(4):549-560
7. Mattiasson G, Shamloo M, Gido G, et al. Uncoupling protein 2 prevents neuronal death and diminishes brain dysfunction after stroke and brain trauma. Nature Med 2003,9(8):1062-1068
8. Stuart JA, HarperJA, BrindleKM, et al. Physiological level so fmam malian uncoupling protein 2 do not uncouple yeast mitochondria. JBiolChem 2001, 276(21):18633-18639
9. Chan CB, De Leo D, Joseph JW, et al. Increased uncoupling protein level sin beta cells are associated with impaired glucose stimulated insulin secretion: mechanism ofaction. Diabetes 2001,50(6):1302-1310
10. Karen L, Furie, Scott E, et al. Uncoupling protein-2:a novel gene linked to obesity and hyperinsu linemia. Nat Genet 1997,15(3):269-272
11. Li LX, Skorpen F, EgebergK, et al. Uncoupling protein 2 participate sin cellular defense against oxidative stressing clonal beta cells. Biochem Biophys Res Commun 2001,282(1):273-277
12. Barazzoni R, Nair KS. Changes in uncoupling protein 2 and expression in ageing rat skeletal muscle, liver, and heart. Am JPhysiol Endocrinol Metab 2001,280(3): 413-419
13. Arsenijevic D, Onuma H, Pecqueur C, et al. Disruption of the uncoupling protein 2 gene in micereveal sarolein immunity and reactive oxygens pecies production. Nat Genet 2000,26(4):435-439
14. Hjentnes N, Fernstrom M, Zierath JR, et al. Regulation of UCP2 and UCP3 by muscle disuse and physical activity in subjects. Diabetologia 1999,42(5): 826-830
15. O'Rahilly S. Uncoupling protein2:Adiposity angel and diabetes devil? Nat Med 2001,7(7):770-772
16. Klingenberg M, Echtay KS. Uncoupling proteins:the issues from abio chemist point of view. Biochim Biophys Acta 2001,1504(1):128-143
17. Gnanalingham MG, Mostyn A, Forhead AJ, et al. Increased uncoupling protein2 mRNA abundance and gluco corticoidactionin adipose tissue in the sheep fetus during lategestationis dependent on plasma cortisol and triiodothyronine. J Physiol 2005,567(1):283-292
18. Sullivan PG, Springer JE, Hall ED, et al. Mitochondrial uncoupling as a therapeutic target following neuronal injury. J Bioenerg Biomembr 2004,36(4): 353-356
19. Blass JP. Brain metabolism and brain disease:is metabolic deficiency the proximate cause of Alzheimer dementia? JNeurosci Res 2001,66(5):851-856
20. Horvath TL, Diano S, Mivamoto S, et al. Uncoupling proteins 2 and 3 influence obesity and inflammation in transgenic mice. Int J Obes Relat Metab Disord 2003, 27(4):433-442
21. Chan SL, Liu D, Kvriazis GA, et al. Mitochondrial uncoupling protein 2: regulates calcium homeostasis and sensitivity to store depletion-induced apoptosis in neural cells. J Biol Chem 2006,281(49):37391-37403
22. Liu SS. Cooperation of a"reactive oxygen cycle"with the Q cycle and the proton cycle in the respiratory chain 2 superoxide generating and cycling mechanisms in mitochondria. JBioenerg Biomembr 1999,31(4):367-376
23. Andrews ZB, Horvath B, Barnstable CJ, et al. Uncoupling protein 2 is critical for nigral dopamine cell survival in a mouse model of Parkinson's disease. JNeurosci 2005,25(1):184-191
24. Echtay KS, Roussel D, Stepierre J, et al. Superoxide activates mitochondrial uncoupling proteins. Nature 2002,415(6857):96-99
25. Arsenijevic D, Onuma H, Pecqueur C, et al. Disruption of the uncoupling protein-2 gene in mice reveals a role in immunity and reactive oxygen species production. Nat Genet 2000,26:435-439
26. Blanc J, Alves-Guerra MC, Esposito B, et al. Protective role of uncoupling protein 2 in atherosclerosis. Circulation 2003,107:388-390
27. Lee KU, Lee IK, Han J, et al. Effects of recombinant adenovirus-mediated uncoupling protein 2 overexpression on endothelial function and apoptosis. Circ Res 2005,96:1200-1207
