血脂康对db/db糖尿病小鼠胰岛功能和形态的影响及机制研究
|
摘要
背景：
2型糖尿病(Type2Diabetes Mellitus, T2DM)及其并发症严重影响了人民的健康状况及生活质量,加重了社会负担。T2DM患者最终表现为胰岛p细胞分泌功能进行性衰竭,故胰岛和β细胞在糖尿病的发生发展过程中发挥着关键性的作用。高糖水平引起的氧化应激(Oxidative stress)是胰岛功能的损害机制之一,而氧化型烟酰胺腺嘌呤二核苷酸磷酸氧化酶(Nicotinamide adenine dinucleotide phosphate, NADPH, oxidase, NOX)是活性氧簇(Reactive oxygen species, ROS)的主要来源。因此抑制氧化应激对于改善胰岛功能具有关键性意义。近年来,有研究者提出“胰岛微环境”的概念,并认为“胰岛微环境”的局部调控是糖尿病发病机制中的中心环节。改善胰岛素微环境也可能成为糖尿病的治疗另一个方向。JUPITER研究显示他汀会增加病人患2型糖尿病的风险,使得他汀治疗的安全性问题再次成为医学界的热点研究方向。然而他汀治疗是否会影响葡萄糖代谢目前仍存在争议。血脂康是从红曲中提取的一种具有调节血脂作用的中药,被称为“天然他汀”。临床研究提示血脂康可能存在调节葡萄糖代谢的功效。目前还没有基础实验证实血脂康对葡萄糖代谢的影响。db/db小鼠是一种先天肥胖性T2DM小鼠模型,是研究T2DM的理想模型。本研究在国内首先使用db/db T2DM小鼠,体外实验,用离体胰岛灌流系统来评估血脂康干预后胰岛素第一时相分泌功能的变化；体内实验通过观察血脂康干预后小鼠代谢指标、葡萄糖代谢、胰岛微环境、胰岛超微结构的变化,并探索其对氧化应激反应的作用靶点和机制,此外还分析其对胰岛p细胞葡萄糖感受器信号通路的影响。
目的：
本研究拟通过db/db2型DM小鼠模型,
1、观察血脂康对db/db小鼠的体重和甘油三酯、总胆固醇、低密度脂蛋白胆固醇、空腹血糖、空腹胰岛素的血清水平等代谢参数的影响。
2、观察血脂康对db/db小鼠的葡萄糖耐量、胰岛分泌功能的影响
3、观察血脂康对db/db小鼠的胰岛β细胞含量、胰岛微环境与超微结构的损伤修复功能。
4、观察血脂康对db/db小鼠的葡萄糖感受器基因和蛋白水平表达的影响。
5、观察血脂康对db/db小鼠的氧化应激反应的抑制作用。
方法：
40只8周龄清洁级雄性db/db小鼠,体重约34-42克,随机分为两组,每组20只,分别给予8周的血脂康300mg/kg/d(血脂康组)和安慰剂(5%阿拉伯胶,db/db对照组)。20只同周龄同窝出生的db/m小鼠为非DM对照(db/m对照组)。投药前和8周后测定生理生化指标,投药8周后行腹腔葡萄糖耐量试验。投药8周后行胰岛分离后,用离体胰岛灌流系统进行胰岛灌流,检测胰岛素分泌动力学的改变。免疫组织化学标记并用Image-Pro Plus5.01定量分析胰岛β细胞含量、胰岛微环境与超微结构的变化。免疫组织化学标记并用Image-Pro Plus5.01半定量分析8-OHdG、4-HNE和gp91phox的组织表达水平变化。应用荧光实时定量PCR(qRT-PCR)检测葡萄糖转运子2(GLUT-2)、葡萄糖激酶(GCK)的mRNA水平的表达变化,并结合Western blot检测上述蛋白水平的表达变化。各组间比较采用单因素方差分析,组间两两比较采用LSD检验,投药前后的资料比较用配对t检验。
结果：
1、基线水平时,血脂康组和db/db对照组的体重、血脂、血糖均无明显差异。在8周龄,db/db小鼠的空腹血糖均已超过15mmol/L。血脂康组在治疗8周后开始出现血糖逐渐下降,8周末时空腹血糖(FBG),空腹胰岛素水平(FSI)显著低于db/db对照组(P<0.05)。8周末时,血脂康组总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白(LDL-C)、甘油三酯(TG)明显低于db/db对照组(P<0.05)。此外,与db/db对照组小鼠相比较,体重(BW)在血脂康组小鼠的体重增加程度减弱(P<0.05)。
2、投药8周后,糖负荷后120分钟,血脂康组的血糖显著降低(P<0.05),葡萄糖曲线下面积低于db/db对照组(P<0.05),同时在30分钟时血浆胰岛素水平升高,且AUCINSO-30高于db/db对照组,提示血脂康能改善糖耐量及早期相胰岛素分泌。
3、与db/db对照组比较,血脂康组在低糖灌流时胰岛素分泌无明显升高,而给予高糖刺激1分钟后胰岛素分泌明显升高(P<0.05),提示血脂康组胰岛第一时相分泌得到改善,尽管低于db/m组。
4、免疫组化组织染色结合半定量分析表明db/db对照组的胰岛β细胞数量、质量显著减低,血脂康治疗8周后胰岛p细胞数量、质量较db/db对照组明显增加(P<0.05)。
5、免疫组化组织染色结合半定量分析显示与db/m对照组小鼠相比,db/db对照组的胰岛血管内皮细胞标志物CD31明显减少,且超微结构下线粒体、内质网、线粒体形态损伤明显,而治疗后血脂康组的db/db小鼠,相比较于db/db对照组,CD31减少和内质网、线粒体形态损伤趋势明显缓解。
6、与db/m对照组相比,db/db对照组GLUT-2、GCK的mRNA和蛋白水平表达明显下降,而血脂康组GCK和GLUT-2的mRNA和蛋白水平表达都升高(P<0.01)。
7、血脂康治疗前,db/db对照组的氧化应激标志物8-OHdG和4-HNE蛋白水平表达较db/m对照组小鼠明显升高,而且NOX的活性亚基gp91phox的mRNA和蛋白水平表达都升高,投药8周后,血脂康组8-OHdG和4-HNE蛋白水平表达下降,gp91phox蛋白水平表达亦下降(P<0.01)。
结论：
1、血脂康在降低db/db T2DM小鼠血脂、体重等代谢指标的同时,可以降低血糖,改善葡萄糖耐量。
2、血脂康通过改善db/db T2DM小鼠胰岛p细胞第一时相分泌功能来降低血糖水平及维持β细胞功能。
3、血脂康通过提高db/db T2DM小鼠的p细胞含量,增加血管内皮细胞密度,修复超微结构的损伤,来保护胰岛微环境从而达到降血糖及改善β细胞功能衰竭。
4、血脂康通过上调GLU-2、GCK的表达,影响葡萄糖感受器的作用,降低胰岛素抵抗,恢复葡萄糖诱导的胰岛素分泌,降低血糖。
5、血脂康通过抑制NOX来抵御氧化应激造成的胰岛p细胞损害,从而改善胰岛分泌功能和形态改变。
BACKGROUND:
Type2Diabetes Mellitus (T2DM) and its complications severely influence the human's healthy status and life quality as well as increase the social burden. One of the final manifestations in T2DM is the progressive secretory dysfunction of pancreatic islet and β-cell, which play the crucial role in the pathogenesis and development of T2DM. Meanwhile, the hyperglycemia-induced oxidative stress is one of the mechanisms involved in the injury of islet function. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) is the major source of reactive oxygen species. So the inhibition of oxidative stress is essential for the conservation of islet function. Recently, the concept of "Islet microenvironment" was proposed by some researchers, who regarded that the local regulation of islet microenvironment was the central point of the T2DM pathogenesis. The improvement of islet microenvironment would be another promising therapeutical target of diabetes. The increasing incidence of diabetes associated with statin has raised concerns about the effect of statins on glucose metabolism. To date, it remains questionable whether statin treatment has a detrimental or favorable effect on diabetes. Xuezhikang, purified from red yeast rice, is a traditional Chinese medicine with the major potency, lipid-lowering. Described as the "natural statin", xuezhikang was proved to have potential benefits on glucose metabolism by the clinical trials. So far, there has not been basic research involved in the effect of xuezhikang on glucose metabolism. The db/db mouse is a genetically obese mouse model of T2DM, and has been adopted as the ideal T2DM model for experimental study. In our study, the db/db mice were subjected to the xuezhikang intake for eight weeks. In vitro, the islet perifusion system was used to evaluate the first-phase insulin secretory function of β cells after xuezhikang treatment, which has not been investigated yet. In vivo, we measured the metabolic parameters and observed the change of glucose metabolism, islet microenviroment, untrastructure and so on. In addition, the glucose-sensing apparatus was analyzed for the attempt to investigate whether xuezhikang could modulate the glucose-sensing signal pathway of β-cell in db/db mice. We moved a forward step to explore the possible target and underlying mechanism of xuezhikang in the oxidative stress reaction.
OBJECTIVES:
Through the db/db T2DM mouse model, the present study aims to:
1. To assess the influence of xuezhikang on metabolism profile including TC, LDL-C, TG, FBG, and FSI in serum.
2. To observe the impact of xuezhikang on the glucose tolerance and islet endocrine function.
3. To investigate the protection of xuezhikang against the injury in the context of pancreatic β-cell content, microenvironment and ultrastructure.
4. To evaluate the role of xuezhikang in regulating the expression of glucose-sensing apparatus in mRNA and protein level.
5. To explore the bioactivity of xuezhikang in the inhibition of oxidative stress.
METHODS:
A total of40male genetically diabetic C57BL/KsJ-db/db mice, weighing 34-42g, were randomly assigned into two groups (n=20per group).These animals were treated with xuezhikang at300mg/kg/d (xuezhikang group) or placebo (placebo group) for8weeks. In addition, another20aged-matched lean non-diabetic C57BL/KsJ-db/m littermates served as a wild-type control (non-diabetic control, n=20).
During8-week treatment, the physiological and metabolic parameters (BW, TC, LDL-C, TG, FBG and FSI) were measured every week. After8-week treatment,10mice were randomly selected from each group and received intraperitoneal glucose tolerance test (IPGTT). The concentration of glucose and insulin were determined in the blood samples collected at different time points:0,30,60,120min. At the end of experiment, the in vitro insulin release kinetics was studied with the perifusion system.
Meanwhile, animals were anesthetized with sodium phenobarbital prior to pancreatectomy. We applied the semi-quantitative analysis to assess the content of β-cell with Image-Pro Plus5.0.1after immunohistochemistry for insulin. The similar method was used for the detection of CD31expression surrounding the β-cell. The pancreas tissues were cut into small pieces with razor blades, which were examined on a electron microscope in order to observe the ultrastructure of organelles in the β-cell. In addition, the expression level of glucose-sensing apparatus, GLUT-2, GCK was measured in mRNA level by qRT-PCR and in protein level by western blot.
On the other hand, with respect to immunohistochemistrical analysis, ABC method was employed for the detection of insulin, gp91phox,8-hydroxy-20-deoxyguanosine (8-OHdG),4-hydroxynonenal modified protein (4-HNE).
All values were expressed as mean±standard deviation. Means among groups were compared with one way analysis of variance, and those between two groups were compared with LSD test. Data before and after experiment were compared with paired test.
RESULTS:
1. At baseline, there were no marked differences in the BW, FBG, FSI, TC, LDL-C and TG between xuezhikang group and placebo group. However, all of these values were lower in db/m group than those of two db/db groups. In particular, the db/db mice aged8weeks had the FBG of>15mmol/L. After treatment with xuezhikang, the development of hyperglycemia was alleviated, and FBG and FSI at the terminal stage of treatment in the db/db mice was markedly lower than that in the placebo-treated db/db mice (P<0.05), although there is no difference between before and after xuezhikang treatment. Likewise, TC, LDL-C and TG in the xuezhikang group were markedly reduced as compared to the db/db control (P<0.05). Besides, the8-week of xuezhikang intake blunted weight gain in db/db mice (P<0.05).
2. During the120-minute glucose tolerance test, the blood glucose level after glucose loading in the xuezhikang group was lower than that of placebo group (P<0.05), which was standardized to that of non-diabetic group. Moreover, insulin secretion stimulated by glucose loading in the xuezhikang group was higher than that of db/db control. The AUCINS0-30in the xuezhikang-treated mice at30minutes after the test was higher than that of the placebo-treated db/db mice (P<0.05). The experiments involving the islets perifusion in vitro revealed that in contrast to the db/db control, the insulin secretion derived from isolated islets was not noticeably raised in xuezhikang group pretreated with a low-concentration glucose solution (2.8mM). However, it was moderately increased at1minute after perfusion with the high-concentration glucose solution (16.7mM)(P<0.05).
3. The less intense dark brown staining, which implied the reduced amount of P-cells, could be observed in islets from db/db control mice compared to db/m mice. Xuezhikang therapy seemed to decline the trend of β-cell reduction (P<0.05). Similarly, the favorable effect of xuezhikang treatment was presented again by the restored β-cell mass (P<0.05). As an endothelial cell marker, the CD31expression was depleted in db/db diabetic animals. Interestingly, the staining intensity of CD31was higher in xuezhikang group than in placebo group. On the other hand, the alleviated mitochondria swelling and the increased proportion of intact mitochondria were achieved in xuezhikang-treated mice vs. the placebo-treated counterpart.
4. We measured the mRNA and protein levels of GLUT-2and GCK in an attempt to determine a possible impact of xuezhikang on glucose sensing. The result of qRT-PCR showed the reduced mRNA level of GLUT-2and GCK in db/db mice compared with db/m mice. Western blotting revealed decreased levels of both GLUT-2and GCK in db/db mice compared with db/m mice. The final analysis further validated that the expression of GLUT-2and GCK ascended relatively, both in mRNA and protein level, in xuezhikang group as opposed to placebo group (P<0.01).