28. Arsenijevic D, Onuma H, Pecqueur C, et al. Disruption of the uncoupling protein-2 gene in mice reveals a role in immunity and reactive oxygen species production. Nat Genet 2000,26:435-439
29. Mattiasson G, Shamloo M, Gido G, Mathi K, et al. Uncoupling protein-2 prevents neuronal death and diminishes brain dysfunction after stroke and brain trauma. Nat Med 2003,9:1062-1068
30. Mattiasson G, Sullivan PG. The emerging functions of UCP-2 in health, disease, and therapeutics. Antioxid Redox Signal 2006,8:1-38
31. Ne'gre-Salvayre A, Hirtz C, Carrera G, et al. A role for uncoupling protein-2 as a regulator of mitochondrial hydrogen peroxide generation. FASEB J 1997,11:809 -815
32. Park JY, Park KG, Kim HJ, et al. The effects of the overexpression of recombinant uncoupling protein 2 on proliferation, migration and plasminogen activator inhibitor 1 expression in human vascular smooth muscle cells. Diabetologia 2005, 48:1022-1028
33. Marre M, Lievre M, Chatellier G, et al. Effects of low dose ramipril on cardiovascular and renal outcomes in patients with type 2 diabetes and raised excretion of urinary albumin:randomized, double blind, placebo controlled trial (the DIABHYCAR study). BMJ 2004,328:495-498
34. Blanc J, Alves-Guerra MC, Esposito B, et al. Protective role of uncoupling protein 2 in atherosclerosis. Circulation 2003,107:388-390
35. Lee KU, Lee IK, Han J, et al. Effects of recombinant adenovirus-mediated uncoupling protein 2 overexpression on endothelial function and apoptosis. Circ Res 2005,96:1200-1207
36. Negre-Salvayre A, Hirtz C, Carrera G, et al. A role for uncoupling protein-2 as a regulator of mitochondrial hydrogen peroxide generation. FASEB J1997,11:809-815
37. Chevillotte E, Giralt M, Miroux B, et al. Uncoupling protein-2 controls adiponectin gene expression in adipose tissue through the modulation of reactive oxygen species production. Diabetes 2007,56:1042-1050
38. Ouchi N, Kihara S, Arita Y, et al. Novel modulator for endothelial adhesion molecules:adipocytederived plasma protein adiponectin. Circulation 1999,100: 2473-2476
39. Ouchi N, Kihara S, Arita Y, Nishida M, et al. Adipocyte-derived plasma protein, adiponectin, suppresses lipid accumulation and class A scavenger receptor expression in human monocyte-derived macrophages. Circulation 2001,103: 1057-1063
40. Reis AF, Dubois-Laforgue D, Bellanne'-Chantelot C, et al. A polymorphism in the promoter of UCP2 gene modulates lipid levels in patients with type 2 diabetes. Mol Genet Metab 2004,82:339-344
41. Sesti G, Cardellini M, Marini MA, et al. A common polymorphism in the promoter of UCP2 contributes to the variation in insulin secretion in glucose-tolerant subjects. Diabetes 2003,52:1280-1283
42. Zee RY, Ridker PM, Chasman DI. Mitochondrial uncoupling protein gene cluster variation (UCP2-UCP3) and the risk of incident type 2 diabetes mellitus:The Women's Genome Health Study. Atherosclerosis 2010, Oct 20
43. Krempler F, Esterbauer H, Weitgasser R, et al. A functional polymorphism in the promoter of UCP2 enhances obesity risk but reduces type 2 diabetes risk in obese middle-aged humans. Diabetes 2002,51:3331-3335
44. Wang H, Chu WS, Lu T, et al. Uncoupling protein-2 polymorphisms in type 2 diabetes, obesity, and insulin secretion. Am J Physiol Endocrinol Metab 2004,86: E1-E7
45. Beitelshees AL, Finck BN, Leone TC, et al. Interaction between the UCP2-866 G>A polymorphism, diabetes, and beta-blocker use among patients with acute coronary syndromes. Pharmacogenet Genomics 2010,20(4):231-238
46. Heidari J, Akrami SM, Heshmat R, et al. Association study of the-866G/A UCP-2 gene promoter polymorphism with type 2 diabetes and obesity in a Tehran population:a case control study. Arch Iran Med 2010,13(5):384-390
1.谭志学.聚焦2007-2008年全国糖尿病流行病学调查.药品评价2009,6(1)：4.
2. Kissela BM, Khoury J, Kleindorfer D, et al. Epidemiology of ischemic st roke in patient s with diabetes:the greater Cincinnati/Northern Kentucky Stroke Study. Diabetes Care 2005,28:355
3.向红丁.住院病例高血压与糖尿病慢性并发症患病率的研究.中华流行病学杂志2008,24(9)：819
4. Murphy MP. Development of lipophilic cation as therapies for disorders due to mitochondrial dysfunction. Expert opin Biol Ther 2008(6):753-764
5. Fleury C, Neverova M, Collins S, et al. Uncoupling protein-2:a novel gene linked to obesity and hyperinsu linemia. Nat Genet 1997,15(3):269-272
6. Echtay KS, Roussel D, St-Pierre J, et al. Superoxide activates mitochondrial uncoupling proteins. Nature 2002,415(6867):96-99
7. Pecqueur C, Alves-Guerra MC, Gelly C, et al. Uncoupling protein 2, in vivo distribution, induction upon oxidative stress, and evidence for translantional regulation. Biol Chem 2001,276(12):8705-8712
8. Chan CB, De Leo D, Joseph JW, et al. Increased uncoupling protein-2 levels in beta-cells are associated with impaired glucose-stimulated insulin secretion: mechanism of action. Diabetes 2001,50(6):1302-1310
9. Joseph JW, Koshkin V, Zhang CY, et al. Uncoupling protein 2 knockout mice have enhanced insulin secretory capacity after a high-fat diet. Diabetes 2002,51(11): 3211-3219
10. Li L, Prabhakaran K, Zhang X, et al. PPARalpha mediated unregulation of uncoupling protein-2 switches cyanide induced apoptosis in primary cortical cells. Toxicol Sci 2006,93(1):136-145
11. Liu S S. Cooperation of a"reactive oxygen cycle"with the Q cycle and the proton cycle in the respiratory chain superoxide generating and cycling mechanisms in mitochondria. JBioenerg Biomem-br 1999,31(4):367-376
12. Andrews ZB, Horvath B, Barnstable CJ, et al. Uncoupling protein-2 is critical for nigral dopamine cell survival in a mouse model of Parkinson's disease. J Neurosci 2005,25(1):184-191
13. Mattiasson G, Shamloo M, Gido G, et al. Uncoupling protein 2 revents neuronal death and diminishes brain dysfunction after stroke and brain trauma. NatureMed 2003,9(8):1062-1068
14. Sasahara M, Nishi M, Kawashima H, et al. Uncoupling protein 2 promoter polymorphism -866G/A affects its expression in beta-cells and modulates clinical profiles of Japanese type 2 diabetic patients. Diabetes 2004,53:482-485
15. Reis AF, Dubois-Laforgue D, Bellanne'-Chantelot C, et al. A polymorphism in the promoter of UCP2 gene modulates lipid levels in patients with type 2 diabetes. Mol Genet Metab 2004,82:339-344
16. Sesti G, Cardellini M, Marini MA, et al. A common polymorphism in the promoter of UCP2 contributes to the variation in insulin secretion in glucose-tolerant subjects. Diabetes 2003,52:1280-1283
17. Zee RY, Ridker PM, Chasman DI. Mitochondrial uncoupling protein gene cluster variation (UCP2-UCP3) and the risk of incident type 2 diabetes mellitus:The Women's Genome Health Study. Atherosclerosis 2010, Oct 20
18. Krempler F, Esterbauer H, Weitgasser R, et al. A functional polymorphism in the promoter of UCP-2 enhances obesity risk but reduces type 2 diabetes risk in obese middle-aged humans. Diabetes 2002,51:3331-3335
19. Wang H, Chu WS, Lu T, et al. Uncoupling protein-2 polymorphisms in type 2 diabetes, obesity, and insulin secretion. Am J Physiol Endocrinol Metab 2004,86: E1-E7
20. Beitelshees AL, Finck BN, Leone TC, et al. Interaction between the UCP-2-866 G>A polymorphism, diabetes, and beta-blocker use among patients with acute coronary syndromes. Pharmacogenet Genomics 2010,20(4):231-238
21. Heidari J, Akrami SM, Heshmat R, et al. Association study of the-866G/A UCP-2 gene promoter polymorphism with type 2 diabetes and obesity in a Tehran population:a case control study. Arch Iran Med 2010,13(5):384-390