5. The percentage of β-cells expressing8-OHdG and4-HNE was higher in db/db mice than in db/m mice (P<0.05). Xuezhikang significantly reduced the expression levels of these two markers to the normal level. Furthermore, we studied the expression levels of gp91phox, which is one of the major components of NADPH oxidase. Semiquantitative analysis revealed that the uptake of xuezhikang cut down the expression of gp91phox almost to the extent of wild-type control, lower than that of db/db control (P<0.01).
CONCLUSIONS:
1. Xuezhikang not only reduced the blood lipids, but also alleviated blood high glucose, improved the glucose tolerance and elevated the serum insulin concentration of db/db mice.
2. Xuezhikang could alleviate blood high glucose and protect the function of β cells by improving first phase insulin secretion.
3. Xuezhikang-treatment alleviated blood high glucose and protected the function of β cells db/db mice by the conservation of islet microenvironment and the increment of β cell content.
4. Xuezhikang increased the expressions of glucose-sensing apparatus, GLUT-2&GCK, in both mRNA and protein level. It implied that xuezhikang would possibly serve as the mediator in the pathway of insulin resistance.
5. Xuezhikang reduced the expression of reactive oxygen species and inhibited one of the active subunits of nicotinamide adenine dinucleotide phosphate oxidase. Xuezhikang could exert the protection against oxidative stress.
2型糖尿病(Type2Diabetes Mellitus, T2DM)及其并发症严重影响了人民的健康状况及生活质量,加重了社会负担。T2DM患者最终表现为胰岛p细胞分泌功能进行性衰竭,故胰岛和β细胞在糖尿病的发生发展过程中发挥着关键性的作用。高糖水平引起的氧化应激(Oxidative stress)是胰岛功能的损害机制之一,而氧化型烟酰胺腺嘌呤二核苷酸磷酸氧化酶(Nicotinamide adenine dinucleotide phosphate, NADPH, oxidase, NOX)是活性氧簇(Reactive oxygen species, ROS)的主要来源。因此抑制氧化应激对于改善胰岛功能具有关键性意义。近年来,有研究者提出“胰岛微环境”的概念,并认为“胰岛微环境”的局部调控是糖尿病发病机制中的中心环节。改善胰岛素微环境也可能成为糖尿病的治疗另一个方向。JUPITER研究显示他汀会增加病人患2型糖尿病的风险,使得他汀治疗的安全性问题再次成为医学界的热点研究方向。然而他汀治疗是否会影响葡萄糖代谢目前仍存在争议。血脂康是从红曲中提取的一种具有调节血脂作用的中药,被称为“天然他汀”。临床研究提示血脂康可能存在调节葡萄糖代谢的功效。目前还没有基础实验证实血脂康对葡萄糖代谢的影响。db/db小鼠是一种先天肥胖性T2DM小鼠模型,是研究T2DM的理想模型。本研究在国内首先使用db/db T2DM小鼠,体外实验,用离体胰岛灌流系统来评估血脂康干预后胰岛素第一时相分泌功能的变化；体内实验通过观察血脂康干预后小鼠代谢指标、葡萄糖代谢、胰岛微环境、胰岛超微结构的变化,并探索其对氧化应激反应的作用靶点和机制,此外还分析其对胰岛p细胞葡萄糖感受器信号通路的影响。
目的：
本研究拟通过db/db2型DM小鼠模型,
1、观察血脂康对db/db小鼠的体重和甘油三酯、总胆固醇、低密度脂蛋白胆固醇、空腹血糖、空腹胰岛素的血清水平等代谢参数的影响。
2、观察血脂康对db/db小鼠的葡萄糖耐量、胰岛分泌功能的影响
3、观察血脂康对db/db小鼠的胰岛β细胞含量、胰岛微环境与超微结构的损伤修复功能。
4、观察血脂康对db/db小鼠的葡萄糖感受器基因和蛋白水平表达的影响。
5、观察血脂康对db/db小鼠的氧化应激反应的抑制作用。
方法：
40只8周龄清洁级雄性db/db小鼠,体重约34-42克,随机分为两组,每组20只,分别给予8周的血脂康300mg/kg/d(血脂康组)和安慰剂(5%阿拉伯胶,db/db对照组)。20只同周龄同窝出生的db/m小鼠为非DM对照(db/m对照组)。投药前和8周后测定生理生化指标,投药8周后行腹腔葡萄糖耐量试验。投药8周后行胰岛分离后,用离体胰岛灌流系统进行胰岛灌流,检测胰岛素分泌动力学的改变。免疫组织化学标记并用Image-Pro Plus5.01定量分析胰岛β细胞含量、胰岛微环境与超微结构的变化。免疫组织化学标记并用Image-Pro Plus5.01半定量分析8-OHdG、4-HNE和gp91phox的组织表达水平变化。应用荧光实时定量PCR(qRT-PCR)检测葡萄糖转运子2(GLUT-2)、葡萄糖激酶(GCK)的mRNA水平的表达变化,并结合Western blot检测上述蛋白水平的表达变化。各组间比较采用单因素方差分析,组间两两比较采用LSD检验,投药前后的资料比较用配对t检验。
结果：
1、基线水平时,血脂康组和db/db对照组的体重、血脂、血糖均无明显差异。在8周龄,db/db小鼠的空腹血糖均已超过15mmol/L。血脂康组在治疗8周后开始出现血糖逐渐下降,8周末时空腹血糖(FBG),空腹胰岛素水平(FSI)显著低于db/db对照组(P<0.05)。8周末时,血脂康组总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白(LDL-C)、甘油三酯(TG)明显低于db/db对照组(P<0.05)。此外,与db/db对照组小鼠相比较,体重(BW)在血脂康组小鼠的体重增加程度减弱(P<0.05)。
2、投药8周后,糖负荷后120分钟,血脂康组的血糖显著降低(P<0.05),葡萄糖曲线下面积低于db/db对照组(P<0.05),同时在30分钟时血浆胰岛素水平升高,且AUCINSO-30高于db/db对照组,提示血脂康能改善糖耐量及早期相胰岛素分泌。
3、与db/db对照组比较,血脂康组在低糖灌流时胰岛素分泌无明显升高,而给予高糖刺激1分钟后胰岛素分泌明显升高(P<0.05),提示血脂康组胰岛第一时相分泌得到改善,尽管低于db/m组。
4、免疫组化组织染色结合半定量分析表明db/db对照组的胰岛β细胞数量、质量显著减低,血脂康治疗8周后胰岛p细胞数量、质量较db/db对照组明显增加(P<0.05)。
5、免疫组化组织染色结合半定量分析显示与db/m对照组小鼠相比,db/db对照组的胰岛血管内皮细胞标志物CD31明显减少,且超微结构下线粒体、内质网、线粒体形态损伤明显,而治疗后血脂康组的db/db小鼠,相比较于db/db对照组,CD31减少和内质网、线粒体形态损伤趋势明显缓解。
6、与db/m对照组相比,db/db对照组GLUT-2、GCK的mRNA和蛋白水平表达明显下降,而血脂康组GCK和GLUT-2的mRNA和蛋白水平表达都升高(P<0.01)。
7、血脂康治疗前,db/db对照组的氧化应激标志物8-OHdG和4-HNE蛋白水平表达较db/m对照组小鼠明显升高,而且NOX的活性亚基gp91phox的mRNA和蛋白水平表达都升高,投药8周后,血脂康组8-OHdG和4-HNE蛋白水平表达下降,gp91phox蛋白水平表达亦下降(P<0.01)。
结论：
1、血脂康在降低db/db T2DM小鼠血脂、体重等代谢指标的同时,可以降低血糖,改善葡萄糖耐量。
2、血脂康通过改善db/db T2DM小鼠胰岛p细胞第一时相分泌功能来降低血糖水平及维持β细胞功能。
3、血脂康通过提高db/db T2DM小鼠的p细胞含量,增加血管内皮细胞密度,修复超微结构的损伤,来保护胰岛微环境从而达到降血糖及改善β细胞功能衰竭。
4、血脂康通过上调GLU-2、GCK的表达,影响葡萄糖感受器的作用,降低胰岛素抵抗,恢复葡萄糖诱导的胰岛素分泌,降低血糖。
5、血脂康通过抑制NOX来抵御氧化应激造成的胰岛p细胞损害,从而改善胰岛分泌功能和形态改变。
BACKGROUND:
Type2Diabetes Mellitus (T2DM) and its complications severely influence the human's healthy status and life quality as well as increase the social burden. One of the final manifestations in T2DM is the progressive secretory dysfunction of pancreatic islet and β-cell, which play the crucial role in the pathogenesis and development of T2DM. Meanwhile, the hyperglycemia-induced oxidative stress is one of the mechanisms involved in the injury of islet function. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) is the major source of reactive oxygen species. So the inhibition of oxidative stress is essential for the conservation of islet function. Recently, the concept of "Islet microenvironment" was proposed by some researchers, who regarded that the local regulation of islet microenvironment was the central point of the T2DM pathogenesis. The improvement of islet microenvironment would be another promising therapeutical target of diabetes. The increasing incidence of diabetes associated with statin has raised concerns about the effect of statins on glucose metabolism. To date, it remains questionable whether statin treatment has a detrimental or favorable effect on diabetes. Xuezhikang, purified from red yeast rice, is a traditional Chinese medicine with the major potency, lipid-lowering. Described as the "natural statin", xuezhikang was proved to have potential benefits on glucose metabolism by the clinical trials. So far, there has not been basic research involved in the effect of xuezhikang on glucose metabolism. The db/db mouse is a genetically obese mouse model of T2DM, and has been adopted as the ideal T2DM model for experimental study. In our study, the db/db mice were subjected to the xuezhikang intake for eight weeks. In vitro, the islet perifusion system was used to evaluate the first-phase insulin secretory function of β cells after xuezhikang treatment, which has not been investigated yet. In vivo, we measured the metabolic parameters and observed the change of glucose metabolism, islet microenviroment, untrastructure and so on. In addition, the glucose-sensing apparatus was analyzed for the attempt to investigate whether xuezhikang could modulate the glucose-sensing signal pathway of β-cell in db/db mice. We moved a forward step to explore the possible target and underlying mechanism of xuezhikang in the oxidative stress reaction.
OBJECTIVES:
Through the db/db T2DM mouse model, the present study aims to:
1. To assess the influence of xuezhikang on metabolism profile including TC, LDL-C, TG, FBG, and FSI in serum.
2. To observe the impact of xuezhikang on the glucose tolerance and islet endocrine function.
3. To investigate the protection of xuezhikang against the injury in the context of pancreatic β-cell content, microenvironment and ultrastructure.
4. To evaluate the role of xuezhikang in regulating the expression of glucose-sensing apparatus in mRNA and protein level.
5. To explore the bioactivity of xuezhikang in the inhibition of oxidative stress.
METHODS:
A total of40male genetically diabetic C57BL/KsJ-db/db mice, weighing 34-42g, were randomly assigned into two groups (n=20per group).These animals were treated with xuezhikang at300mg/kg/d (xuezhikang group) or placebo (placebo group) for8weeks. In addition, another20aged-matched lean non-diabetic C57BL/KsJ-db/m littermates served as a wild-type control (non-diabetic control, n=20).
During8-week treatment, the physiological and metabolic parameters (BW, TC, LDL-C, TG, FBG and FSI) were measured every week. After8-week treatment,10mice were randomly selected from each group and received intraperitoneal glucose tolerance test (IPGTT). The concentration of glucose and insulin were determined in the blood samples collected at different time points:0,30,60,120min. At the end of experiment, the in vitro insulin release kinetics was studied with the perifusion system.
Meanwhile, animals were anesthetized with sodium phenobarbital prior to pancreatectomy. We applied the semi-quantitative analysis to assess the content of β-cell with Image-Pro Plus5.0.1after immunohistochemistry for insulin. The similar method was used for the detection of CD31expression surrounding the β-cell. The pancreas tissues were cut into small pieces with razor blades, which were examined on a electron microscope in order to observe the ultrastructure of organelles in the β-cell. In addition, the expression level of glucose-sensing apparatus, GLUT-2, GCK was measured in mRNA level by qRT-PCR and in protein level by western blot.
On the other hand, with respect to immunohistochemistrical analysis, ABC method was employed for the detection of insulin, gp91phox,8-hydroxy-20-deoxyguanosine (8-OHdG),4-hydroxynonenal modified protein (4-HNE).
All values were expressed as mean±standard deviation. Means among groups were compared with one way analysis of variance, and those between two groups were compared with LSD test. Data before and after experiment were compared with paired test.
RESULTS:
1. At baseline, there were no marked differences in the BW, FBG, FSI, TC, LDL-C and TG between xuezhikang group and placebo group. However, all of these values were lower in db/m group than those of two db/db groups. In particular, the db/db mice aged8weeks had the FBG of>15mmol/L. After treatment with xuezhikang, the development of hyperglycemia was alleviated, and FBG and FSI at the terminal stage of treatment in the db/db mice was markedly lower than that in the placebo-treated db/db mice (P<0.05), although there is no difference between before and after xuezhikang treatment. Likewise, TC, LDL-C and TG in the xuezhikang group were markedly reduced as compared to the db/db control (P<0.05). Besides, the8-week of xuezhikang intake blunted weight gain in db/db mice (P<0.05).
2. During the120-minute glucose tolerance test, the blood glucose level after glucose loading in the xuezhikang group was lower than that of placebo group (P<0.05), which was standardized to that of non-diabetic group. Moreover, insulin secretion stimulated by glucose loading in the xuezhikang group was higher than that of db/db control. The AUCINS0-30in the xuezhikang-treated mice at30minutes after the test was higher than that of the placebo-treated db/db mice (P<0.05). The experiments involving the islets perifusion in vitro revealed that in contrast to the db/db control, the insulin secretion derived from isolated islets was not noticeably raised in xuezhikang group pretreated with a low-concentration glucose solution (2.8mM). However, it was moderately increased at1minute after perfusion with the high-concentration glucose solution (16.7mM)(P<0.05).