22. Marre M, Lievre M, Chatellier G, et al. Effects of low dose ramipril on cardiovascular and renal outcomes in patients with type 2 diabetes and raised excretion of urinary albumin:randomized, double blind, placebo controlled trial (the DIABHYCAR study).BMJ2004,328:495
23. Nadir Cheurfa, Danie' le, Dubois-Laforgue, et al. The Common-866G>A Variant in the Promoter of UCP-2 Is Associated With Decreased Risk of Coronary Artery Disease in Type 2 Diabetic Men. Diabetes 2008,8(57):1063-1068
24. Fleury C, Neverova M, Collins S, et al. Uncoupling protein 2:anovel gene linked to obesity and hyper insulinemia. Nat Genet 1997,15(3):269-272
25. Enerback S, Jacobsson A, Simpson EM, et al. Mice lacking mitochondrial uncoupling protein are cold-sensitive but not obese. Nature 1997,387:90-94
26. Krauss S, Zhang CY, Lowell BB. A significant portion of mitochondrial proton leak in intact thymocytes depends on expression of UCP-2. Proc Natl Acad Sci USA 2002,99:118-122
27. Tomlinson DR, Gardiner NJ. Glucose neurotoxicity. Nat Rev Neurosci 2008,9: 36-45
28. Lukovits TG, Mazzone TM, Gorelick TM, et al. Diabetesmellitus and cerebrovascular isease. Neuroep idemiology 1999,18 (1):1-14
29. Maragos WF, Korde AS. Mitochondrial uncoupling as a potential therapeutic target in acute central nervous system injury. J Neurochem 2004,91:257-262
30. Arsenijevic D, Onuma H, Pecqueur C, et al. Disruption of the uncoupling protein-2 gene in mice reveals a role in immunity and reactive oxygen species production. Nat Genet 2000,26:435-439
31. Mattiasson G, Shamloo M, Gido G, Mathi K, et al. Uncoupling protein-2 prevents neuronal death and diminishes brain dysfunction after stroke and brain trauma. Nat Med 2003,9:1062-1068
32. Mattiasson G, Sullivan PG. The emerging functions of UCP-2 in health, disease, and therapeutics. Antioxid Redox Signal 2006,8:1-38
33. Sasahara M, Nishi M, Kawashima H, et al. Uncoupling protein 2 promoter polymorphism-866G/A affects its expression in beta-cells and modulates clinical profiles of Japanese type 2 diabetic patients. Diabetes 2004,53:482-485
34. Reis AF, Dubois-Laforgue D, Bellanne'-Chantelot C, et al. A polymorphism in the promoter of UCP-2 gene modulates lipid levels in patients with type 2 diabetes. Mol Genet Metab 2004,82:339-344
35. Sesti G, Cardellini M, Marini MA, et al. A common polymorphism in the promoter of UCP-2 contributes to the variation in insulin secretion in glucose-tolerant subjects. Diabetes 2003,52:1280-1283
36. Esterbauer H, Schneitler C, Oberkofler H, et al. A common polymorphism in the promoter of UCP-2 is associated withdecreased risk of obesity in middle-aged humans. Nat Genet 2001,28:178-183
1. Enerback S, Jacobsson A, Simpson EM, et al. Mice lacking mitochondrial uncoupling protein are cold-sensitive but not obese. Nature 1997,387:90-94
2. Krauss S, Zhang C.Y., Lowell B.B. A significant portion of mitochondrial proton leak in intact thymocytes depends on expression of UCP-2. Proc Natl Acad Sci USA 2002,99:118-122
3. Tomlinson DR, Gardiner NJ. Glucose neurotoxicity. Nat Rev Neurosci 2008,9: 36-45
4. Lukovits TG, Mazzone TM, Gorelick TM, et al. Diabetesmellitus and cerebrovascular isease. Neuroep idemiology 1999,18(1):1-14
5. Maragos WF, Korde AS. Mitochondrial uncoupling as a potential therapeutic target in acute central nervous system injury. JNeurochem 2004,91:257-262
6. Arsenijevic D, Onuma H, Pecqueur C, et al. Disruption of the uncoupling protein-2 gene in mice reveals a role in immunity and reactive oxygen species production. Nat Genet 2000,26:435-439
7. Mattiasson G, Shamloo M, Gido G, Mathi K, et al. Uncoupling protein-2 prevents neuronal death and diminishes brain dysfunction after stroke and brain trauma. Nat Med 2003,9:1062-1068
8. Mattiasson G, Sullivan PG. The emerging functions of UCP-2 in health, disease, and therapeutics. Antioxid Redox Signal 2006,8:1-38
9. Sasahara M, Nishi M, Kawashima H, et al. Uncoupling protein 2 promoter polymorphism -866G/A affects its expression in beta-cells and modulates clinical profiles of Japanese type 2 diabetic patients. Diabetes 2004,53:482-485
10. Reis AF, Dubois-Laforgue D, Bellanne'-Chantelot C, et al. A polymorphism in the promoter of UCP-2 gene modulates lipid levels in patients with type 2 diabetes. Mol Genet Metab 2004,82:339-344
11. Sesti G, Cardellini M, Marini MA, et al. A common polymorphism in the promoter of UCP-2 contributes to the variation in insulin secretion in glucose-tolerant subjects. Diabetes 2003,52:1280-1283
12. Esterbauer H, Schneitler C, Oberkofler H, et al. A common polymorphism in the promoter of UCP-2 is associated withdecreased risk of obesity in middle-aged humans. Nat Genet 2001,28:178-183
13. Krempler F, Esterbauer H, Weitgasser R, et al. A functional polymorphism in the promoter of UCP-2 enhances obesity risk but reduces type 2 diabetes risk in obese middle-aged humans. Diabetes 2002,51:3331-3335
14. Wang H, Chu WS, Lu T, et al. Uncoupling protein-2 polymorphisms in type 2 diabetes, obesity, and insulin secretion. Am JPhysiol Endocrinol Metab 2004,86: E1-E7
15. Le Fur S, Le Stunff C, Dos Santos C, et al. The common-866 G/A polymorphism in the promoter of uncoupling protein 2 is associated with increased carbohydrate and decreased lipid oxidation in juvenile obesity. Diabetes 2004,53:235-239
16. Oberkofler H, Iglseder B, Klein K, et al. Associations of the UCP-2 gene locus with asymptomatic carotid atherosclerosis in middle-aged women. Arterioscler Thromb Vasc Biol 2005,25(3):604-610
17. Marre M, Lievre M, Chatellier G, et al. Effects of low dose ramipril on cardiovascular and renal outcomes in patients with type 2 diabetes and raised excretion of urinary albumin:randomized, double blind, placebo controlled trial (the DIABHYCAR study). BMJ 2004,328:495
18. Zee RY, Ridker PM, Chasman DI. Mitochondrial uncoupling protein gene cluster variation (UCP2-UCP3) and the risk of incident type 2 diabetes mellitus:The Women's Genome Health Study. Atherosclerosis 2010, Oct 20
19. Krempler F, Esterbauer H, Weitgasser R, et al. A functional polymorphism in the promoter of UCP-2 enhances obesity risk but reduces type 2 diabetes risk in obese middle-aged humans. Diabetes 2002,51:3331-3335
20. Wang H, Chu WS, Lu T, et al. Uncoupling protein-2 polymorphisms in type 2 diabetes, obesity, and insulin secretion. Am J Physiol Endocrinol Metab 2004,86: E1-E7
21. Beitelshees AL, Finck BN, Leone TC, et al. Interaction between the UCP-2-866 G>A polymorphism, diabetes, and beta-blocker use among patients with acute coronary syndromes. Pharmacogenet Genomics 2010,20(4):231-238
22. Heidari J, Akrami SM, Heshmat R, et al. Association study of the-866G/A UCP-2 gene promoter polymorphism with type 2 diabetes and obesity in a Tehran population:a case control study. Arch Iran Med 2010,13(5):384-390
23. Marre M, Lievre M, Chatellier G, et al. Effects of low dose ramipril on cardiovascular and renal outcomes in patients with type 2 diabetes and raised excretion of urinary albumin:randomized, double blind, placebo controlled trial (the DIABHYCAR study).BMJ 2004,328:495
24. Nadir Cheurfa, Danie'le, Dubois-Laforgue, et al. The Common -866G>A Variant in the Promoter of UCP-2 Is Associated With Decreased Risk of Coronary Artery Disease in Type 2 Diabetic Men. Diabetes 2008,8(57):1063-1068