3. The less intense dark brown staining, which implied the reduced amount of P-cells, could be observed in islets from db/db control mice compared to db/m mice. Xuezhikang therapy seemed to decline the trend of β-cell reduction (P<0.05). Similarly, the favorable effect of xuezhikang treatment was presented again by the restored β-cell mass (P<0.05). As an endothelial cell marker, the CD31expression was depleted in db/db diabetic animals. Interestingly, the staining intensity of CD31was higher in xuezhikang group than in placebo group. On the other hand, the alleviated mitochondria swelling and the increased proportion of intact mitochondria were achieved in xuezhikang-treated mice vs. the placebo-treated counterpart.
4. We measured the mRNA and protein levels of GLUT-2and GCK in an attempt to determine a possible impact of xuezhikang on glucose sensing. The result of qRT-PCR showed the reduced mRNA level of GLUT-2and GCK in db/db mice compared with db/m mice. Western blotting revealed decreased levels of both GLUT-2and GCK in db/db mice compared with db/m mice. The final analysis further validated that the expression of GLUT-2and GCK ascended relatively, both in mRNA and protein level, in xuezhikang group as opposed to placebo group (P<0.01).
5. The percentage of β-cells expressing8-OHdG and4-HNE was higher in db/db mice than in db/m mice (P<0.05). Xuezhikang significantly reduced the expression levels of these two markers to the normal level. Furthermore, we studied the expression levels of gp91phox, which is one of the major components of NADPH oxidase. Semiquantitative analysis revealed that the uptake of xuezhikang cut down the expression of gp91phox almost to the extent of wild-type control, lower than that of db/db control (P<0.01).
CONCLUSIONS:
1. Xuezhikang not only reduced the blood lipids, but also alleviated blood high glucose, improved the glucose tolerance and elevated the serum insulin concentration of db/db mice.
2. Xuezhikang could alleviate blood high glucose and protect the function of β cells by improving first phase insulin secretion.
3. Xuezhikang-treatment alleviated blood high glucose and protected the function of β cells db/db mice by the conservation of islet microenvironment and the increment of β cell content.
4. Xuezhikang increased the expressions of glucose-sensing apparatus, GLUT-2&GCK, in both mRNA and protein level. It implied that xuezhikang would possibly serve as the mediator in the pathway of insulin resistance.
5. Xuezhikang reduced the expression of reactive oxygen species and inhibited one of the active subunits of nicotinamide adenine dinucleotide phosphate oxidase. Xuezhikang could exert the protection against oxidative stress.
引文
[1]Wenying Yang, Juming Lu, Jianping Weng, et al. Prevalence of Diabetes among Men and Women in China.N Engl J Med 2010;362:1090-101.
[2]吕树铮.糖尿病合并冠心病流行病学现状研究进展.中华老年心脑血管病杂志,2009；12：910-911.
[3]唐振娟.糖尿病合并冠状动脉粥样硬化性心脏病治疗研究进展.医学综述,2009；15：892-893.
[4]黄元铸.糖尿病合并冠心病研究进展.实用老年医学,2007；21：292-293.
[5]Porte D, Jr. & Kahn SE. Beta-cell dysfunction and failure in type 2 dia betes:potential mechanisms. Diabetes,2001,:S160-163.
[6]Prentki M & Nolan CJ. Islet beta cell failure in type 2 diabetes. The Jo urnal of clinical investigation,2006,116(7):1802-1812.
[7]McGarry JD. Banting lecture 2001:dysregulation of fatty acid metabolism in the etiology of type 2 diabetes. Diabetes.2002 Jan;51(1):7-18.
[8]Lingohr MK, Buettner R, & Rhodes CJ. Pancreatic beta-cell growth and survival--a role in obesity-linked type 2 diabetes? Trends in molecular medici ne,2002,8(8):375-384.
[9]Lupi R, et al. Prolonged exposure to free fatty acids has cytostatic and pro-apoptotic effects on human pancreatic islets:evidence that beta-cell death is caspase mediated, partially dependent on ceramide pathway, and Bcl-2 re gulated. Diabetes,2002,51(5):1437-1442.
[10]Fariss MW, Chan CB, Patel M, Van Houten B, & Orrenius S. Role of mitochondria in toxic oxidative stress. Molecular interventions,2005,5(2):94-111.
[11]Wang H, Kouri G, & Wollheim CB. ER stress and SREBP-1 activation are implicated in beta-cell glucolipotoxicity. Journal of cell science 118(Pt 1 7):3905-3915.
[12]Veret J, et al. Ceramide synthase 4 and de novo production of ceramide s with specific N-acyl chain lengths are involved in glucolipotoxicity-induced apoptosis of INS-1 beta-cells. The Biochemical journal,2011,438(1):177-18 9.
[13]Lin CY, Gurlo T, Haataja L, Hsueh WA, & Butler PC. Activation of p eroxisome proliferator-activated receptor-gamma by rosiglitazone protects hum an islet cells against human islet amyloid polypeptide toxicity by a phosphati dylinositol 3'-kinase-dependent pathway. The Journal of clinical endocrinology and metabolism,2005,90(12):6678-6686.
[14]Elsner M, Gehrmann W, & Lenzen S. Peroxisome-generated hydrogen p eroxide as important mediator of lipotoxicity in insulin-producing cells. Diabe tes,2011,60(1):200-208.
[15]Alquier T, et al. Deletion of GPR40 impairs glucose-induced insulin sec retion in vivo in mice without affecting intracellular fuel metabolism in islets. Diabetes,2009,58(11):2607-2615.
[16]Wu J, et al. Inhibition of GPR40 protects MIN6 beta-cells from palmita te-induced ER stress and apoptosis. Journal of cellular biochemistry.2012, Apr;113(4):1152-1158.
[17]Preiss D,Seshasai SR,Welsh P,et al.Risk of incident diabetes with intensi ve-dose compared with moderate-dose statin therapy:a meta-analysis.JAMA,20 11;305:2556-25564.
[18]Simsek S,Schalkwijk CG,Wolffenbuttel BH.Effects of rosuvastatin and atorvastatin on glycaemic control in type 2diabetes-the CORALL study.Diab Med,2011;29:628-631.
[19]叶平.血脂康胶囊有效减少老年冠心病患者心血管事件及死亡率[J].中国心血管病研究,2008,6(1)：1-2.
[20]吴秋英,柯明远,陈弼沧,等.血脂康治疗2型糖尿病38例临床研究[J].中国实用内科杂志,2005,25(12)：1118-1119.
[21]韩英等.血脂康治疗2型糖尿病血脂异常患者55例[J].广东药学院学报2 004,20(5)：558-559
[22]王彩玲,李曙远,张伟.血脂康对2型糖尿病人胰岛素敏感性的影响[J]中国糖尿病杂志,2001,9(3)：171-173.
[23]Zhao SP, Lu ZL, Du BM, et al. Xuezhikang, an extract of cholest in, reduces cardiovascular events in type 2 diabetes patients with coronary he art disease:subgroup analysis of patients with type 2 diabetes from China co ronary secondary prevention study (CCSPS) [J]. J Cardiov Pharm,2007,49 (2):81-84.
[24]Zhao SP, Liu L, Cheng YC, Shishehbor MH, Liu MH, Peng DQ, Li YL. Xuezhikang, an extract of cholestin, protects endothelial function through anti inflammatory and lipid-lowering mechanisms in patients with coronary heart disease. Circulation.2004;110:915-920.
[25]Li JJ, Hu SS, Fang CH, Hui RT, Miao LF, Yang YJ, Gao RL. Effects of xuezhikang, an extract of cholestin, on lipid profile and C-reactive protein: a short-term time course study in patients with stable angina. Clin Chim Act a.2005;352:217-224.
[26]Zhai WJ, Li AQ. Effect of Xuezhikang on the serum highsensitivity C-reactive protein and blood lipid in patients with type 2 diabetes mellitus an d hyperlipidemia [J]. Acta Acad Med Xuzhou,2010,30(2):102-103.
[27]Yao W, Zhang XL, Wang FZ. Effect of Xuezhikang on expressions of P-selectin, soluble intercellular adhesion molecule-1 and matrix metalloprotein ase-9 of patients with acute coronary artery syndrome [J]. Chin J Cardiol,200 6,34(1):1004.
[28]Pen Y, Zhao S, Liu J. Effect of Xuezhikang on expressions of inflamm atory factors and functions of the blood vessel endothelium[J]. Acta Acad M ed Milit Tertiae,2009,31(7):636-638.
[29]Xu GZ. Effect of amlodipine combined with Xuezhikang Capsule on tre atment of hypertension[J]. Chin Pharm,2008,11(2):219-220.
[30]Li H. Effects of valsartan and valsartan/HCTZ combined with Xuezhik ang in treating mild to moderate hypertensive patients[J]. Pract J Cardiac Cer ebr Pneumal Vascul Dis,2008,16(12):12-13.
[31]Zhu ZT, Wang J, Hou B, et al. The effect of Xuezhikang and antih ypertensive therapy on the ambulatory blood pressure and the smoothness ind ex[J]. Chin J Hypertens,2008,16(6):558-559.
[32]Lin J, Li JL. Effect of lovastatin on brachial endotheliumdependent va sodilation in patients with hypercholesterolemia [J]. Pract Prev Med,2006, 13(3):729-730.
[33]Wei W, Li RL, Tu L, et al. The damage of plasmal hypertriglycerid emia on the blood vessel endothelium functions in the aged and the repair o f Xuezhikang [J]. J Clin Cardiol,2002,18(7):336-337.
[34]Lu XX, Liang GF. Effects of oxidized low-density lipoprotein and Xu ezhikang on nitric oxide synthase activity and intercellular adhesion molecule-1 in cultured human umbilical vein endothelial cells [J]. J Clin Cardiol, 2004,20(6):355-357.
[35]徐伯平,程蕴琳,鲁翔.血脂康及氧化低密度脂蛋白对牛血管平滑肌细胞增殖的影响[J].中华老年医学杂志,2001,20(5)：384-385.
[36]赵淑健,金玉怀,叶平,等.血脂康对新生大鼠心肌成纤维细胞增殖及胶原合成的影响[J].中国生物制品学杂志,2008,21(4)：318-322.
[37]刘志高,辛奠霞,刘浩,等.血脂康对高血压病患者高脂餐后凝血纤溶功能的影响[J].中国中西医结合杂志,2010,30(2)：212-214.
[38]刘浩,刘志高,杨健,等.高甘油三酯患者凝血纤溶活性的变化及血脂康对其的影响[J].中国中西医结合杂志,2008,28(1)：35.
[39]赵昱,刘素宾.胰岛素第一时相分泌的研究进展.中国糖尿病杂志,2008；16：317-318.
[40]Del Prato S, Marchetti P,Bonadanna RC. Phasicinsulin release and meta bolic regulation in type 2 diabetes. Diabetes,2002;51(Suppl 1):109-116.
[41]李光伟.胰岛p细胞功能评估.国外医学内分泌学分册,2001,21：412-414.
[42]朱铁虹,尹滩,高淑玮.钙通道拮抗剂对大鼠胰岛细胞胰岛素分泌的影响.中华内科杂志,2004；43：29-32.
[43]宋科瑛,王瑞涛,卢列盛,等.小鼠胰岛的分离纯化及体外功能检测的实验研究.中国现代普通外科进展,2007；10：80-83.
[44]惠晓丽,王惠芳,刘惊涛,等.游离脂肪酸对大鼠胰岛细胞体外分泌功能的影响.西安交通大学学报：医学版,2006；27：173-176.
[45]谢晓雁,手晓,顾燕云,等.原代分离的大鼠胰岛细胞对葡萄糖刺激胰岛素分泌的反应性研究.放射免疫学杂志,2005；18：356-359.
[46]邵加庆,顾萍,杜宏,等.建立离体胰岛灌流系统用于评估胰岛素第一相分泌功能.中华医学杂志,2010；21：134-138.
[47]Metabolic response to chemotherapy in colon cancer patients[J]. JPEN J Parenter Enteral Nutr,1992,16(6Suppl):65S-71S.
[48]Bonner-Weir S, Go VLW, Dimagno EP, Gardner JD, Lebenthal E, Reb er HA, Scheele GA:The pancreas. Biology, pathobiology and disease. In Th e microvasculature of the pancreas, with special emphasis on that of the islet s of Langerhans. Anatomy and functional implications. New York, Raven Pre ss,1993, pp 759-768.
[49]Konstantinova I, Lammert E:Microvascular development:learning from pancreatic islets. Bioessays 2004,26:1069-1075.
[50]Lammert E, Gu G, McLaughlin M, Brown D, Brekken R, Murtaugh L C, Gerber HP, Ferrara N, Melton DA:Role of VEGF-A in vascularization o f pancreatic islets. Curr Biol 2003,13:1070-1074.
[51]Sakamoto C, Goldfine ID, Roach E, Williams JA:Localization of satura ble CCK binding sites in rat pancreatic islets by light and electron microsco pe autoradiography. Diabetes 1985,34:390-394.
[52]Olsson R, Carlsson PO. The pancreatic islet endothelial cell:emerging r oles in islet function and disease. Int J Biochem Cell Biol 2006,38:492-49 7.
[53]Lammert E, Cleaver O, Melton D:Induction of pancreatic differentiation by signals from blood vessels. Science 2001,294:564-567.
[54]Kramer J, Moeller EL, Hachey A, et al.Differential expression of GLUT 2 in pancreatic islets and kidneys of New and Old World nonhuman primate s. Am J Physiol Regul Integr Comp Physiol.2009;296:R786-793.
[55]Tanaka Y, Gleason CE, Tran PO, Harmon JS, Robertson RP:Preventio n of glucose toxicity in HIT-T15 cells and Zucker diabetic fatty rats by anti oxidants. PNAS,1999,14:10857-10862.
[56]Lenzen S, Drinkgern J, Tiedge M. Low antioxidant enzyme gene expres sion in pancreatic islets compared with various other mouse tissues. Free Ra dic Biol Med,1996,20:463-466.
[57]Oliveira HR, Curi R, Carpinelli AR:Glucose induces an acute increase of superoxide dismutase activity in incubated rat pancreatic islets. Am J Phy siol,1999,276:C507-C510.
[58]Laybutt DR, Kaneto H, Hasenkamp W, Grey S, Jonas JC, Sgroi DC, G roff A, Ferran C, Bonner-Weir S, Sharma A, Weir GC. Increased expression of antioxidant and antiapoptotic genes in islets that may contribute to beta-c ell survival during chronic hyperglycemia. Diabetes,2002,51:413-423.
[59]Lu D, Maulik N, Moraru II, Kreutzer DL, Das DK:Molecular adaptatio n of vascular endothelial cells to oxidative stress. Am J Physiol,1993,264: C715-C722.
[60]Ceriello A, dello Russo P, Amstad P, Cerutti P:High glucose induces antioxidant enzymes in human endothelial cells in culture:evidence linking h yperglycemia and oxidative stress. Diabetes,1996,45:471-477.
[61]Armstrong JS. Mitochondrial medicine:pharmacological targeting of mit ochondria in disease. Br J Pharmacol,2007,151:1154-1165.
[1]肖新华.糖尿病的脂代谢紊乱[J].临床内科杂志,2003,20(3)：119-121.
[2]Feher M, Elkeles R. Lipid modification and coronary heart disease in type 2 diabetes:different from the general population.Heart,1999;81:10-11.
[3]Holman R. The UKPDS:implications for the dyslipidaemic patient.Acta Diabet- ol,2001;38:S9-14.
[4]Executive Summary of The Third Report of The Nat ional Cholesterol Educat ion Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA,2001; 285: 2486-2497.
[5]Porte D, Jr. & Kahn SE. Beta-cell dysfunction and failure in type 2 diabetes: potential mechanisms. Diabetes,2001,50 Suppl 1:S 160-163.
[6]Prentki M & Nolan CJ. Islet beta cell failure in type 2 diabetes. The Journal of clinical investigation,2006,116(7):1802-1812.
[7]《中国糖尿病防治指南》编写组.中国糖尿病防治指南。北京大学医学出版社,2005.
[8]邵加庆,顾萍,杜宏,等.建立离体胰岛灌流系统用于评估胰岛素第一相分泌功能。中华医学杂志,2010；21：134-138.
[9]McGarry JD. Dysregulation of fatty acid metabolism in the etiology of type 2 diabete.Diabetes 2001,50 (1):7-18.
[10]孙美珍,田林华,迟家敏.血脂康对Ⅱ型糖尿病患者糖、脂代谢的影响.中华内科杂志,1998,37(6)：374-376.
[11]The scandinavian simvastatin survival study group. Randomised trial of cholesterol lovering in4444patients with coronary heart disease:the scandinavian simvastatin survival study (4S). lancet,1994,344:1383-1389.
[12]ShepherdJ, Cobbe SM, Ford I, et al.preventinon ofcoronary heart disease with pravastatin in men with hypercho;esterolemia.N Engl J Med,1995,333:1301-1307.
[13]Leong L Ng, Joan E, Davies.3-Hydroxy-3Methy1-Gludary1Coen- zyme A reductase inhibition modulates vasopressinstimulated Ca2+ responses in rat Alovascularsmooth muscle cells.Cire Res,1994,94:173-181.
[14]Zhao SP, Lu ZL, Du BM, et al. Xuezhikang, an extract ofcholestin, reduces cardiovascular events in type 2 diabetespatients with coronary heart disease:subgroup analysis ofpatients with type 2 diabetes from China coronary secondaryprevention study (CCSPS)[J]. J Cardiov Pharm,2007,49(2):81-84.
[15]血脂康调整血脂对冠心病二级预防研究协作组.中国冠心病二级预防研究.中华心血管病杂志,2005,33(2)：6-10.
[16]卢斌,顾萍,邵加庆,等.吡格列酮对db/db小鼠骨骼肌蛋白酪氨酸磷酸酶1B表达的影响.中国比较医学杂志,2012；22：48-50.
[17]杨少勇,周建华.血脂康对老年糖尿病血糖的影响[J].当代医学,2009,15(3)：35-36.
[18]王曦云,盛莉,刘艳萍,等.洛伐他汀治疗冠心病高胆固醇血症对血管内皮功能微循环及胰岛素敏感性的影响[J].中国实用内科杂志,2003,23(11)：660-662.
[19]陈黎,涂燕云,陈枝俏.血脂康胶囊治疗合并高脂血症的非酒精性脂肪性肝病[J].中成药,2007,29(3)：326-329.
[20]Freeman DJ, Norrie J, Sattar N et al:Pravastatin and the Developmentof Diabetes Mellitus Evidence for a Protective Treatment Effect in the West of Scotland Coronary Prevention Study. Circulation,2001; 103:357-6210.
[21]Prasad GV, Kim SJ, Huang M et al:Reduced incidence of new-onset diabetesmellitus after renal transplantation with 3-hydroxy-3-methylglutaryl-coenzyme a reductase inhibitors (statins). Am J Transplant,2004;4:1897-90311.
[22]Paniagua JA, Lopez-Miranda J, Escribano A et al:Cerivastatin improves insulin sensitivity and insulin secretion in early-state obese type 2 diabetes. Diabetes, 2002; 51:2596-60312.
[23]Metz SA, Rabaglia ME, Stock JB, Kowluru A. Modulation of insulin secretion from normal rat islets by inhibitors of the post-translational modifications of GTP-binding proteins. Biochem J.1993,295 (Pt 1):31-40.
[24]Yada T, Nakata M, Shiraishi T, Kakei M (1999) Inhibition by simvastatin, but not pravastatin, of glucoseinduced cytosolic Ca2+ signalling and insulin secretion due to blockade of L-type Ca2+ channels in rat isletbeta-cells. Br J Pharmacol 126: 1205-1213.
[25]Nakata M, Nagasaka S, Kusaka I, Matsuoka H, Ishibashi S, Yada T (2006) Effects of statins on the adipocyte maturation and expression of glucose transporter 4 (SLC2A4):implications in glycaemic control. Diabetologia 49:1881-1892.
[26]Suzuki M, Kakuta H, Takahashi A, Shimano H, Tada-Iida K, Yokoo T, Kihara R, Yamada N (2005) Effects of atorvastatin on glucose metabolism and insulin resistance in KK/Ay mice. J Atheroscler Thromb 12:77-84.
[27]Chen Y, Ohmori K,Mizukawa M, et al. Differential impact of atorvastatin vs pravastatin on progressive insulin resistance and lert ventricular diastolic dysfunction in a rat model of type II diabetes. Circ J,2007;71:144-152.
[28]Auer J, Berent R, Weber T, Eber B. Statins for patients with type 2 diabetes.Lancet,2004;364:1933-1934.
[29]Osaki F, Ikeda S, Suehiro T, et al. Effect of statins on glucose metabolism(in Japanese, with title translated by the authors). Jpn J Clin Exp Med,2005;82: 359-363.
[30]Sasaki J, Iwashita M, Kono S. Statins:beneficial or adverse for glucose metabolism.J Athroscler Thromb,2006;13:123-129.
[31]Preiss D, Seshasai SR, Welsh P, et al. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy:a meta-analysis. JAMA.2011; 305:2556-2564.
[32]Goldberg R B, Jacobson T A. Efects of niacin on glucose control in patients with dyslipidemia. Mayo Clin Proc,2008;83:470-478.
[33]Tenenbauma H,Behar S,Boyko V,et al.Long-term effect of bezafibrate on pancreatic beta-cell function and insulin resistance in patients with diabetes. Atherosclerosis,2006; 13:7-18.
[34]秦利,殷峻,邢惠莉.非诺贝特缓释微丸对糖尿病患者糖脂代谢紊乱的影响. 上海第二医科大学学报,2003；23：261-263.
[35]血脂康胶囊临床应用中国专家共识组.血脂康胶囊临床应用中国专家共识[J].中国社区医师,2009,25(14)：9-10.
[36]杨文英,邢小燕,林红,等.高甘油三酯血症是胰岛素依赖型糖尿病发病的危险因素[J].中华内科杂志,1996,35(9)：583-586.
[37]王彩玲.血脂康对2型糖尿病人胰岛素敏感性的影响[J].中华糖尿病杂志,2001,9(3)：171-173.
[38]Gerasi E.胰岛素生成,胰岛素分泌及2型糖尿病：问题的核心在于p细胞.中华内分泌代谢杂志,2005；21：194-198.
[39]Iwashita N, Uehida T, Choi JB, et al.Impaired insulin secretion in vivo but enhanced insulin secretion from isolated islets in pancreatic beta cell-specific vascular endothelial growth factor-A knock-out mice.Diabetologia,2007;50:380-389.
[40]Hao M, Head WS, Gunawardana SC et al:Direct effect of cholesterolon insulin secretion:a novel mechanism for pancreatic beta-cell dysfunction. Diabetes,2007; 56: 2328-382.
[41]Brunham LR, Kruit JK, Verchere CB, Hayden MR:Cholesterol in islet dysfunction and type 2 diabetes. J Clin Invest,2008; 118:403-83.
[42]Roehrich ME, Mooser V, Lenain V et al:Insulin-secreting β-Cell Dysfunction Induced by Human Lipoproteins. J Biol Chem,2003;278:18368-758.
[43]Abderrahmani A, Niederhauser G, Favre D et al. Human high-density lipoprotein particles prevent activation of the JNK pathway induced by human oxidised low-density lipoprotein particles in pancreatic betacells. Diabetologia,2007; 50:1304-14.
[1]Feher M, Elkeles R. Lipid modification and coronary heart disease in Typ e 2 diabetes:differen t from the general population.Heart,1999;81:10-11.
[2]Holman R. The UKPDS:implications for the dyslipidaemic patient.Acta D iabetol,2001;38:S9-14.
[3]Auer J, Berent R, Weber T, et al. Statins for patients with type 2 diabete s.Lancet.2004,364:1933-1934.
[4]Preiss D,Seshasai SR,Welsh P,et al. Risk of incident diabetes with intensiv e-dose compared with moderate-dose statin therapy:a meta-analysis.JAMA,2011; 305:2556-25564.
[5]Simsek S,Schalkwijk CG,Wolffenbuttel BH. Effects of rosuvastatin and ato rvastatin on glycaemic control in type 2diabetes-the CORALL study. Diab Med, 2011;29:628-631.
[6]Roper MG, Qian WJ, Zhang BB, et al. Effect of the insulin mimetic L-7 83,281 on intracellular[Ca2+] and insulin secretion from pancreatic β cells. Dia betes,2002;51(Suppl):43-49.
[7]Verspohl EJ, Amnon HP. Evidence for presence of insulin receptors in rat islets of Langerhans. J Clin Invest,1980;65:1230-1237.
[8]Van Schravendijk CF, Foriers A, Hooghe-Peters EL, et al. Pancreatic hor mone receptors on islet cells.Endocrinology,1985;117:841-848.
[9]Stolarczyk E,Le GallM, Even P, et al. Loss of sugar detection by GLUT2 affects glucose homeostasis in mice[J]. PLoS ONE.2007, Dec 12;2(12):e1288.
[10]Chankiewitz E, Peschke D, HerbergL, et al. Did the gradual loss of GL UT2 cause a shift to diabetic disorders in the New Zealand obese mouse (NZ O/HI)? [J]. Exp Clin Endocrinol Diabetes,2006,114(5):262-269.
[11]Kiraly MA, Bates HE, Kaniuk NA, et al. Swim training prevents hyper glycemia in in ZDF rats:mechanisms involved in the partial maintenance of b eta-cell function[J]. Am J Physiol Endocrinol Metab,2008,294(2):271-283.
[12]Im SS, Kim SY, Kim H I, et al. Transcriptional regulation of glucose sensors in pancreatic beta cells and liver[J]. Curr Diabetes Rev,2006,2(1):11-18.
[13]Garcia-Flores, Zueco JA, Arenas J, et al. Expression of glucose transporter-2, glucokinase and mitochondrial glycerol phosphate de-hydrogenase in pancreatic islets during rat ontogenesis[J]. Eur J Biochem,2002,269(l):119-127.
[14]A. Mizuno, Y. Noma, M. Kuwajima, et al. Changes in islet capillary angioarchitecture coincide with impaired B-cell function but not with insulin resistance in male Otsuka-Long-Evans-Tokushima fatty rats:dimorphism of the diabetic phenotype at an advanced age, Metabolism 48 (1999) 477-483.
[15]Tayek JA, Chlebowski RT. Metabolic response to chemotherapy in colon cancer patients[J]. JPEN J Parenter Enteral Nutr,1992,16(6 Suppl):65S-71S.
[16]Atkinson MA, Rhodes CJ. Pancreatic regeneration in type 1 diabetes:dreams on a deserted island? Diabetologia 48:2200-2202,2005.
[17]Lammert E, Cleaver O, Melton D. Role of endothelial cells in pancreas and liver development. Mech Development 120:59-64,2003.
[18]Nikolova G, Jabs N, Konstantinova I, et al. The vascular basement membrane: a niche for insulin gene expression and beta-cell proliferation. Dev Cell 10:397-405, 2006.
[19]Johannson M, Mattsson G, Andersson A, et al. Islet endothelial cells and pancreatic beta-cell proliferation:studies in vitro and during pregnancy in adult rats. Endocrinology 147:2314-2324,2006.