1. Enerback S, Jacobsson A, Simpson EM,.et al. Mice lacking mitochondrial uncoupling protein are cold-sensitive but not obese. Nature 1997,387:90-94
2. Krauss S, Zhang C.Y., Lowell B.B. A significant portion of mitochondrial proton leak in intact thymocytes depends on expression of UCP-2. Proc Natl Acad Sci USA 2002,99:118-122
3. Tomlinson DR., Gardiner NJ. Glucose neurotoxicity. Nat Rev Neurosci 2008,9: 36-45
4. Lukovits TG, Mazzone TM, Gorelick TM, et al. Diabetesmellitus and cerebrovascular isease. Neuroepidemiology 1999,18 (1):1-14
5. Maragos WF, Korde AS. Mitochondrial uncoupling as a potential therapeutic target in acute central nervous system injury. JNeurochem 2004,91:257-262
6. Arsenijevic D, Onuma H, Pecqueur C, et al. Disruption of the uncoupling protein-2 gene in mice reveals a role in immunity and reactive oxygen species production. Nat Genet 2000,26:435-439
7. Mattiasson G, Shamloo M, Gido G, Mathi K. et al. Uncoupling protein-2 prevents neuronal death and diminishes brain dysfunction after stroke and brain trauma. Nat Med'2003,9:1062-1068
8. Mattiasson G, Sullivan PG. The emerging functions of UCP-2 in health, disease, and therapeutics. Antioxid Redox Signal 2006,8:1-38
9. Sasahara M, Nishi M, Kawashima H, et al. Uncoupling protein 2 promoter polymorphism-866G/A affects its expression in beta-cells and modulates clinical profiles of Japanese type 2 diabetic patients. Diabetes 2004,53:482-485
10. Reis AF, Dubois-Laforgue D, Bellanne'-Chantelot C, et al. A polymorphism in the promoter of UCP-2 gene modulates lipid levels in patients with type 2 diabetes. Mol Genet Metab 2004,82:339-344
11. Sesti G, Cardellini M, Marini MA, et al. A common polymorphism in the promoter of UCP-2 contributes to the variation in insulin secretion in glucose-tolerant subjects. Diabetes 2003,52:1280-1283
12. Esterbauer H, Schneitler C, Oberkofler H, et al. A common polymorphism in the promoter of UCP-2 is associated withdecreased risk of obesity in middle-aged humans. Nat Genet 2001,28:178-183
13. Krempler F, Esterbauer H, Weitgasser R, et al. A functional polymorphism in the promoter of UCP-2 enhances obesity risk but reduces type 2 diabetes risk in obese middle-aged humans. Diabetes 2002,51:3331-3335
14. Wang H, Chu WS, Lu T, et al. Uncoupling protein-2 polymorphisms in type 2 diabetes, obesity, and insulin secretion. Am JPhysiol Endocrinol Metab 2004,86: E1-E7
15. Le Fur S, Le Stunff C, Dos Santos C, et al. The common-866 G/A polymorphism in the promoter of uncoupling protein 2 is associated with increased carbohydrate and decreased lipid oxidation in juvenile obesity. Diabetes 2004,53:235-239
16. Oberkofler H, Iglseder B, Klein K, et al. Associations of the UCP-2 gene locus with asymptomatic carotid atherosclerosis in middle-aged women. Arterioscler Thromb Vasc Biol 2005,25(3):604-610
17. Marre M, Lievre M, Chatellier G, et al. Effects of low dose ramipril on cardiovascular and renal outcomes in patients with type 2 diabetes and raised excretion of urinary albumin:randomised, double blind, placebo controlled trial (the DIABHYCAR study).BMJ2004,328:495
18. Zee RY, Ridker PM, Chasman DI. Mitochondrial uncoupling protein gene cluster variation (UCP-2-UCP3) and the risk of incident type 2 diabetes mellitus:The Women's Genome Health Study. Atherosclerosis,2010, Oct 20
19. Krempler F, Esterbauer H, Weitgasser R, et al. A functional polymorphism in the promoter of UCP-2 enhances obesity risk but reduces type 2 diabetes risk in obese middle-aged humans. Diabetes 2002,51:3331-3335
20. Wang H, Chu WS, Lu T, et al. Uncoupling protein-2 polymorphisms in type 2 diabetes, obesity, and insulin secretion. Am J Physiol Endocrinol Metab 2004,86: E1-E7