[20]Rydgren T, Vaarala O, Sandler S. Simvastatin protects against multiple low-dose streptozotocin-induced type 1 diabetes in CD-1 mice and recurrence of disease in non-obese diabetic mice. J Pharmacol Exper Therapeut 323:180-185,2007.
[21]Rydgren T, Sandler S. The protective effect of simvastatin against low dose streptozotocin induced type 1 diabetes in mice is independent of inhibition of HMG-CoA reductase. Biochem Biophys Res Commun 379:1076-1079,2009.
[22]Dulak J, Loboda A, Jazwa A, et al. Atorvastatin affects several angiogenic mediators in endothelial cells. Endothelium 12:233-241,2005.
[23]J. Styrud, U.J. Eriksson, L. Jansson, A continuous 48-hour glucose infusion in rats causes both an acute and a persistent redistribution of the blood flow within the pancreas, Endocrinology 1992,130:2692-2696.
[24]A.M. Svensson, S.M. Abdel-Halim, S. Efendic, et al. Ostenson, Pancreatic and islet blood flow in Fl-hybrids of the noninsulin-dependent diabetic GK-Wistar rat, Eur. J. Endocrinol.1994,130:612-616.
[25]A.M. Svensson, C.G. Ostenson, S. Sandler, et al. Inhibition of nitric oxide synthase by NG-nitro-L-arginine causes a preferential decrease in pancreatic islet blood flow in normal rats and spontaneously diabetic GK rats. Endocrinology 1994,135:849-853.
[26]G.C. Weir, D.R. Laybutt, H. Kaneto, et al. Beta-cell adaptation and decompensation during the progression of diabetes, Diabetes 2001,50(Suppl. 1):S154-S159.
[27]Bonner-Weir S, Go VLW, Dimagno EP, Gardner JD, Lebenthal E, Reber HA, Scheele GA:The pancreas. Biology, pathobiology and disease. In The microvasculature of the pancreas, with special emphasis on that of the islets of Langerhans. Anatomy and functional implications. New York, Raven Press,1993, pp 759-768.
[28]Konstantinova I, Lammert E:Microvascular development:learning from pancreatic islets. Bioessays 2004,26:1069-1075.
[29]Lammert E, Gu G, McLaughlin M, Brown D, Brekken R, Murtaugh LC, Gerber HP, Ferrara N, Melton DA:Role of VEGF-A in vascularization of pancreatic islets. Curr Biol 2003,13:1070-1074.
[30]Sakamoto C, Goldfine ID, Roach E, Williams JA:Localization of saturable CCK binding sites in rat pancreatic islets by light and electron microscope autoradiography. Diabetes 1985,34:390-394.
[31]Olsson R, Carlsson PO:The pancreatic islet endothelial cell:emerging roles in islet function and disease. Int J Biochem Cell Biol 2006,38:492-497.
[32]Lammert E, Cleaver O, Melton D:Induction of pancreatic differentiation by signals from blood vessels. Science 2001,294:564-567.
[33]Brissova M, Shostak A, Shiota M, Wiebe PO, Poffenberger G, Kantz J, Chen Z, Carr C, Jerome WG, Chen J, Baldwin HS, Nicholson W, Bader DM, Jetton T, Gannon M, Powers AC:Pancreatic islet production of vascular endothelial growth factor-a is essential for islet vas cularization, revascularization, and function. Diabetes 2006,55:2974-2985.
[34]Li X, Zhang L, Meshinchi S, Dias-Leme C, Raffin D, Johnson JD, Treutelaar MK, Burant CF:Islet microvasculature in islet hyperplasia and failure in a model of type 2 diabetes. Diabetes 2006,55:2965-2973.
[35]Favaro E, Miceli I, Bussolati B, et al. Hyperglycemia induces apoptosis of human pancreatic islet endothelial cells:effects of pravastatin on the Akt survival pathway. Am J Pathol 2008; 173:442-50.
[36]Huang Z, Jansson L, Sjoholm A. Vasoactive drugs enhance pancreatic islet blood flow, augment insulin secretion and improve glucose tolerance in female rats. Clin Sci (Lond) 2007; 112:69-76.
[37]Huang Z, Jansson L, Sjoholm A. Gender-specific regulation of pancreatic islet blood flow, insulin levels and glycaemia in spontaneously diabetic Goto-Kakizaki rats. Clin Sci (Lond) 2008; 115:35-42.
[38]Armstrong JS. Mitochondrial medicine:pharmacological targeting of mitochondria in disease. Br J Pharmacol,2007,151:1154-1165.
[39]Kramer J, Moeller EL, Hachey A, et al.Differential expression of GLUT2 in pancreatic islets and kidneys of New and Old World nonhuman primates. Am J Physiol Regul Integr Comp Physiol.2009;296:R786-793.
[40]Matschinsky FM. Banting Lecture 1995. A lesson in metabolic regulation inspired by the glucokinase glucose sensor paradigm. Diabetes 1996,45:223-41.
[41]Unger RH. Diabetic hyperglycemia:link to impaired glucose transport in pancreatic 3 cells. Science 1991,251:1200-5.
[42]Guillam MT, Hummler E, Schaerer E, Yeh JI, Birnbaum MJ, Beermann F, Schmidt A, Deriaz N, Thorens B. Early diabetes and abnormal postnatal pancreatic islet development in mice lacking GLUT2. Nat Genet 1997,17:327-30.
[43]Matschinsky FM, Glaser B, Magnuson MA. Pancreatic β -cell glucokinase: closing the gap between theoretical concepts and experimental realities. Diabetes 1998,47:307-15.
[44]Terauchi Y, Sakura H, Yasuda K, et al. Pancreatic β-cell-specific targeted disruption of glucokinase gene. J Biol Chem 1995,270:30253-6.
[45]ReimerMK, Ahren B. Altered beta2cell distribution of pdx21 andGLUT22 after a short2term challenge with a high2fat diet inC57BL/6J mice[J]. Diabetes, 2002,51 (Suppl 1):1382143.
[46]ThorensB,Wu YJ,Leahy JL, et al. The loss of GLUT2 exp ressionby glucose2unresponsive beta2cells of db/db mice is reversible andis induced by the diabetic environment[J]. J Clin Invest,1992,90(1):772-5.
[47]杨文英,邢小燕,林红,等.高甘油三酯血症是非胰岛素依赖型糖尿病发病的危险因素[J].中华内科杂志,1995,34：583-586.
[48]王曦云,盛莉,刘艳萍,等.洛伐他汀治疗冠心病高胆固醇血症对血管内皮功能微循环及胰岛素敏感性的影响[J].中国实用内科杂志,2003,23(11)：660-662.
[49]姚瑾,陈刚,梁继兴,等.血脂康对血脂正常2型糖尿病患者心血管事件的预防机制研究[J].海峡预防医学杂志,2007,13(3)：75-76.
[50]赵红丽,李潞,刘丽敏,等.血脂康与普伐他汀对血脂正常冠心病患者脂联素及肿瘤坏死因子水平影响的对比研究[J].中国医药导刊,2008,10(1)：113-114.
[1]Oliveira HR, Curi R, Carpinelli AR:Glucose induces an acute increase of superoxide dismutase activity in incubated rat pancreatic islets. Am J Physiol 276:C507-C510,1999.
[2]Ihara Y, Toyokuni S, Uchida K, et al. Hyperglycemia causes oxidative str ess in pancreatic beta cells of GK rats, a model of type 2 diabetes. Diabetes 4 8:927-932,1999.
[3]Tanaka Y, Gleason CE, Tran PO, et al. Prevention of glucose toxicity in HIT-T15 cells and Zucker diabetic fatty rats by antioxidants. Proc Natl Acad S ci U S A 14:10857-10862,1999.
[4]Lenzen S, Drinkgern J, Tiedge M:Low antioxidant enzyme gene expressi on in pancreatic islets compared with various other mouse tissues. Free Radic Biol Med 20:463-466,1996.
[5]Laybutt DR, Kaneto H, Hasenkamp W, et al. Increased expression of anti oxidant and antiapoptotic genes in islets that may contribute to beta-cell surviv al during chronic hyperglycemia. Diabetes 51:413-423,2002.
[6]Lu D, Maulik N, Moraru II, Kreutzer DL, Das DK:Molecular adaptation of vascular endothelial cells to oxidative stress. Am J Physiol 264:C715-C722, 1993.
[7]Ceriello A, dello Russo P, Amstad P, Cerutti P:High glucose induces ant ioxidant enzymes in human endothelial cells in culture:evidence linking hyperg lycemia and oxidative stress. Diabetes 45:471-477,1996.
[8]M. A. Modak, P. B. Parab, and S. S. Ghaskadbi. Pancreatic islets are ver y poor in rectifying oxidative DNA damage. Pancreas, vol.38, no.1, pp.23-29,2009.
[9]Y. Ihara, S. Toyokuni, K. Uchida et al., "Hyperglycemia causes oxidative stress in pancreatic β-cells of GK rats, a model of type 2 diabetes," Diabetes, vol.48, no.4, pp.927-932,1999.
[10]S. Del Guerra, R. Lupi, L. Marselli et al., "Functional and molecular def ects of pancreatic islets in human Type 2 diabetes," Diabetes, vol.54, no.3, p p.727-735,2005.
[11]S. I. Gorogawa, Y. Kajimoto, Y. Umayahara et al., "Probucol preserves pancreatic β-cell function through reduction of oxidative stress in type 2 diabet es," Diabetes Research and Clinical Practice, vol.57, no.1, pp.1-10,2002.
[12]Babior BM, Lambeth JD, Nuseef W:The neutrophil NADPH oxidase. Arch Biochem Biophys 397:342-344,2002.
[13]Pithon-Curi TC, Levada AC, Lopes LR, Doi SQ, Curi R:Glutamine p1 ays a role in superoxide production and the expression of p47PHOX in rat neu trophils. Clin Sci 103:403-408,2002.
[14]M. Nakayama, T. Inoguchi, T. Sonta et al., "Increased expression of N AD(P)H oxidase in islets of animal models of type 2 diabetes and its improve ment by an AT1 receptor antagonist," Biochemical and Biophysical Research C ommunications, vol.332, no.4, pp.927-933,2005.
[15]H. R. Oliveira, R. Verlengia, C. R. O. Carvalho, etal. "Pancreatic β-ce lls express phagocyte-like NAD(P)H oxidase," Diabetes, vol.52, no.6,pp.1457-1463,2003.
[16]Y. Uchizono, R. Takeya, M. Iwase et al., "Expression of isoforms of N ADPH oxidase components in rat pancreatic islets," Life Sciences, vol.80, no. 2, pp.133-139,2006.
[17]P. Newsholme, C. Gaudel, and M. Krause, "Mitochondria and diabetes. An intriguing pathogenetic role," Advances in Experimental Medicine and Biolo gy, vol.942, pp.235-247,2012.
[18]Miura Y, Kato M, Ogino K, Matsui H. Impaired cytosolic Ca2+ response t o glucose and gastric inhibitory polypeptide in pancreatic beta-cells from triphenylti n-induced diabetic hamster. Endocrinology.1997 Jul;138(7):2769-75.
[19]Burdon RH:Superoxide and hydrogen peroxide in relation to mammalia n cell proliferation. Free Radic Biol Med 18:775-794,1995.
[20]Schoonbroodt S, Piette J:Oxidative stress interference with the nuclear factor-kappa B activation pathways. Biochem Pharmacol 60:1075-1083,2000.
[21]Lu D, Maulik N, Moraru II, Kreutzer DL, Das DK:Molecular adaptati on of vascular endothelial cells to oxidative stress. Am J Physiol 264:C715-C7 22,1993.
[22]Lo YY, Wong JM, Cruz TF:Reactive oxygen species mediate cytokine activation of c-Jun NH2-terminal kinases. J Biol Chem 271:15703-15707,199 6.
[23]Vega-Saenz de Miera E, Rudy B:Modulation of K+ channels by hydro gen peroxide. Biochem Biophys Res Commun 186:1681-1687,1992.
[24]Wang D, Youngson C, Wong V, et al. NADPH-oxidase and a hydroge n peroxide-sensitive K+ channel may function as an oxygen sensor complex in airway chemoreceptors and small cell lung carcinoma cell lines. Proc Natl Aca d Sci U S A 93:13182-13187,1996.
[25]Li P, Yang Y, Liu M. Xuezhikang, extract of red yeast rice, inhibited tiss ue factor and hypercoagulable state through suppressing nicotinamide adenine di nucleotide phosphate oxidase and extracellular signal-regulated kinase activation. J Cardiovasc Pharmacol.2011 Sep;58(3):307-18.
[26]Brownlee M.:Biochemistry and molecular cell biology of diabetic comp lications. Nature 2001;414:813-820.
[27]黄彦生,王树人,智艳芳等。血脂康胶囊对冠心病患者血管内皮功能及氧化还原态的影响。中西医结合学报,2006,3：251-255。
[28]Hong XZ, Li LD, Wu LM.. Effects Of Fenofibrate And Xuezhikang On High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease. Clin Exp Pharmacol Physiol.2007 Jan-Feb;34(1-2):27-35.
[29]Wu LL, Chiou CC, Chang PY, Wu JT. Urinary 8-OHdG:a marker of oxid ative stress to DNA and a risk factor for cancer, atherosclerosis and diabetics. C lin Chim Acta.2004 Jan;339(1-2):1-9.
[30]Shida T, Nozawa T, Sobajima M, et al. Fluvastatin-induced reduction of o xidative stress ameliorates diabetic cardiomyopathy in association with improvin g coronary microvasculature. Heart Vessels.2013 Aug 25. [Epub ahead of prin t]
[31]血脂康胶囊临床应用中国专家共识组.血脂康胶囊临床应用中国专家共识[J].中国社区医师,2009,25(14)：9-10.