21. Beitelshees AL, Finck BN, Leone TC, et al. Interaction between the UCP-2-866 G>A polymorphism, diabetes, and beta-blocker use among patients with acute coronary syndromes. Pharmacogenet Genomics 2010,20(4):231-238
22. Heidari J, Akrami SM, Heshmat R, et al. Association study of the -866G/A UCP-2 gene promoter polymorphism with type 2 diabetes and obesity in a Tehran population:a case control study. Arch Iran Med 2010,13(5):384-390
23. Marre M, Lievre M, Chatellier G, et al. Effects of low dose ramipril on cardiovascular and renal outcomes in patients with type 2 diabetes and raised excretion of urinary albumin:randomized, double blind, placebo controlled trial (the DIABHYCAR study). BMJ2004,328:495
24. Nadir Cheurfa, Daniele, Dubois-Laforgue, et al. The Common-866G>A Variant in the Promoter of UCP-2 Is Associated With Decreased Risk of Coronary Artery Disease in Type 2 Diabetic Men. Diabetes 2008,8(57):1063-1068
25. Frere C, Cuisset T, Morange PE. Effect of cytochrome p450 polymorphisms on platelet reactivity after treatment with clopidogrel in acute coronary syndrome. Am J Cardiol 2008,101:1088-1093
26. Gurbel PA, Bliden KP, Hiatt BL, et al. Clopidogrel for coronary stenting:response variability, drug resistance, and the effect of pretreatment platelet reactivily. Circulation 2003,107:2908-2913
27. Wenaweser P, Dorffler-Melly J, Imboden K, et al. Stent thrombosis is associated with an impaired response to anti-platelet therapy. J Coil Cardiol 2005,45: 1748-1752
1. Fleury C, Neverova M, Collins S, et al. Uncoup ling protein2:a novel gene linked to obesity and hyperinsulinemia. Nat Genet 1997,15 (3):269-272
2. Boss O, Samec S, Paoloni-Giacobino A, et al. Uncoupling protein23:a new member of the mitochondrial carrier family with tissue specific expression. FEBS Lett 1997,408 (1):39-42
3. Mao W, Yu XX, Zhong A, et al. UCP4, a novel brain2specific mitochondrial p rotein that reducesmembrane potential in mammalian cells. FEBS Lett 1999,443 (3):326-330
4. Sanchis D, Fleury C, Chomiki N, et al. BMCP1, a novel mitochondrial carrierwith high expression in the central nervous system of humans and rodents, and resp iration uncoup ling activity in recombinant yeast. J B iol Chem 1998, 273(51):34611-34615
5. Richard D, Rivest R, Huang Q, et al. Distribution of the uncoupling p rotein 2 mRNA in the mouse brain. J Comp Neurol 1998,397(4):549-560
6. Kim2Han J S, Reichert S A, Quick K L, et al. BMCP1:a mito2chondrial uncoup ling protein in neuronswhich regulatesmitochondrial function and oxidant p roduction[J].JN eurochem,2001,79(3):658-68.
7. Maclellan JD, Gerrits MF, Gowing A, et al. Physiological increases in uncoup ling p rotein 2 augment fatty acid oxidation and decrease reactive oxygen species production without uncoupling respiration in muscle cells. Diabetes 2005,54 (8): 2343-2350
8.魏翠凤,陈璐璐,王保平等。非诺贝特对高脂喂养的糖尿病大鼠骨骼肌UCP-3基因表达的影响。中国药理学通报2007,23(3)：399-402
9. Wei CF, Chen LL, Wang BP, et al. Effect of fenofibrate on the expression of uncoupling protein 3 gene in skeletal muscle of diabetic rats fed with high fat diet. Chin Pharm acol B ull 2007,23(3):399-402
10. Li L, Prabhakaran K, Zhang X, et al. PPARalpha mediated unregulation of uncoupling protein22 switches cyanide-induced apoptosis in primary cortical cells. Toxicol Sci 2006,93(1):136-145
11. Yamada S, Isojima Y, Yamatodani A, et al. Uncoupling protein influences dopamine secretion in PC12h cells. JNeurochem 2003,87(2):461-469
12. Chan SL, Liu D, Kvriazis GA, et al. Mitochondrial uncoupling protein2 regulates calcium homeostasis and sensitivity to store depletion-induced apop tosis in neural cells. J Biol Chem 2006,281(49):37391-37403
13. Liu SS. Cooperation of a"reactive oxygen cycle"with the Q cycle and the p roton cycle in the resp iratory chain2superoxide generating and cycling mechanisms in mitochondria. J Bioenerg Biomembr 1999,31(4):367-376
14. Andrews ZB, Horvath B, Barnstable CJ, et al. Uncoup ling p rotein-2 is critical for nigral dopamine cell survival in a mouse model of Parkinson's disease. J Neurosci 2005,25(1):184-191
15. Echtay KS, Roussel D, Stepierre J, et al. Superoxide activates mitochondrial uncoupling proteins. Nature 2002,415(6857):96-99
16. Echtay KS, Esteves TC, Pakay JL, et al. A signaling role for hydroxyl nonenal in regulation of mitochondrial uncoupling. EMBO J 2003,22(16):4103-4110
17. Krauss S, Zhang CY, Lowell BB. Themitochondrial uncoupling protein homologues. Nat Rev Mol Cell B iol 2005,6(3):248-261
18. Andrews ZB, Diano S, Horvath TL. Mitochondrial uncoupling proteins in the CNS:in support of function and survival. Nat Rev Neurosci 2005,6(11): 829-840
19. Diano S, Mattews RT, Patrylo P, et al. Uncoupling protein 2 prevents neuronal death including that occurring during seizures:a mechanism for p reconditioning. Endocrinology 2003,144(11):5014-5021
20. Sullivan PG, Rippy NA, Dorenbos K, et al. The ketogenic diet increases mitochondrial uncoupling protein levels and activity. Ann Neurol 2004,55(4): 576-580
21. Mattiasson G, Shamloo M, Gido G, et al. Uncoupling protein2 prevents neuronal death and diminishes brain dysfunction after stroke and brain trauma. Nature Med 2003,9(8):1062-1068
22. Sullivan PG, Springer JE, Hall ED, et al. Mitochondrial uncoupling as a therapeutic target following neuronal injury. J Bioenerg Biomembr 2004,36(4): 353-356
23. Blass JP. Brain metabolism and brain disease:is metabolic deficiency the proximate cause ofAlzheimer dementia?. JNeurosci Res 2001,66(5):851-856
24. Horvath TL, Diano S, Mivamoto S, et al. Uncoupling proteins2 and 3 influence obesity and inflammation in transgenic mice. Int J Obes Relat Metab Disord 2003,27(4):433-442
25. Fridell YW, Sanchez-Blanco A, Silvia BA, et al. Targeted expression of the human uncoupling protein 2 (hUCP-2) to adult neurons extends life span in the fly. Cell Metab 2005,1(2):145-152
26. Urhammer SA, Dalgaard LT, Sorensen TI, et al. Mutation analysis of the codingregion of the uncoupling protein2 gene inobese NIDDM patients:impact of a common amino acid polymorphism on jurenile and maturity onset forms of obesity and insulin resistance. Diabetologia 1997,40(10):1227-1230
27. Shiinoki T, Suehiro T, Ikeda Y, et al. Screening forvariants of the un coupling protein2 gene in Japanese patients with NIDDM. Metabolism 1999,48(5): 581-584
28. Yu X, Jacobs DRJ, Schreiner PJ, et al. The uncoupling protein Ala55Val polymorphismis associated with diabetes mellitus:the CARDIA study. Clin Chem 2005,51(8):1451-1456
29. Reis AF, Dubois-Laforgue D, Bellanne-Chantelot C, et al. A polymorphism in the promoter of UCP-2 gene modulates lipid levels in patients with type2 diabetes. Mol Genet Metab 2004,82(4):339-344
30. Vogler S, Goedde R, Miterski B, et al. Association of acommonpoly morphism in the promoter of UCP-2 with susceptibility to multiples clerosis. J Mol Med 2005,83(10):806-811
31. Kovacs P, Ma L, Hanson RL, et al. Genetic variation in UCP-2 (uncoupling protein-2) is associated with energymetabolism in Pima Indians. Diabetologia 2005,16(8):731-737
32. Maragos WF, Korde AS. Mitochondrial uncoupling as a potential therapeutic target in acute central nervous system injury. JNeurochem 2004,91:257-262
33. Arsenijevic D, Onuma H, Pecqueur C, et al. Disruption of the uncoupling protein-2 gene in mice reveals a role in immunity and reactive oxygen species production. Nat Genet 2000,26:435-439