[32]魏炜,李仁立,涂玲,等.血浆高甘油三酯对老年人血管内皮功能的损害及血脂康的修复作用[J].临床心血管病杂志,2002,18(7)：336-337.
[33]周建红,常獍宇,李会恩,等.脂质异常家兔抗氧化能力与血管细胞黏附因子-1的变化以及血脂康对其影响[J].天津药学,2010,22(1)：1-3.
[34]程茅薇,顾萍,马健,杜宏,卢斌,邵加庆.血脂康对db/db糖尿病小鼠周围神经病变的保护作用研究.现代中西医结合杂志.2011 Nov,20(31),3921-3923.
[35]Kaneto H, Kajimoto Y, Miyagawa J, et al. Beneficial effects of antioxid ants in diabetes:possible protection of pancreatic beta-cells against glucose toxi city. Diabetes.1999 Dec;48(12):2398-406.
[36]A. R. Giniatullin, F. Darios, A. Shakirzyanova, B. Davletov, and R. Gi niatullin, "SNAP25 is a pre-synaptic target for the depressant action of reactive oxygen species on transmitter release," Journal of Neurochemistry, vol.98, no. 6, pp.1789-1797,2006.
[37]R. Ivarsson, R. Quintens, S. Dejonghe et al., "Redox control of exocyto sis:regulatory role of NADPH, thioredoxin, and glutaredoxin," Diabetes, vol.5 4, no.7, pp.2132-2142,2005.
[2]吕树铮.糖尿病合并冠心病流行病学现状研究进展.中华老年心脑血管病杂志,2009；12：910-911.
[3]唐振娟.糖尿病合并冠状动脉粥样硬化性心脏病治疗研究进展.医学综述,2009；15：892-893.
[4]黄元铸.糖尿病合并冠心病研究进展.实用老年医学,2007；21：292-293.
[5]Porte D, Jr. & Kahn SE. Beta-cell dysfunction and failure in type 2 dia betes:potential mechanisms. Diabetes,2001,:S160-163.
[6]Prentki M & Nolan CJ. Islet beta cell failure in type 2 diabetes. The Jo urnal of clinical investigation,2006,116(7):1802-1812.
[7]McGarry JD. Banting lecture 2001:dysregulation of fatty acid metabolism in the etiology of type 2 diabetes. Diabetes.2002 Jan;51(1):7-18.
[8]Lingohr MK, Buettner R, & Rhodes CJ. Pancreatic beta-cell growth and survival--a role in obesity-linked type 2 diabetes? Trends in molecular medici ne,2002,8(8):375-384.
[9]Lupi R, et al. Prolonged exposure to free fatty acids has cytostatic and pro-apoptotic effects on human pancreatic islets:evidence that beta-cell death is caspase mediated, partially dependent on ceramide pathway, and Bcl-2 re gulated. Diabetes,2002,51(5):1437-1442.
[10]Fariss MW, Chan CB, Patel M, Van Houten B, & Orrenius S. Role of mitochondria in toxic oxidative stress. Molecular interventions,2005,5(2):94-111.
[11]Wang H, Kouri G, & Wollheim CB. ER stress and SREBP-1 activation are implicated in beta-cell glucolipotoxicity. Journal of cell science 118(Pt 1 7):3905-3915.
[12]Veret J, et al. Ceramide synthase 4 and de novo production of ceramide s with specific N-acyl chain lengths are involved in glucolipotoxicity-induced apoptosis of INS-1 beta-cells. The Biochemical journal,2011,438(1):177-18 9.
[13]Lin CY, Gurlo T, Haataja L, Hsueh WA, & Butler PC. Activation of p eroxisome proliferator-activated receptor-gamma by rosiglitazone protects hum an islet cells against human islet amyloid polypeptide toxicity by a phosphati dylinositol 3'-kinase-dependent pathway. The Journal of clinical endocrinology and metabolism,2005,90(12):6678-6686.
[14]Elsner M, Gehrmann W, & Lenzen S. Peroxisome-generated hydrogen p eroxide as important mediator of lipotoxicity in insulin-producing cells. Diabe tes,2011,60(1):200-208.
[15]Alquier T, et al. Deletion of GPR40 impairs glucose-induced insulin sec retion in vivo in mice without affecting intracellular fuel metabolism in islets. Diabetes,2009,58(11):2607-2615.
[16]Wu J, et al. Inhibition of GPR40 protects MIN6 beta-cells from palmita te-induced ER stress and apoptosis. Journal of cellular biochemistry.2012, Apr;113(4):1152-1158.
[17]Preiss D,Seshasai SR,Welsh P,et al.Risk of incident diabetes with intensi ve-dose compared with moderate-dose statin therapy:a meta-analysis.JAMA,20 11;305:2556-25564.
[18]Simsek S,Schalkwijk CG,Wolffenbuttel BH.Effects of rosuvastatin and atorvastatin on glycaemic control in type 2diabetes-the CORALL study.Diab Med,2011;29:628-631.
[19]叶平.血脂康胶囊有效减少老年冠心病患者心血管事件及死亡率[J].中国心血管病研究,2008,6(1)：1-2.
[20]吴秋英,柯明远,陈弼沧,等.血脂康治疗2型糖尿病38例临床研究[J].中国实用内科杂志,2005,25(12)：1118-1119.
[21]韩英等.血脂康治疗2型糖尿病血脂异常患者55例[J].广东药学院学报2 004,20(5)：558-559
[22]王彩玲,李曙远,张伟.血脂康对2型糖尿病人胰岛素敏感性的影响[J]中国糖尿病杂志,2001,9(3)：171-173.
[23]Zhao SP, Lu ZL, Du BM, et al. Xuezhikang, an extract of cholest in, reduces cardiovascular events in type 2 diabetes patients with coronary he art disease:subgroup analysis of patients with type 2 diabetes from China co ronary secondary prevention study (CCSPS) [J]. J Cardiov Pharm,2007,49 (2):81-84.
[24]Zhao SP, Liu L, Cheng YC, Shishehbor MH, Liu MH, Peng DQ, Li YL. Xuezhikang, an extract of cholestin, protects endothelial function through anti inflammatory and lipid-lowering mechanisms in patients with coronary heart disease. Circulation.2004;110:915-920.
[25]Li JJ, Hu SS, Fang CH, Hui RT, Miao LF, Yang YJ, Gao RL. Effects of xuezhikang, an extract of cholestin, on lipid profile and C-reactive protein: a short-term time course study in patients with stable angina. Clin Chim Act a.2005;352:217-224.
[26]Zhai WJ, Li AQ. Effect of Xuezhikang on the serum highsensitivity C-reactive protein and blood lipid in patients with type 2 diabetes mellitus an d hyperlipidemia [J]. Acta Acad Med Xuzhou,2010,30(2):102-103.
[27]Yao W, Zhang XL, Wang FZ. Effect of Xuezhikang on expressions of P-selectin, soluble intercellular adhesion molecule-1 and matrix metalloprotein ase-9 of patients with acute coronary artery syndrome [J]. Chin J Cardiol,200 6,34(1):1004.
[28]Pen Y, Zhao S, Liu J. Effect of Xuezhikang on expressions of inflamm atory factors and functions of the blood vessel endothelium[J]. Acta Acad M ed Milit Tertiae,2009,31(7):636-638.
[29]Xu GZ. Effect of amlodipine combined with Xuezhikang Capsule on tre atment of hypertension[J]. Chin Pharm,2008,11(2):219-220.
[30]Li H. Effects of valsartan and valsartan/HCTZ combined with Xuezhik ang in treating mild to moderate hypertensive patients[J]. Pract J Cardiac Cer ebr Pneumal Vascul Dis,2008,16(12):12-13.
[31]Zhu ZT, Wang J, Hou B, et al. The effect of Xuezhikang and antih ypertensive therapy on the ambulatory blood pressure and the smoothness ind ex[J]. Chin J Hypertens,2008,16(6):558-559.
[32]Lin J, Li JL. Effect of lovastatin on brachial endotheliumdependent va sodilation in patients with hypercholesterolemia [J]. Pract Prev Med,2006, 13(3):729-730.
[33]Wei W, Li RL, Tu L, et al. The damage of plasmal hypertriglycerid emia on the blood vessel endothelium functions in the aged and the repair o f Xuezhikang [J]. J Clin Cardiol,2002,18(7):336-337.
[34]Lu XX, Liang GF. Effects of oxidized low-density lipoprotein and Xu ezhikang on nitric oxide synthase activity and intercellular adhesion molecule-1 in cultured human umbilical vein endothelial cells [J]. J Clin Cardiol, 2004,20(6):355-357.
[35]徐伯平,程蕴琳,鲁翔.血脂康及氧化低密度脂蛋白对牛血管平滑肌细胞增殖的影响[J].中华老年医学杂志,2001,20(5)：384-385.
[36]赵淑健,金玉怀,叶平,等.血脂康对新生大鼠心肌成纤维细胞增殖及胶原合成的影响[J].中国生物制品学杂志,2008,21(4)：318-322.
[37]刘志高,辛奠霞,刘浩,等.血脂康对高血压病患者高脂餐后凝血纤溶功能的影响[J].中国中西医结合杂志,2010,30(2)：212-214.
[38]刘浩,刘志高,杨健,等.高甘油三酯患者凝血纤溶活性的变化及血脂康对其的影响[J].中国中西医结合杂志,2008,28(1)：35.
[39]赵昱,刘素宾.胰岛素第一时相分泌的研究进展.中国糖尿病杂志,2008；16：317-318.
[40]Del Prato S, Marchetti P,Bonadanna RC. Phasicinsulin release and meta bolic regulation in type 2 diabetes. Diabetes,2002;51(Suppl 1):109-116.
[41]李光伟.胰岛p细胞功能评估.国外医学内分泌学分册,2001,21：412-414.
[42]朱铁虹,尹滩,高淑玮.钙通道拮抗剂对大鼠胰岛细胞胰岛素分泌的影响.中华内科杂志,2004；43：29-32.
[43]宋科瑛,王瑞涛,卢列盛,等.小鼠胰岛的分离纯化及体外功能检测的实验研究.中国现代普通外科进展,2007；10：80-83.
[44]惠晓丽,王惠芳,刘惊涛,等.游离脂肪酸对大鼠胰岛细胞体外分泌功能的影响.西安交通大学学报：医学版,2006；27：173-176.
[45]谢晓雁,手晓,顾燕云,等.原代分离的大鼠胰岛细胞对葡萄糖刺激胰岛素分泌的反应性研究.放射免疫学杂志,2005；18：356-359.
[46]邵加庆,顾萍,杜宏,等.建立离体胰岛灌流系统用于评估胰岛素第一相分泌功能.中华医学杂志,2010；21：134-138.
[47]Metabolic response to chemotherapy in colon cancer patients[J]. JPEN J Parenter Enteral Nutr,1992,16(6Suppl):65S-71S.
[48]Bonner-Weir S, Go VLW, Dimagno EP, Gardner JD, Lebenthal E, Reb er HA, Scheele GA:The pancreas. Biology, pathobiology and disease. In Th e microvasculature of the pancreas, with special emphasis on that of the islet s of Langerhans. Anatomy and functional implications. New York, Raven Pre ss,1993, pp 759-768.
[49]Konstantinova I, Lammert E:Microvascular development:learning from pancreatic islets. Bioessays 2004,26:1069-1075.
[50]Lammert E, Gu G, McLaughlin M, Brown D, Brekken R, Murtaugh L C, Gerber HP, Ferrara N, Melton DA:Role of VEGF-A in vascularization o f pancreatic islets. Curr Biol 2003,13:1070-1074.
[51]Sakamoto C, Goldfine ID, Roach E, Williams JA:Localization of satura ble CCK binding sites in rat pancreatic islets by light and electron microsco pe autoradiography. Diabetes 1985,34:390-394.
[52]Olsson R, Carlsson PO. The pancreatic islet endothelial cell:emerging r oles in islet function and disease. Int J Biochem Cell Biol 2006,38:492-49 7.
[53]Lammert E, Cleaver O, Melton D:Induction of pancreatic differentiation by signals from blood vessels. Science 2001,294:564-567.
[54]Kramer J, Moeller EL, Hachey A, et al.Differential expression of GLUT 2 in pancreatic islets and kidneys of New and Old World nonhuman primate s. Am J Physiol Regul Integr Comp Physiol.2009;296:R786-793.
[55]Tanaka Y, Gleason CE, Tran PO, Harmon JS, Robertson RP:Preventio n of glucose toxicity in HIT-T15 cells and Zucker diabetic fatty rats by anti oxidants. PNAS,1999,14:10857-10862.
[56]Lenzen S, Drinkgern J, Tiedge M. Low antioxidant enzyme gene expres sion in pancreatic islets compared with various other mouse tissues. Free Ra dic Biol Med,1996,20:463-466.
[57]Oliveira HR, Curi R, Carpinelli AR:Glucose induces an acute increase of superoxide dismutase activity in incubated rat pancreatic islets. Am J Phy siol,1999,276:C507-C510.
[58]Laybutt DR, Kaneto H, Hasenkamp W, Grey S, Jonas JC, Sgroi DC, G roff A, Ferran C, Bonner-Weir S, Sharma A, Weir GC. Increased expression of antioxidant and antiapoptotic genes in islets that may contribute to beta-c ell survival during chronic hyperglycemia. Diabetes,2002,51:413-423.
[59]Lu D, Maulik N, Moraru II, Kreutzer DL, Das DK:Molecular adaptatio n of vascular endothelial cells to oxidative stress. Am J Physiol,1993,264: C715-C722.
[60]Ceriello A, dello Russo P, Amstad P, Cerutti P:High glucose induces antioxidant enzymes in human endothelial cells in culture:evidence linking h yperglycemia and oxidative stress. Diabetes,1996,45:471-477.
[61]Armstrong JS. Mitochondrial medicine:pharmacological targeting of mit ochondria in disease. Br J Pharmacol,2007,151:1154-1165.
[1]肖新华.糖尿病的脂代谢紊乱[J].临床内科杂志,2003,20(3)：119-121.
[2]Feher M, Elkeles R. Lipid modification and coronary heart disease in type 2 diabetes:different from the general population.Heart,1999;81:10-11.
[3]Holman R. The UKPDS:implications for the dyslipidaemic patient.Acta Diabet- ol,2001;38:S9-14.
[4]Executive Summary of The Third Report of The Nat ional Cholesterol Educat ion Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA,2001; 285: 2486-2497.
[5]Porte D, Jr. & Kahn SE. Beta-cell dysfunction and failure in type 2 diabetes: potential mechanisms. Diabetes,2001,50 Suppl 1:S 160-163.
[6]Prentki M & Nolan CJ. Islet beta cell failure in type 2 diabetes. The Journal of clinical investigation,2006,116(7):1802-1812.
[7]《中国糖尿病防治指南》编写组.中国糖尿病防治指南。北京大学医学出版社,2005.
[8]邵加庆,顾萍,杜宏,等.建立离体胰岛灌流系统用于评估胰岛素第一相分泌功能。中华医学杂志,2010；21：134-138.
[9]McGarry JD. Dysregulation of fatty acid metabolism in the etiology of type 2 diabete.Diabetes 2001,50 (1):7-18.
[10]孙美珍,田林华,迟家敏.血脂康对Ⅱ型糖尿病患者糖、脂代谢的影响.中华内科杂志,1998,37(6)：374-376.
[11]The scandinavian simvastatin survival study group. Randomised trial of cholesterol lovering in4444patients with coronary heart disease:the scandinavian simvastatin survival study (4S). lancet,1994,344:1383-1389.
[12]ShepherdJ, Cobbe SM, Ford I, et al.preventinon ofcoronary heart disease with pravastatin in men with hypercho;esterolemia.N Engl J Med,1995,333:1301-1307.
[13]Leong L Ng, Joan E, Davies.3-Hydroxy-3Methy1-Gludary1Coen- zyme A reductase inhibition modulates vasopressinstimulated Ca2+ responses in rat Alovascularsmooth muscle cells.Cire Res,1994,94:173-181.
[14]Zhao SP, Lu ZL, Du BM, et al. Xuezhikang, an extract ofcholestin, reduces cardiovascular events in type 2 diabetespatients with coronary heart disease:subgroup analysis ofpatients with type 2 diabetes from China coronary secondaryprevention study (CCSPS)[J]. J Cardiov Pharm,2007,49(2):81-84.
[15]血脂康调整血脂对冠心病二级预防研究协作组.中国冠心病二级预防研究.中华心血管病杂志,2005,33(2)：6-10.
[16]卢斌,顾萍,邵加庆,等.吡格列酮对db/db小鼠骨骼肌蛋白酪氨酸磷酸酶1B表达的影响.中国比较医学杂志,2012；22：48-50.
[17]杨少勇,周建华.血脂康对老年糖尿病血糖的影响[J].当代医学,2009,15(3)：35-36.
[18]王曦云,盛莉,刘艳萍,等.洛伐他汀治疗冠心病高胆固醇血症对血管内皮功能微循环及胰岛素敏感性的影响[J].中国实用内科杂志,2003,23(11)：660-662.
[19]陈黎,涂燕云,陈枝俏.血脂康胶囊治疗合并高脂血症的非酒精性脂肪性肝病[J].中成药,2007,29(3)：326-329.
[20]Freeman DJ, Norrie J, Sattar N et al:Pravastatin and the Developmentof Diabetes Mellitus Evidence for a Protective Treatment Effect in the West of Scotland Coronary Prevention Study. Circulation,2001; 103:357-6210.
[21]Prasad GV, Kim SJ, Huang M et al:Reduced incidence of new-onset diabetesmellitus after renal transplantation with 3-hydroxy-3-methylglutaryl-coenzyme a reductase inhibitors (statins). Am J Transplant,2004;4:1897-90311.
[22]Paniagua JA, Lopez-Miranda J, Escribano A et al:Cerivastatin improves insulin sensitivity and insulin secretion in early-state obese type 2 diabetes. Diabetes, 2002; 51:2596-60312.
[23]Metz SA, Rabaglia ME, Stock JB, Kowluru A. Modulation of insulin secretion from normal rat islets by inhibitors of the post-translational modifications of GTP-binding proteins. Biochem J.1993,295 (Pt 1):31-40.
[24]Yada T, Nakata M, Shiraishi T, Kakei M (1999) Inhibition by simvastatin, but not pravastatin, of glucoseinduced cytosolic Ca2+ signalling and insulin secretion due to blockade of L-type Ca2+ channels in rat isletbeta-cells. Br J Pharmacol 126: 1205-1213.
[25]Nakata M, Nagasaka S, Kusaka I, Matsuoka H, Ishibashi S, Yada T (2006) Effects of statins on the adipocyte maturation and expression of glucose transporter 4 (SLC2A4):implications in glycaemic control. Diabetologia 49:1881-1892.
[26]Suzuki M, Kakuta H, Takahashi A, Shimano H, Tada-Iida K, Yokoo T, Kihara R, Yamada N (2005) Effects of atorvastatin on glucose metabolism and insulin resistance in KK/Ay mice. J Atheroscler Thromb 12:77-84.
[27]Chen Y, Ohmori K,Mizukawa M, et al. Differential impact of atorvastatin vs pravastatin on progressive insulin resistance and lert ventricular diastolic dysfunction in a rat model of type II diabetes. Circ J,2007;71:144-152.
[28]Auer J, Berent R, Weber T, Eber B. Statins for patients with type 2 diabetes.Lancet,2004;364:1933-1934.
[29]Osaki F, Ikeda S, Suehiro T, et al. Effect of statins on glucose metabolism(in Japanese, with title translated by the authors). Jpn J Clin Exp Med,2005;82: 359-363.
[30]Sasaki J, Iwashita M, Kono S. Statins:beneficial or adverse for glucose metabolism.J Athroscler Thromb,2006;13:123-129.
[31]Preiss D, Seshasai SR, Welsh P, et al. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy:a meta-analysis. JAMA.2011; 305:2556-2564.
[32]Goldberg R B, Jacobson T A. Efects of niacin on glucose control in patients with dyslipidemia. Mayo Clin Proc,2008;83:470-478.
[33]Tenenbauma H,Behar S,Boyko V,et al.Long-term effect of bezafibrate on pancreatic beta-cell function and insulin resistance in patients with diabetes. Atherosclerosis,2006; 13:7-18.
[34]秦利,殷峻,邢惠莉.非诺贝特缓释微丸对糖尿病患者糖脂代谢紊乱的影响. 上海第二医科大学学报,2003；23：261-263.
[35]血脂康胶囊临床应用中国专家共识组.血脂康胶囊临床应用中国专家共识[J].中国社区医师,2009,25(14)：9-10.
[36]杨文英,邢小燕,林红,等.高甘油三酯血症是胰岛素依赖型糖尿病发病的危险因素[J].中华内科杂志,1996,35(9)：583-586.
[37]王彩玲.血脂康对2型糖尿病人胰岛素敏感性的影响[J].中华糖尿病杂志,2001,9(3)：171-173.
[38]Gerasi E.胰岛素生成,胰岛素分泌及2型糖尿病：问题的核心在于p细胞.中华内分泌代谢杂志,2005；21：194-198.
[39]Iwashita N, Uehida T, Choi JB, et al.Impaired insulin secretion in vivo but enhanced insulin secretion from isolated islets in pancreatic beta cell-specific vascular endothelial growth factor-A knock-out mice.Diabetologia,2007;50:380-389.
[40]Hao M, Head WS, Gunawardana SC et al:Direct effect of cholesterolon insulin secretion:a novel mechanism for pancreatic beta-cell dysfunction. Diabetes,2007; 56: 2328-382.
[41]Brunham LR, Kruit JK, Verchere CB, Hayden MR:Cholesterol in islet dysfunction and type 2 diabetes. J Clin Invest,2008; 118:403-83.
[42]Roehrich ME, Mooser V, Lenain V et al:Insulin-secreting β-Cell Dysfunction Induced by Human Lipoproteins. J Biol Chem,2003;278:18368-758.
[43]Abderrahmani A, Niederhauser G, Favre D et al. Human high-density lipoprotein particles prevent activation of the JNK pathway induced by human oxidised low-density lipoprotein particles in pancreatic betacells. Diabetologia,2007; 50:1304-14.
[1]Feher M, Elkeles R. Lipid modification and coronary heart disease in Typ e 2 diabetes:differen t from the general population.Heart,1999;81:10-11.
[2]Holman R. The UKPDS:implications for the dyslipidaemic patient.Acta D iabetol,2001;38:S9-14.
[3]Auer J, Berent R, Weber T, et al. Statins for patients with type 2 diabete s.Lancet.2004,364:1933-1934.
[4]Preiss D,Seshasai SR,Welsh P,et al. Risk of incident diabetes with intensiv e-dose compared with moderate-dose statin therapy:a meta-analysis.JAMA,2011; 305:2556-25564.
[5]Simsek S,Schalkwijk CG,Wolffenbuttel BH. Effects of rosuvastatin and ato rvastatin on glycaemic control in type 2diabetes-the CORALL study. Diab Med, 2011;29:628-631.
[6]Roper MG, Qian WJ, Zhang BB, et al. Effect of the insulin mimetic L-7 83,281 on intracellular[Ca2+] and insulin secretion from pancreatic β cells. Dia betes,2002;51(Suppl):43-49.
[7]Verspohl EJ, Amnon HP. Evidence for presence of insulin receptors in rat islets of Langerhans. J Clin Invest,1980;65:1230-1237.
[8]Van Schravendijk CF, Foriers A, Hooghe-Peters EL, et al. Pancreatic hor mone receptors on islet cells.Endocrinology,1985;117:841-848.
[9]Stolarczyk E,Le GallM, Even P, et al. Loss of sugar detection by GLUT2 affects glucose homeostasis in mice[J]. PLoS ONE.2007, Dec 12;2(12):e1288.
[10]Chankiewitz E, Peschke D, HerbergL, et al. Did the gradual loss of GL UT2 cause a shift to diabetic disorders in the New Zealand obese mouse (NZ O/HI)? [J]. Exp Clin Endocrinol Diabetes,2006,114(5):262-269.
[11]Kiraly MA, Bates HE, Kaniuk NA, et al. Swim training prevents hyper glycemia in in ZDF rats:mechanisms involved in the partial maintenance of b eta-cell function[J]. Am J Physiol Endocrinol Metab,2008,294(2):271-283.
[12]Im SS, Kim SY, Kim H I, et al. Transcriptional regulation of glucose sensors in pancreatic beta cells and liver[J]. Curr Diabetes Rev,2006,2(1):11-18.
[13]Garcia-Flores, Zueco JA, Arenas J, et al. Expression of glucose transporter-2, glucokinase and mitochondrial glycerol phosphate de-hydrogenase in pancreatic islets during rat ontogenesis[J]. Eur J Biochem,2002,269(l):119-127.
[14]A. Mizuno, Y. Noma, M. Kuwajima, et al. Changes in islet capillary angioarchitecture coincide with impaired B-cell function but not with insulin resistance in male Otsuka-Long-Evans-Tokushima fatty rats:dimorphism of the diabetic phenotype at an advanced age, Metabolism 48 (1999) 477-483.
[15]Tayek JA, Chlebowski RT. Metabolic response to chemotherapy in colon cancer patients[J]. JPEN J Parenter Enteral Nutr,1992,16(6 Suppl):65S-71S.
[16]Atkinson MA, Rhodes CJ. Pancreatic regeneration in type 1 diabetes:dreams on a deserted island? Diabetologia 48:2200-2202,2005.
[17]Lammert E, Cleaver O, Melton D. Role of endothelial cells in pancreas and liver development. Mech Development 120:59-64,2003.
[18]Nikolova G, Jabs N, Konstantinova I, et al. The vascular basement membrane: a niche for insulin gene expression and beta-cell proliferation. Dev Cell 10:397-405, 2006.
[19]Johannson M, Mattsson G, Andersson A, et al. Islet endothelial cells and pancreatic beta-cell proliferation:studies in vitro and during pregnancy in adult rats. Endocrinology 147:2314-2324,2006.
[20]Rydgren T, Vaarala O, Sandler S. Simvastatin protects against multiple low-dose streptozotocin-induced type 1 diabetes in CD-1 mice and recurrence of disease in non-obese diabetic mice. J Pharmacol Exper Therapeut 323:180-185,2007.
[21]Rydgren T, Sandler S. The protective effect of simvastatin against low dose streptozotocin induced type 1 diabetes in mice is independent of inhibition of HMG-CoA reductase. Biochem Biophys Res Commun 379:1076-1079,2009.
[22]Dulak J, Loboda A, Jazwa A, et al. Atorvastatin affects several angiogenic mediators in endothelial cells. Endothelium 12:233-241,2005.
[23]J. Styrud, U.J. Eriksson, L. Jansson, A continuous 48-hour glucose infusion in rats causes both an acute and a persistent redistribution of the blood flow within the pancreas, Endocrinology 1992,130:2692-2696.
[24]A.M. Svensson, S.M. Abdel-Halim, S. Efendic, et al. Ostenson, Pancreatic and islet blood flow in Fl-hybrids of the noninsulin-dependent diabetic GK-Wistar rat, Eur. J. Endocrinol.1994,130:612-616.
[25]A.M. Svensson, C.G. Ostenson, S. Sandler, et al. Inhibition of nitric oxide synthase by NG-nitro-L-arginine causes a preferential decrease in pancreatic islet blood flow in normal rats and spontaneously diabetic GK rats. Endocrinology 1994,135:849-853.
[26]G.C. Weir, D.R. Laybutt, H. Kaneto, et al. Beta-cell adaptation and decompensation during the progression of diabetes, Diabetes 2001,50(Suppl. 1):S154-S159.
[27]Bonner-Weir S, Go VLW, Dimagno EP, Gardner JD, Lebenthal E, Reber HA, Scheele GA:The pancreas. Biology, pathobiology and disease. In The microvasculature of the pancreas, with special emphasis on that of the islets of Langerhans. Anatomy and functional implications. New York, Raven Press,1993, pp 759-768.
[28]Konstantinova I, Lammert E:Microvascular development:learning from pancreatic islets. Bioessays 2004,26:1069-1075.
[29]Lammert E, Gu G, McLaughlin M, Brown D, Brekken R, Murtaugh LC, Gerber HP, Ferrara N, Melton DA:Role of VEGF-A in vascularization of pancreatic islets. Curr Biol 2003,13:1070-1074.
[30]Sakamoto C, Goldfine ID, Roach E, Williams JA:Localization of saturable CCK binding sites in rat pancreatic islets by light and electron microscope autoradiography. Diabetes 1985,34:390-394.
[31]Olsson R, Carlsson PO:The pancreatic islet endothelial cell:emerging roles in islet function and disease. Int J Biochem Cell Biol 2006,38:492-497.
[32]Lammert E, Cleaver O, Melton D:Induction of pancreatic differentiation by signals from blood vessels. Science 2001,294:564-567.
[33]Brissova M, Shostak A, Shiota M, Wiebe PO, Poffenberger G, Kantz J, Chen Z, Carr C, Jerome WG, Chen J, Baldwin HS, Nicholson W, Bader DM, Jetton T, Gannon M, Powers AC:Pancreatic islet production of vascular endothelial growth factor-a is essential for islet vas cularization, revascularization, and function. Diabetes 2006,55:2974-2985.
[34]Li X, Zhang L, Meshinchi S, Dias-Leme C, Raffin D, Johnson JD, Treutelaar MK, Burant CF:Islet microvasculature in islet hyperplasia and failure in a model of type 2 diabetes. Diabetes 2006,55:2965-2973.
[35]Favaro E, Miceli I, Bussolati B, et al. Hyperglycemia induces apoptosis of human pancreatic islet endothelial cells:effects of pravastatin on the Akt survival pathway. Am J Pathol 2008; 173:442-50.
[36]Huang Z, Jansson L, Sjoholm A. Vasoactive drugs enhance pancreatic islet blood flow, augment insulin secretion and improve glucose tolerance in female rats. Clin Sci (Lond) 2007; 112:69-76.
[37]Huang Z, Jansson L, Sjoholm A. Gender-specific regulation of pancreatic islet blood flow, insulin levels and glycaemia in spontaneously diabetic Goto-Kakizaki rats. Clin Sci (Lond) 2008; 115:35-42.
[38]Armstrong JS. Mitochondrial medicine:pharmacological targeting of mitochondria in disease. Br J Pharmacol,2007,151:1154-1165.
[39]Kramer J, Moeller EL, Hachey A, et al.Differential expression of GLUT2 in pancreatic islets and kidneys of New and Old World nonhuman primates. Am J Physiol Regul Integr Comp Physiol.2009;296:R786-793.
[40]Matschinsky FM. Banting Lecture 1995. A lesson in metabolic regulation inspired by the glucokinase glucose sensor paradigm. Diabetes 1996,45:223-41.
[41]Unger RH. Diabetic hyperglycemia:link to impaired glucose transport in pancreatic 3 cells. Science 1991,251:1200-5.
[42]Guillam MT, Hummler E, Schaerer E, Yeh JI, Birnbaum MJ, Beermann F, Schmidt A, Deriaz N, Thorens B. Early diabetes and abnormal postnatal pancreatic islet development in mice lacking GLUT2. Nat Genet 1997,17:327-30.
[43]Matschinsky FM, Glaser B, Magnuson MA. Pancreatic β -cell glucokinase: closing the gap between theoretical concepts and experimental realities. Diabetes 1998,47:307-15.
[44]Terauchi Y, Sakura H, Yasuda K, et al. Pancreatic β-cell-specific targeted disruption of glucokinase gene. J Biol Chem 1995,270:30253-6.
[45]ReimerMK, Ahren B. Altered beta2cell distribution of pdx21 andGLUT22 after a short2term challenge with a high2fat diet inC57BL/6J mice[J]. Diabetes, 2002,51 (Suppl 1):1382143.
[46]ThorensB,Wu YJ,Leahy JL, et al. The loss of GLUT2 exp ressionby glucose2unresponsive beta2cells of db/db mice is reversible andis induced by the diabetic environment[J]. J Clin Invest,1992,90(1):772-5.
[47]杨文英,邢小燕,林红,等.高甘油三酯血症是非胰岛素依赖型糖尿病发病的危险因素[J].中华内科杂志,1995,34：583-586.
[48]王曦云,盛莉,刘艳萍,等.洛伐他汀治疗冠心病高胆固醇血症对血管内皮功能微循环及胰岛素敏感性的影响[J].中国实用内科杂志,2003,23(11)：660-662.
[49]姚瑾,陈刚,梁继兴,等.血脂康对血脂正常2型糖尿病患者心血管事件的预防机制研究[J].海峡预防医学杂志,2007,13(3)：75-76.
[50]赵红丽,李潞,刘丽敏,等.血脂康与普伐他汀对血脂正常冠心病患者脂联素及肿瘤坏死因子水平影响的对比研究[J].中国医药导刊,2008,10(1)：113-114.
[1]Oliveira HR, Curi R, Carpinelli AR:Glucose induces an acute increase of superoxide dismutase activity in incubated rat pancreatic islets. Am J Physiol 276:C507-C510,1999.
[2]Ihara Y, Toyokuni S, Uchida K, et al. Hyperglycemia causes oxidative str ess in pancreatic beta cells of GK rats, a model of type 2 diabetes. Diabetes 4 8:927-932,1999.
[3]Tanaka Y, Gleason CE, Tran PO, et al. Prevention of glucose toxicity in HIT-T15 cells and Zucker diabetic fatty rats by antioxidants. Proc Natl Acad S ci U S A 14:10857-10862,1999.
[4]Lenzen S, Drinkgern J, Tiedge M:Low antioxidant enzyme gene expressi on in pancreatic islets compared with various other mouse tissues. Free Radic Biol Med 20:463-466,1996.
[5]Laybutt DR, Kaneto H, Hasenkamp W, et al. Increased expression of anti oxidant and antiapoptotic genes in islets that may contribute to beta-cell surviv al during chronic hyperglycemia. Diabetes 51:413-423,2002.
[6]Lu D, Maulik N, Moraru II, Kreutzer DL, Das DK:Molecular adaptation of vascular endothelial cells to oxidative stress. Am J Physiol 264:C715-C722, 1993.
[7]Ceriello A, dello Russo P, Amstad P, Cerutti P:High glucose induces ant ioxidant enzymes in human endothelial cells in culture:evidence linking hyperg lycemia and oxidative stress. Diabetes 45:471-477,1996.
[8]M. A. Modak, P. B. Parab, and S. S. Ghaskadbi. Pancreatic islets are ver y poor in rectifying oxidative DNA damage. Pancreas, vol.38, no.1, pp.23-29,2009.
[9]Y. Ihara, S. Toyokuni, K. Uchida et al., "Hyperglycemia causes oxidative stress in pancreatic β-cells of GK rats, a model of type 2 diabetes," Diabetes, vol.48, no.4, pp.927-932,1999.
[10]S. Del Guerra, R. Lupi, L. Marselli et al., "Functional and molecular def ects of pancreatic islets in human Type 2 diabetes," Diabetes, vol.54, no.3, p p.727-735,2005.
[11]S. I. Gorogawa, Y. Kajimoto, Y. Umayahara et al., "Probucol preserves pancreatic β-cell function through reduction of oxidative stress in type 2 diabet es," Diabetes Research and Clinical Practice, vol.57, no.1, pp.1-10,2002.
[12]Babior BM, Lambeth JD, Nuseef W:The neutrophil NADPH oxidase. Arch Biochem Biophys 397:342-344,2002.
[13]Pithon-Curi TC, Levada AC, Lopes LR, Doi SQ, Curi R:Glutamine p1 ays a role in superoxide production and the expression of p47PHOX in rat neu trophils. Clin Sci 103:403-408,2002.
[14]M. Nakayama, T. Inoguchi, T. Sonta et al., "Increased expression of N AD(P)H oxidase in islets of animal models of type 2 diabetes and its improve ment by an AT1 receptor antagonist," Biochemical and Biophysical Research C ommunications, vol.332, no.4, pp.927-933,2005.
[15]H. R. Oliveira, R. Verlengia, C. R. O. Carvalho, etal. "Pancreatic β-ce lls express phagocyte-like NAD(P)H oxidase," Diabetes, vol.52, no.6,pp.1457-1463,2003.
[16]Y. Uchizono, R. Takeya, M. Iwase et al., "Expression of isoforms of N ADPH oxidase components in rat pancreatic islets," Life Sciences, vol.80, no. 2, pp.133-139,2006.
[17]P. Newsholme, C. Gaudel, and M. Krause, "Mitochondria and diabetes. An intriguing pathogenetic role," Advances in Experimental Medicine and Biolo gy, vol.942, pp.235-247,2012.
[18]Miura Y, Kato M, Ogino K, Matsui H. Impaired cytosolic Ca2+ response t o glucose and gastric inhibitory polypeptide in pancreatic beta-cells from triphenylti n-induced diabetic hamster. Endocrinology.1997 Jul;138(7):2769-75.
[19]Burdon RH:Superoxide and hydrogen peroxide in relation to mammalia n cell proliferation. Free Radic Biol Med 18:775-794,1995.
[20]Schoonbroodt S, Piette J:Oxidative stress interference with the nuclear factor-kappa B activation pathways. Biochem Pharmacol 60:1075-1083,2000.
[21]Lu D, Maulik N, Moraru II, Kreutzer DL, Das DK:Molecular adaptati on of vascular endothelial cells to oxidative stress. Am J Physiol 264:C715-C7 22,1993.
[22]Lo YY, Wong JM, Cruz TF:Reactive oxygen species mediate cytokine activation of c-Jun NH2-terminal kinases. J Biol Chem 271:15703-15707,199 6.
[23]Vega-Saenz de Miera E, Rudy B:Modulation of K+ channels by hydro gen peroxide. Biochem Biophys Res Commun 186:1681-1687,1992.
[24]Wang D, Youngson C, Wong V, et al. NADPH-oxidase and a hydroge n peroxide-sensitive K+ channel may function as an oxygen sensor complex in airway chemoreceptors and small cell lung carcinoma cell lines. Proc Natl Aca d Sci U S A 93:13182-13187,1996.
[25]Li P, Yang Y, Liu M. Xuezhikang, extract of red yeast rice, inhibited tiss ue factor and hypercoagulable state through suppressing nicotinamide adenine di nucleotide phosphate oxidase and extracellular signal-regulated kinase activation. J Cardiovasc Pharmacol.2011 Sep;58(3):307-18.
[26]Brownlee M.:Biochemistry and molecular cell biology of diabetic comp lications. Nature 2001;414:813-820.
[27]黄彦生,王树人,智艳芳等。血脂康胶囊对冠心病患者血管内皮功能及氧化还原态的影响。中西医结合学报,2006,3：251-255。
[28]Hong XZ, Li LD, Wu LM.. Effects Of Fenofibrate And Xuezhikang On High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease. Clin Exp Pharmacol Physiol.2007 Jan-Feb;34(1-2):27-35.
[29]Wu LL, Chiou CC, Chang PY, Wu JT. Urinary 8-OHdG:a marker of oxid ative stress to DNA and a risk factor for cancer, atherosclerosis and diabetics. C lin Chim Acta.2004 Jan;339(1-2):1-9.
[30]Shida T, Nozawa T, Sobajima M, et al. Fluvastatin-induced reduction of o xidative stress ameliorates diabetic cardiomyopathy in association with improvin g coronary microvasculature. Heart Vessels.2013 Aug 25. [Epub ahead of prin t]
[31]血脂康胶囊临床应用中国专家共识组.血脂康胶囊临床应用中国专家共识[J].中国社区医师,2009,25(14)：9-10.
[32]魏炜,李仁立,涂玲,等.血浆高甘油三酯对老年人血管内皮功能的损害及血脂康的修复作用[J].临床心血管病杂志,2002,18(7)：336-337.
[33]周建红,常獍宇,李会恩,等.脂质异常家兔抗氧化能力与血管细胞黏附因子-1的变化以及血脂康对其影响[J].天津药学,2010,22(1)：1-3.
[34]程茅薇,顾萍,马健,杜宏,卢斌,邵加庆.血脂康对db/db糖尿病小鼠周围神经病变的保护作用研究.现代中西医结合杂志.2011 Nov,20(31),3921-3923.
[35]Kaneto H, Kajimoto Y, Miyagawa J, et al. Beneficial effects of antioxid ants in diabetes:possible protection of pancreatic beta-cells against glucose toxi city. Diabetes.1999 Dec;48(12):2398-406.
[36]A. R. Giniatullin, F. Darios, A. Shakirzyanova, B. Davletov, and R. Gi niatullin, "SNAP25 is a pre-synaptic target for the depressant action of reactive oxygen species on transmitter release," Journal of Neurochemistry, vol.98, no. 6, pp.1789-1797,2006.
[37]R. Ivarsson, R. Quintens, S. Dejonghe et al., "Redox control of exocyto sis:regulatory role of NADPH, thioredoxin, and glutaredoxin," Diabetes, vol.5 4, no.7, pp.2132-2142,2005.
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |