五味子油抗大鼠2型糖尿病作用的研究
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摘要
目的：目前临床上治疗糖尿病的药物主要有胰岛素及一些口服降糖。这些药物在治疗糖尿病的同时往往也带来了许多不良反应。因此，寻找高效低毒的抗糖尿病及其并发症的药物目前仍然是医药工作者面临的重大课题。本研究旨在观察五味子油对2型糖尿病大鼠相关血清学生化指标的影响，明确其在2型糖尿病治疗中的保护作用。并进一步分析其对脂肪组织中多种脂肪细胞因子及炎症因子表达以及对胰腺组织凋亡的影响，以阐明五味子油抗2型糖尿病的潜在机制。
材料与方法：第一部分：五味子油对2型糖尿病大鼠生化指标的影响。首先采用高脂饲料喂养SD大鼠4周，然后按30mg/kg(0.24ml/100g)的剂量一次性腹腔注射链脲佐菌素(Streptozotocin, STZ)溶液的方法来制备2型糖尿病大鼠模型。将模型大鼠随机分为模型组、低剂量五味子油组、高剂量五味子油组及罗格列酮阳性对照组，另设空白对照组及五味子油对照组。每组8只，分别按照分组给予不同处理因素：正常对照组继续以普通饲料喂养；五味子油对照组在进行普通饲料喂养的同时，每天以五味子油1.0mg/kg经灌胃给药；模型组继续喂以高脂饲料；五味子油低剂量组在喂以高脂饲料的同时，每天以五味子油0.5mg/kg经灌胃给药；五味子油高剂量组在喂以高脂饲料的同时，每天以五味子油1.0mg/kg经灌胃给药；罗格列酮阳性对照组在喂以高脂饲料的同时，每天以罗格列酮30mg/kg经灌胃给药。各组SD大鼠经处理6周后，每组大鼠随机抽取6只用于采集数据，各组大鼠禁食不禁水12h，用血糖仪检测其空腹血糖；采用乙醚麻醉，颈动脉取血5mL，离心收集血清，检测血脂及胰岛素水平，并计算胰岛素敏感指数。第二部分：五味子油对模型动物脂肪组织中与胰岛素抵抗相关的各种炎症因子及脂肪细胞因子mRNA及蛋白表达的影响。该部分动物饲养、建立动物模型、分组及处理因素与第一部分相同。于用药处理6周后麻醉取腹膜脂肪组织，分别利用RT-PCR及Western blot方法检测胰岛素抵抗相关的炎症因子：白细胞介素6(Interleukin-6, IL-6)、核因子κB(Nuclear factor-κB, NF-κB)、白细胞介素1β(Interleukin-1β,IL-1β)、C反应蛋白(C-reactive protein, CRP)、肿瘤坏死因子α(Tumor necrosis factor-α, TNF-α)及单核细胞趋化蛋白-1(Monocytechemoattranctant protein-1, MCP-1)和脂肪细胞因子：葡萄糖转运体4(Glucosetransporter-4, GLUT-4)、脂联素(Adiponectin)及视黄醇结合蛋白-4(Retinol bindingprotein-4, RBP-4)在转录和翻译水平的表达；第三部分：五味子油对模型动物胰腺组织形态学及凋亡相关蛋白Bcl-2、Bax和cleaved Caspase-3蛋白表达的影响。该部分动物饲养、建立动物模型、分组及处理因素等与第一部分相同。于用药处理6周后麻醉摘取SD大鼠的胰腺组织，用HE染色观察各组大鼠胰腺组织的形态学改变；采用Western blot检测各组大鼠胰腺组织的中凋亡相关蛋白Bcl-2、Bax和cleaved Caspase-3蛋白的表达水平。
结果：
1五味子油对2型糖尿病大鼠生化指标的影响
1.1五味子油对2型糖尿病大鼠一般状况的影响
空白对照组大鼠精神状态良好，皮毛有光泽，反应灵敏，体重维持稳定上升，未见死亡。五味子油对照组大鼠与对照组大鼠情况基本类似。与空白对照组大鼠相比，模型组大鼠饮食和饮水均增加，尿多并且消瘦，精神萎靡不振，反应迟钝，皮毛无光泽。五味子油低剂量及高剂量组，经五味子油治疗6周后，糖尿病大鼠的上述症状均有所好转，且高剂量组的治疗效果显著优于低剂量组。高剂量五味子油的效应与阳性对照药物罗格列酮类似。
1.2五味子油对2型糖尿病大鼠空腹血糖的影响
与空白对照组相比，糖尿病模型组大鼠空腹血糖(fasting blood glucose, FBG)水平明显升高(P<0.01)，五味子油对照组大鼠的FBG表达水平相当，未见明显差异。五味子油低剂量及高剂量组，FBG均明显低于模型组(低剂量组P<0.05；高剂量组P<0.01)，而五味子油高剂量组对FBG的影响与罗格列酮类似，血糖几乎恢复正常值。
1.3五味子油对2型糖尿病大鼠血脂水平的影响
与空白对照组大鼠相比，模型组大鼠血清中总胆固醇(total cholesterol, TC)、甘油三酯(triglyceride, TG)TG、低密度脂蛋白胆固醇（Low density lipoproteincholesterol, LDL-C）水平均显著升高(P<0.01)，而高密度脂蛋白胆固醇（Highdensity lipoprotein cholesterol, HDL-C）水平显著降低(P<0.01)；对于五味子油对照组与空白对照组相比血脂水平无明显差异(P>0.05)，与模型组相比，五味子油低剂量和高剂量组TC、TG、LDL-C水平均显著降低，(P<0.05，P<0.01)，而HDL-C水平则显著升高(P<0.05，P<0.01)，且高剂量组对改善脂类代谢异常作用显著优于低剂量组。五味子油高剂量组对血脂水平的影响与阳性对照药罗格列酮类似。
1.4五味子油对2型糖尿病大鼠空腹胰岛素水平（fasting plasma insulin level,FINS）和胰岛素抵抗指数（insulin resistance index, HOMA-IR）的影响
与空白对照组相比，五味子油对照组FINS和HOMA-IR均无显著差异(P>0.05)，而糖尿病模型组FINS和HOMA-IR水平显著升高(P<0.01)。在用药6周后，与模型组相比，五味子油低剂量、高剂量组均能降低FINS和HOMA-IR水平(P<0.05，P<0.01)，且高剂量组改善FINS和HOMA-IR作用显著优于低剂量组。五味子油高剂量组和罗格列酮组对FINS和HOMA-IR水平的影响类似。
2五味子油对模型动物脂肪组织中与胰岛素抵抗相关的炎症因子及脂肪细胞因子mRNA及蛋白表达的影响
利用RT-PCR检测各组大鼠脂肪组织中脂肪因子(GLUT-4、Adiponectin及RBP-4)和炎症因子(IL-6，CRP，MCP-1，IL1β，TNF-α、NF-κB)mRNA的表达。结果显示，与空白对照组相比，模型组脂肪因子GLUT-4、Adiponectin的表达水平明显降低(P<0.01)，而脂肪因子RBP-4的表达显著升高(P<0.01)，各种炎症因子IL-6，CRP，MCP-1，IL1β，TNF-α、NF-κB的表达均明显升高(P<0.01)。五味子油能显著逆转上述蛋白表达的改变，且高剂量组优于低剂量组。五味子油高剂量可达到药性对照药罗格列酮的水平。五味子油本身不影响对上述因子表达。
利用免疫印迹法检测各组大鼠脂肪组织中脂肪因子(GLUT-4、Adiponectin及RBP-4)和炎症因子(IL-6，CRP，MCP-1，IL1β，TNF-α、NF-κB)翻译水平的表达。结果显示，与空白对照组相比，模型组脂肪因子GLUT-4、Adiponectin的表达水平明显降低(P<0.01)，而脂肪因子RBP-4的表达显著升高(P<0.01)，对于脂肪组织中炎症因子IL-6，CRP，MCP-1，IL1β，TNF-α、NF-κB的表达均明显升高(P<0.01)。五味子油能显著逆转上述蛋白表达的改变，且高剂量组优于低剂量组。五味子油高剂量可达到药性对照药罗格列酮的水平。五味子油本身不影响对上述因子表达。
3五味子油对模型动物胰腺组织形态学及凋亡相关蛋白Bcl-2、Bax和cleavedCaspase-3蛋白表达的影响
经HE染色，镜下观察各组SD大鼠胰腺组织及胰岛细胞的形态，空白对照组及五味子油对照组大鼠胰岛形状规则，呈圆形或椭圆形团索状，边界清晰，胰岛内β细胞分布均匀，排列紧密，胞浆丰富。糖尿病模型组大鼠胰岛体积变小，明显萎缩，结构不清、边缘不整。胰岛内胰岛β细胞细胞数明显减少，排列稀疏，部分细胞肿胀、坏死，有空泡变性发生。经五味子油治疗6周后，与模型组相比，胰岛细胞形态更趋于完整，胰岛边界渐清晰，β细胞数目增加，细胞形态较好，无明显的肿胀及坏死，高剂量组对胰腺组织的保护作用可达到阳性对照药罗格列酮的水平。
经蛋白质免疫印迹检测各组大鼠脂肪组织中Bcl-2、Bax和cleaved Caspase-3蛋白的表达水平。结果显示，与空白对照组相比，模型组的cleaved Caspase-3的表达水平明显升高(P<0.01)，Bcl-2的表达水平显著降低，而Bax表达情况未见明显改变，五味子油对照组中Bcl-2、Bax和cleaved Caspase-3蛋白的表达水平均无明显改变。经五味子油治疗6周后，与模型组相比，五味子油低剂量和高剂量组糖尿病大鼠胰腺组织cleaved Caspase-3的表达均显著降低，而Bcl-2的表达水平均显著升高。且高剂量五味子油组的治疗效果显著优于低剂量组。高剂量五味子油的效果与阳性对照药物罗格列酮相似。
结论：
通过五味子油对2型糖尿病大鼠模型进行干预，并以罗格列酮作为阳性对照药物。本研究得出如下实验结论：
1.五味子油对高脂饮食饲养加小剂量STZ注射诱导的2型糖尿病大鼠血糖、血脂及胰岛素的抵抗状态都有显著的改善作用。
2.五味子油治疗纠正脂肪组织中胰岛素抵抗相关的脂肪因子及炎症因子的表达，进而改善胰岛素抵抗。证实五味子油具有显著的抗炎活性，该活性可能是其发挥抗糖尿病作用的重要机制。
3.五味子油还可以保护2型糖尿病模型鼠受损的胰腺组织，抑制胰腺细胞凋亡。表现为：促进抑凋亡基因Bcl-2的表达；抑制凋亡执行蛋白cleaved-caspase-3的表达。
Purpose：Present therapy for diabetes mellitus (DM) comprehend insulin and someoral hypoglycemic medications including sulphonylurea derivatives, α glucosidaseinhibitors, biguanides as well as thiazolidinediones. Although efficient, theses drugsgenerally have many undesirable adverse reactions such as constipation, obesity, drymouth, valvular heart disease and high blood pressure, etc, and some agents like thefirst-generation and second-generation sulphonylurea derivatives even destroy β cellof Langerhans islands when producing glycemic efffect, all of these side effectsgreatly limit their utilization in the treatment of DM. To date, traditional herbal agentshave received increased attention due to their well-known limited adverse effects.Therefore current work was carried out to examine the beneficial effects ofSchizandrae Fructus oil (SFO), an oily extract of Schisandra chinensis (Turcz.) Baill.,on the serological indicators of rats with type2diabetes, and furtherly, explore itspotential mechanism on two major grounds, i.e., insulin resistance and pancreatictissue apoptosis.
Materials and Methods: Part I: Effects of Schizandrae Fructus oil on theserological indicators of rats with type2diabetes. Through high-fat diet plus low-dosetail vein injection of streptozotocin (STZ), type2diabetic rats were developed andwere divided into the following groups: model group, low-dose SFO group, high-doseSFO group and rosiglitazone group. Additionally, control group and SFO controlgroup, in which high dose of SFO was applied on normal rat were establishedaccordingly.8rats were included in each group and treated according to the protocolas belows: control group received a normal chow diet; SFO control group were treatedwith SFO when fed with a normal chow diet; model group continued on its high-fatdiet; low-dose SFO group and high-dose SFO group were treated with0.5and1.0mg/kg SFO, respectively; and rosiglitazone group recived30mg/kg rosiglitazone.SFO and rosiglitazone were both administered via epi-gastric route using a feeding needle. All the treatment was given daily for6weeks and subsequently,6rats pergroup were sampled and fasted up to12h for the examination of diverse serologicalindicators, including fasting blood glucose (FBG), lipidemic and insulinemic level.Furthermore, index of insulin resistance was estimated and calculated by thehomeostasis model assessment (HOMA). Part II: Effects of Schizandrae Fructus oilon the expresion of insulin resistance related adipokines and inflammatory markers inthe adipose tissue. Procedures including rat feeding, model developing, grouping andtreatment protocol were all in agreement with Part I. After6week treatment,6ratsper group were sampled and peritoneal adipose tissue were taken and subsequentlyreverse transcript polymerase chain reaction (RT-PCR) and westen blotting were usedto examine the expression of diverse insulin resistance related adipokines andinflammatory markers at the transcription and translation level, respectively. Thosesadipokines include glucose transporter-4(GLUT-4), adiponectin and retinal bindingprotein-4(RBP-4), and inflammatory makers are interleukin-6(IL-6), nuclear factorκB (NF-κB), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), C-reactiveprotein (CRP) and monocyte chemoattanctant protein-1(MCP-1). Part III: Effects ofSchizandrae Fructus oil on the pancreatic tissue morphology and its apoptosis relatedprotein expression, including cleaved caspase-3, Bcl-2and Bax. Procedures includingrat feeding, model developing, grouping and treatment protocol were all in agreementwith Part I. After6week treatment,6rats per group were sampled and pancreatictissue was removed for the subsequent test of pancreatic mophorlogy. Meanwhile,Gene expression of cleaved caspase-3, Bcl-2and Bax was also carried out by usingwestern blotting.
Results:
1Effects of Schizandrae Fructus oil on the serological indicators of rats withtype2diabetes.
1.1Effects of Schizandrae Fructus oil on the general status of type2diabetic rats.Rats in control group were in great form with silky coats, quick reflex and bodyweight steadily creeping up. Rats in Schizandrae Fructus oil control group shared similar status with those in control group. Compared with control group, model grouprats exhibited such classical symptoms of DM as polyuria, polydipsia, polyphagia andweight loss. Moreover, these rats were slouchy, slow on the draw and had dim anddark fur. Compared with control group, the performance of rats in low-dose orhigh-dose Schizandrae Fructus oil was greatly improved, with high-dose group muchbetter than low-dose. The effect of high-dose Schizandrae Fructus oil treatment wascomparable to rosigilitazone treatment.
1.2Effects of Schizandrae Fructus oil on fasting blood glucose of type2diabetic rats.Compared with control group, model group had markedly elevated fasting bloodglucose, which was significantly decreased by Schizandrae Fructus oil dosedependently. The fasting blood glucose level in high-dose Schizandrae Fructus oilgroup was similar to rosigilitazone group, almost declined to the normal level.
1.3Effects of Schizandrae Fructus oil on lipidemic level of type2diabetic rats.Compared with control group, model group had markedly elevated levels of totalcholesterol, triglyceride, low density lipoprotein cholesterol as well as decreased levelof high density lipoprotein cholesterol, which were significantly reversed bySchizandrae Fructus oil dose dependently. The fasting lipidemic level in high-doseSchizandrae Fructus oil group was comparable to rosigilitazone group.
1.4Effects of Schizandrae Fructus oil on FINS and HOMA-IR of type2diabetic rats.Compared with control group, while no significant changes of FINS and HOMA-IRwere observed in Schizandrae Fructus oil group, model group exhibited markablelyelevated FINS and HOMA-IR. These abnormal changes were significantlyameliorated, to varying degrees, by application of low or high dose of SchizandraeFructus oil or resiglitazone. The effects of high-dose Schizandrae Fructus oil werecomparable to resiglitazone and better than low-dose Schizandrae Fructus oil.
2Effects of Schizandrae Fructus oil on the expression of insulin resistancerelated adipokines and inflammatory markers in the peritoneal adipose tissue.Reverse transcriptional polymerase chain reaction (RT-PCR) was introduced toexamine the influence of Schizandrae Fructus oil on the expression of variousadipokines and inflammatory markers in the gene (mRNA) transcription level. The results revealed that peritoneal adipose tissue from diabetic model group rats hadhigher mRNA expression of all inflammatory markers including IL-6, CRP, MCP-1,IL1β, TNF-α and NF-κB. Meanwhile, the expression Adipoctokines including andGLUT-4and Adiponectin were also decreased in mRNA level in the peritonealadipose tissue of diabetic model rats, whose expression in RBP-4were, however,lower than that from the control group. These abnormal changes were significantlyreversed, to varying degrees, by application of resiglitazone or low or high dose ofSchizandrae Fructus oil, which itself had no any influence on various geneexpressions. The effects of high-dose Schizandrae Fructus oil on the mRNAexpression were comparable to resiglitazone, oral hypoglycemic agent belonging tothiazolidinediones, and better than low-dose Schizandrae Fructus oil.
Subsequently, Western blot was employed to examine the influence of SchizandraeFructus oil on the expression of various adipokines and inflammatory markers in theprotein translation level. The results demonstrate that all the alteration of theadipokines and inflammatory markers in protein (translation) were reconcilable withtheir changes in mRNA (transcription) level. That is, peritoneal adipose tissue fromdiabetic model group rats had higher protein expression of all inflammatory markersincluding IL-6, CRP, MCP-1, IL1β, TNF-α and NF-κB. Meanwhile, the expressionsof adipoctokines including GLUT-4and Adiponectin were also decreased in proteinlevel in the peritoneal adipose tissue of diabetic model rats, whose expression inRBP-4was, however, lower than that from the control group. These abnormalchanges were significantly reversed, to varying degrees, by application ofresiglitazone or low or high dose of Schizandrae Fructus oil, which itself had no anyinfluence on various gene expressions. The effects of high-dose Schizandrae Fructusoil on the protein expression were comparable to resiglitazone, oral hypoglycemicagent belonging to thiazolidinediones, and better than low-dose Schizandrae Fructusoil.
3Effects of Schizandrae Fructus oil on the pancreatic tissue morphology and itsapoptosis related protein expression.
Application of Schizandrae Fructus oil could take a series of positive influence on thepathological changes including restore shrinked pancrease tissue and decreasednumber of β cells. Besides, Schizandrae Fructus oil greatly protected pancrease fromapoptotic damage, as demonstrated by diverse apoptosis relavant protein expression.Although Bax protein expression was unchanged, model group rats had higher proteinexpression of cleaved caspase-3and lower Bcl-2than control group. Both weregreatly corrected by application of low or high dose of Schizandrae Fructus oil orresiglitazone. The effects of high-dose Schizandrae Fructus oil were comparable toresiglitazone and better than low-dose Schizandrae Fructus oil. Schizandrae Fructusoil itself had no effect on caspase-3and lower Bcl-2expression.
Conclusion:
1. Schizandrae Fructus oil treatment could improve insulin resisrance, attenuatehyperglycemia and hyperlipidemia, and hyperinsulinemia in fat-fed stepzotocininduced type2diabetic rat model.
2. Schizandrae Fructus oil treatment could produce beneficical effects on diabetes bycorrecting insulin resisrance associated gene expression.
3. Schizandrae Fructus oil treatment could preserve pancreatic morphology, decreasepancreatic apoptosis by reducing cleaved caspase-3expressin and increasing Bcl-2.
材料与方法：第一部分：五味子油对2型糖尿病大鼠生化指标的影响。首先采用高脂饲料喂养SD大鼠4周，然后按30mg/kg(0.24ml/100g)的剂量一次性腹腔注射链脲佐菌素(Streptozotocin, STZ)溶液的方法来制备2型糖尿病大鼠模型。将模型大鼠随机分为模型组、低剂量五味子油组、高剂量五味子油组及罗格列酮阳性对照组，另设空白对照组及五味子油对照组。每组8只，分别按照分组给予不同处理因素：正常对照组继续以普通饲料喂养；五味子油对照组在进行普通饲料喂养的同时，每天以五味子油1.0mg/kg经灌胃给药；模型组继续喂以高脂饲料；五味子油低剂量组在喂以高脂饲料的同时，每天以五味子油0.5mg/kg经灌胃给药；五味子油高剂量组在喂以高脂饲料的同时，每天以五味子油1.0mg/kg经灌胃给药；罗格列酮阳性对照组在喂以高脂饲料的同时，每天以罗格列酮30mg/kg经灌胃给药。各组SD大鼠经处理6周后，每组大鼠随机抽取6只用于采集数据，各组大鼠禁食不禁水12h，用血糖仪检测其空腹血糖；采用乙醚麻醉，颈动脉取血5mL，离心收集血清，检测血脂及胰岛素水平，并计算胰岛素敏感指数。第二部分：五味子油对模型动物脂肪组织中与胰岛素抵抗相关的各种炎症因子及脂肪细胞因子mRNA及蛋白表达的影响。该部分动物饲养、建立动物模型、分组及处理因素与第一部分相同。于用药处理6周后麻醉取腹膜脂肪组织，分别利用RT-PCR及Western blot方法检测胰岛素抵抗相关的炎症因子：白细胞介素6(Interleukin-6, IL-6)、核因子κB(Nuclear factor-κB, NF-κB)、白细胞介素1β(Interleukin-1β,IL-1β)、C反应蛋白(C-reactive protein, CRP)、肿瘤坏死因子α(Tumor necrosis factor-α, TNF-α)及单核细胞趋化蛋白-1(Monocytechemoattranctant protein-1, MCP-1)和脂肪细胞因子：葡萄糖转运体4(Glucosetransporter-4, GLUT-4)、脂联素(Adiponectin)及视黄醇结合蛋白-4(Retinol bindingprotein-4, RBP-4)在转录和翻译水平的表达；第三部分：五味子油对模型动物胰腺组织形态学及凋亡相关蛋白Bcl-2、Bax和cleaved Caspase-3蛋白表达的影响。该部分动物饲养、建立动物模型、分组及处理因素等与第一部分相同。于用药处理6周后麻醉摘取SD大鼠的胰腺组织，用HE染色观察各组大鼠胰腺组织的形态学改变；采用Western blot检测各组大鼠胰腺组织的中凋亡相关蛋白Bcl-2、Bax和cleaved Caspase-3蛋白的表达水平。
结果：
1五味子油对2型糖尿病大鼠生化指标的影响
1.1五味子油对2型糖尿病大鼠一般状况的影响
空白对照组大鼠精神状态良好，皮毛有光泽，反应灵敏，体重维持稳定上升，未见死亡。五味子油对照组大鼠与对照组大鼠情况基本类似。与空白对照组大鼠相比，模型组大鼠饮食和饮水均增加，尿多并且消瘦，精神萎靡不振，反应迟钝，皮毛无光泽。五味子油低剂量及高剂量组，经五味子油治疗6周后，糖尿病大鼠的上述症状均有所好转，且高剂量组的治疗效果显著优于低剂量组。高剂量五味子油的效应与阳性对照药物罗格列酮类似。
1.2五味子油对2型糖尿病大鼠空腹血糖的影响
与空白对照组相比，糖尿病模型组大鼠空腹血糖(fasting blood glucose, FBG)水平明显升高(P<0.01)，五味子油对照组大鼠的FBG表达水平相当，未见明显差异。五味子油低剂量及高剂量组，FBG均明显低于模型组(低剂量组P<0.05；高剂量组P<0.01)，而五味子油高剂量组对FBG的影响与罗格列酮类似，血糖几乎恢复正常值。
1.3五味子油对2型糖尿病大鼠血脂水平的影响
与空白对照组大鼠相比，模型组大鼠血清中总胆固醇(total cholesterol, TC)、甘油三酯(triglyceride, TG)TG、低密度脂蛋白胆固醇（Low density lipoproteincholesterol, LDL-C）水平均显著升高(P<0.01)，而高密度脂蛋白胆固醇（Highdensity lipoprotein cholesterol, HDL-C）水平显著降低(P<0.01)；对于五味子油对照组与空白对照组相比血脂水平无明显差异(P>0.05)，与模型组相比，五味子油低剂量和高剂量组TC、TG、LDL-C水平均显著降低，(P<0.05，P<0.01)，而HDL-C水平则显著升高(P<0.05，P<0.01)，且高剂量组对改善脂类代谢异常作用显著优于低剂量组。五味子油高剂量组对血脂水平的影响与阳性对照药罗格列酮类似。
1.4五味子油对2型糖尿病大鼠空腹胰岛素水平（fasting plasma insulin level,FINS）和胰岛素抵抗指数（insulin resistance index, HOMA-IR）的影响
与空白对照组相比，五味子油对照组FINS和HOMA-IR均无显著差异(P>0.05)，而糖尿病模型组FINS和HOMA-IR水平显著升高(P<0.01)。在用药6周后，与模型组相比，五味子油低剂量、高剂量组均能降低FINS和HOMA-IR水平(P<0.05，P<0.01)，且高剂量组改善FINS和HOMA-IR作用显著优于低剂量组。五味子油高剂量组和罗格列酮组对FINS和HOMA-IR水平的影响类似。
2五味子油对模型动物脂肪组织中与胰岛素抵抗相关的炎症因子及脂肪细胞因子mRNA及蛋白表达的影响
利用RT-PCR检测各组大鼠脂肪组织中脂肪因子(GLUT-4、Adiponectin及RBP-4)和炎症因子(IL-6，CRP，MCP-1，IL1β，TNF-α、NF-κB)mRNA的表达。结果显示，与空白对照组相比，模型组脂肪因子GLUT-4、Adiponectin的表达水平明显降低(P<0.01)，而脂肪因子RBP-4的表达显著升高(P<0.01)，各种炎症因子IL-6，CRP，MCP-1，IL1β，TNF-α、NF-κB的表达均明显升高(P<0.01)。五味子油能显著逆转上述蛋白表达的改变，且高剂量组优于低剂量组。五味子油高剂量可达到药性对照药罗格列酮的水平。五味子油本身不影响对上述因子表达。
利用免疫印迹法检测各组大鼠脂肪组织中脂肪因子(GLUT-4、Adiponectin及RBP-4)和炎症因子(IL-6，CRP，MCP-1，IL1β，TNF-α、NF-κB)翻译水平的表达。结果显示，与空白对照组相比，模型组脂肪因子GLUT-4、Adiponectin的表达水平明显降低(P<0.01)，而脂肪因子RBP-4的表达显著升高(P<0.01)，对于脂肪组织中炎症因子IL-6，CRP，MCP-1，IL1β，TNF-α、NF-κB的表达均明显升高(P<0.01)。五味子油能显著逆转上述蛋白表达的改变，且高剂量组优于低剂量组。五味子油高剂量可达到药性对照药罗格列酮的水平。五味子油本身不影响对上述因子表达。
3五味子油对模型动物胰腺组织形态学及凋亡相关蛋白Bcl-2、Bax和cleavedCaspase-3蛋白表达的影响
经HE染色，镜下观察各组SD大鼠胰腺组织及胰岛细胞的形态，空白对照组及五味子油对照组大鼠胰岛形状规则，呈圆形或椭圆形团索状，边界清晰，胰岛内β细胞分布均匀，排列紧密，胞浆丰富。糖尿病模型组大鼠胰岛体积变小，明显萎缩，结构不清、边缘不整。胰岛内胰岛β细胞细胞数明显减少，排列稀疏，部分细胞肿胀、坏死，有空泡变性发生。经五味子油治疗6周后，与模型组相比，胰岛细胞形态更趋于完整，胰岛边界渐清晰，β细胞数目增加，细胞形态较好，无明显的肿胀及坏死，高剂量组对胰腺组织的保护作用可达到阳性对照药罗格列酮的水平。
经蛋白质免疫印迹检测各组大鼠脂肪组织中Bcl-2、Bax和cleaved Caspase-3蛋白的表达水平。结果显示，与空白对照组相比，模型组的cleaved Caspase-3的表达水平明显升高(P<0.01)，Bcl-2的表达水平显著降低，而Bax表达情况未见明显改变，五味子油对照组中Bcl-2、Bax和cleaved Caspase-3蛋白的表达水平均无明显改变。经五味子油治疗6周后，与模型组相比，五味子油低剂量和高剂量组糖尿病大鼠胰腺组织cleaved Caspase-3的表达均显著降低，而Bcl-2的表达水平均显著升高。且高剂量五味子油组的治疗效果显著优于低剂量组。高剂量五味子油的效果与阳性对照药物罗格列酮相似。
结论：
通过五味子油对2型糖尿病大鼠模型进行干预，并以罗格列酮作为阳性对照药物。本研究得出如下实验结论：
1.五味子油对高脂饮食饲养加小剂量STZ注射诱导的2型糖尿病大鼠血糖、血脂及胰岛素的抵抗状态都有显著的改善作用。
2.五味子油治疗纠正脂肪组织中胰岛素抵抗相关的脂肪因子及炎症因子的表达，进而改善胰岛素抵抗。证实五味子油具有显著的抗炎活性，该活性可能是其发挥抗糖尿病作用的重要机制。
3.五味子油还可以保护2型糖尿病模型鼠受损的胰腺组织，抑制胰腺细胞凋亡。表现为：促进抑凋亡基因Bcl-2的表达；抑制凋亡执行蛋白cleaved-caspase-3的表达。
Purpose：Present therapy for diabetes mellitus (DM) comprehend insulin and someoral hypoglycemic medications including sulphonylurea derivatives, α glucosidaseinhibitors, biguanides as well as thiazolidinediones. Although efficient, theses drugsgenerally have many undesirable adverse reactions such as constipation, obesity, drymouth, valvular heart disease and high blood pressure, etc, and some agents like thefirst-generation and second-generation sulphonylurea derivatives even destroy β cellof Langerhans islands when producing glycemic efffect, all of these side effectsgreatly limit their utilization in the treatment of DM. To date, traditional herbal agentshave received increased attention due to their well-known limited adverse effects.Therefore current work was carried out to examine the beneficial effects ofSchizandrae Fructus oil (SFO), an oily extract of Schisandra chinensis (Turcz.) Baill.,on the serological indicators of rats with type2diabetes, and furtherly, explore itspotential mechanism on two major grounds, i.e., insulin resistance and pancreatictissue apoptosis.
Materials and Methods: Part I: Effects of Schizandrae Fructus oil on theserological indicators of rats with type2diabetes. Through high-fat diet plus low-dosetail vein injection of streptozotocin (STZ), type2diabetic rats were developed andwere divided into the following groups: model group, low-dose SFO group, high-doseSFO group and rosiglitazone group. Additionally, control group and SFO controlgroup, in which high dose of SFO was applied on normal rat were establishedaccordingly.8rats were included in each group and treated according to the protocolas belows: control group received a normal chow diet; SFO control group were treatedwith SFO when fed with a normal chow diet; model group continued on its high-fatdiet; low-dose SFO group and high-dose SFO group were treated with0.5and1.0mg/kg SFO, respectively; and rosiglitazone group recived30mg/kg rosiglitazone.SFO and rosiglitazone were both administered via epi-gastric route using a feeding needle. All the treatment was given daily for6weeks and subsequently,6rats pergroup were sampled and fasted up to12h for the examination of diverse serologicalindicators, including fasting blood glucose (FBG), lipidemic and insulinemic level.Furthermore, index of insulin resistance was estimated and calculated by thehomeostasis model assessment (HOMA). Part II: Effects of Schizandrae Fructus oilon the expresion of insulin resistance related adipokines and inflammatory markers inthe adipose tissue. Procedures including rat feeding, model developing, grouping andtreatment protocol were all in agreement with Part I. After6week treatment,6ratsper group were sampled and peritoneal adipose tissue were taken and subsequentlyreverse transcript polymerase chain reaction (RT-PCR) and westen blotting were usedto examine the expression of diverse insulin resistance related adipokines andinflammatory markers at the transcription and translation level, respectively. Thosesadipokines include glucose transporter-4(GLUT-4), adiponectin and retinal bindingprotein-4(RBP-4), and inflammatory makers are interleukin-6(IL-6), nuclear factorκB (NF-κB), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), C-reactiveprotein (CRP) and monocyte chemoattanctant protein-1(MCP-1). Part III: Effects ofSchizandrae Fructus oil on the pancreatic tissue morphology and its apoptosis relatedprotein expression, including cleaved caspase-3, Bcl-2and Bax. Procedures includingrat feeding, model developing, grouping and treatment protocol were all in agreementwith Part I. After6week treatment,6rats per group were sampled and pancreatictissue was removed for the subsequent test of pancreatic mophorlogy. Meanwhile,Gene expression of cleaved caspase-3, Bcl-2and Bax was also carried out by usingwestern blotting.
Results:
1Effects of Schizandrae Fructus oil on the serological indicators of rats withtype2diabetes.
1.1Effects of Schizandrae Fructus oil on the general status of type2diabetic rats.Rats in control group were in great form with silky coats, quick reflex and bodyweight steadily creeping up. Rats in Schizandrae Fructus oil control group shared similar status with those in control group. Compared with control group, model grouprats exhibited such classical symptoms of DM as polyuria, polydipsia, polyphagia andweight loss. Moreover, these rats were slouchy, slow on the draw and had dim anddark fur. Compared with control group, the performance of rats in low-dose orhigh-dose Schizandrae Fructus oil was greatly improved, with high-dose group muchbetter than low-dose. The effect of high-dose Schizandrae Fructus oil treatment wascomparable to rosigilitazone treatment.
1.2Effects of Schizandrae Fructus oil on fasting blood glucose of type2diabetic rats.Compared with control group, model group had markedly elevated fasting bloodglucose, which was significantly decreased by Schizandrae Fructus oil dosedependently. The fasting blood glucose level in high-dose Schizandrae Fructus oilgroup was similar to rosigilitazone group, almost declined to the normal level.
1.3Effects of Schizandrae Fructus oil on lipidemic level of type2diabetic rats.Compared with control group, model group had markedly elevated levels of totalcholesterol, triglyceride, low density lipoprotein cholesterol as well as decreased levelof high density lipoprotein cholesterol, which were significantly reversed bySchizandrae Fructus oil dose dependently. The fasting lipidemic level in high-doseSchizandrae Fructus oil group was comparable to rosigilitazone group.
1.4Effects of Schizandrae Fructus oil on FINS and HOMA-IR of type2diabetic rats.Compared with control group, while no significant changes of FINS and HOMA-IRwere observed in Schizandrae Fructus oil group, model group exhibited markablelyelevated FINS and HOMA-IR. These abnormal changes were significantlyameliorated, to varying degrees, by application of low or high dose of SchizandraeFructus oil or resiglitazone. The effects of high-dose Schizandrae Fructus oil werecomparable to resiglitazone and better than low-dose Schizandrae Fructus oil.
2Effects of Schizandrae Fructus oil on the expression of insulin resistancerelated adipokines and inflammatory markers in the peritoneal adipose tissue.Reverse transcriptional polymerase chain reaction (RT-PCR) was introduced toexamine the influence of Schizandrae Fructus oil on the expression of variousadipokines and inflammatory markers in the gene (mRNA) transcription level. The results revealed that peritoneal adipose tissue from diabetic model group rats hadhigher mRNA expression of all inflammatory markers including IL-6, CRP, MCP-1,IL1β, TNF-α and NF-κB. Meanwhile, the expression Adipoctokines including andGLUT-4and Adiponectin were also decreased in mRNA level in the peritonealadipose tissue of diabetic model rats, whose expression in RBP-4were, however,lower than that from the control group. These abnormal changes were significantlyreversed, to varying degrees, by application of resiglitazone or low or high dose ofSchizandrae Fructus oil, which itself had no any influence on various geneexpressions. The effects of high-dose Schizandrae Fructus oil on the mRNAexpression were comparable to resiglitazone, oral hypoglycemic agent belonging tothiazolidinediones, and better than low-dose Schizandrae Fructus oil.
Subsequently, Western blot was employed to examine the influence of SchizandraeFructus oil on the expression of various adipokines and inflammatory markers in theprotein translation level. The results demonstrate that all the alteration of theadipokines and inflammatory markers in protein (translation) were reconcilable withtheir changes in mRNA (transcription) level. That is, peritoneal adipose tissue fromdiabetic model group rats had higher protein expression of all inflammatory markersincluding IL-6, CRP, MCP-1, IL1β, TNF-α and NF-κB. Meanwhile, the expressionsof adipoctokines including GLUT-4and Adiponectin were also decreased in proteinlevel in the peritoneal adipose tissue of diabetic model rats, whose expression inRBP-4was, however, lower than that from the control group. These abnormalchanges were significantly reversed, to varying degrees, by application ofresiglitazone or low or high dose of Schizandrae Fructus oil, which itself had no anyinfluence on various gene expressions. The effects of high-dose Schizandrae Fructusoil on the protein expression were comparable to resiglitazone, oral hypoglycemicagent belonging to thiazolidinediones, and better than low-dose Schizandrae Fructusoil.
3Effects of Schizandrae Fructus oil on the pancreatic tissue morphology and itsapoptosis related protein expression.
Application of Schizandrae Fructus oil could take a series of positive influence on thepathological changes including restore shrinked pancrease tissue and decreasednumber of β cells. Besides, Schizandrae Fructus oil greatly protected pancrease fromapoptotic damage, as demonstrated by diverse apoptosis relavant protein expression.Although Bax protein expression was unchanged, model group rats had higher proteinexpression of cleaved caspase-3and lower Bcl-2than control group. Both weregreatly corrected by application of low or high dose of Schizandrae Fructus oil orresiglitazone. The effects of high-dose Schizandrae Fructus oil were comparable toresiglitazone and better than low-dose Schizandrae Fructus oil. Schizandrae Fructusoil itself had no effect on caspase-3and lower Bcl-2expression.
Conclusion:
1. Schizandrae Fructus oil treatment could improve insulin resisrance, attenuatehyperglycemia and hyperlipidemia, and hyperinsulinemia in fat-fed stepzotocininduced type2diabetic rat model.
2. Schizandrae Fructus oil treatment could produce beneficical effects on diabetes bycorrecting insulin resisrance associated gene expression.
3. Schizandrae Fructus oil treatment could preserve pancreatic morphology, decreasepancreatic apoptosis by reducing cleaved caspase-3expressin and increasing Bcl-2.
引文
[1]中华医学会糖尿病分会.中国2型糖尿病防治指南(2010版).中国医学前沿杂志(电子版).2011,3(6):54-109
[2] Yumuk VD, Hatemi H, Tarakchi T, et al. High prevalence of obesity and diabetesmellitus in Konya, a central Anatolian city in Turkey. Diabetes Res ClinicalPrac.2005,70:151-158
[3] Bailey CJ. Insulin resistance and antidiabetic drugs. Biochem Pharmacol.1999,58:1511-1520.]
[4] Umar AR, Ahmed QU, Muhammad BY, et al. Antiobesity hyperglycemic activityof the leaves of Tetarcera scandens Linn. Merr. In allaxon induced diabetes rats. JEthnopharmacol.2010,131:140-145.
[5] Butler AE, Janson J, Bonner-Weir, et al. B-cell deficit and increased B-cellapootosis in humans with type2diabetes. Diabetes.2003,52(1):102-110.
[6] Weir GC, Laybutt DR, Kaneto H, et al. B-cell adaptation and decompensationduring the progression of diabetes. Diabetes.2001,50(1): s154-159.
[7] Slovacek L, Pavlik V, Slovackova B. The effect of sibutramine therapy onoccurance of depression symptoms among obese patients. Nutr MetabCardiovascular Disease.2008,18:43–44
[8]刘彦。磺脲类药物对胰岛β细胞凋亡影响的研究进展.国际内科学杂志.2009,36（4）:189-205.
[9]雷定超,张兰兰,周水平等.中药治疗糖尿病现状与研究进展.中国医药导报.2012,9（21）：8-12
[10]范美华.五味子的研究新进展.西北药学杂志.2007,22(5):281-282.
[11]金祖汉，王香英，毛培江等.治疗糖尿病高频中药的降血糖作用研究.中国现代应用药学杂志.2009,26(4):267-270.
[12]柴可夫,覃志成,王亚丽.北五味子油对糖尿病小鼠胰岛细胞形态及功能的影响.中国中医药科技.2007,14(3):177-178.
[1] Hotamisligil GS. Inflammation and metabolic disorders. Nature.2006,444(7121):860–867.
[2] Ouchi N, Parker JL, Lugus JJ, et al. Adipokines in inflammation and metabolicdisease. Nat Rev Immunol.2011,11(2):85–97.
[3] Nishimura S, Manabe I, Nagasaki M, et al. CD8Ceffector T cells contribute tomacrophage recruitment and adipose tissue inflammation in obesity. Nat Med.2009,15(8):914–920.
[4] Reiter LT, Potocki L, Chien S, et al. A systematic analysis of humandisease-associated gene sequences in Drosophila melanogaster. Genome Res.2001,11(6):1114–1125.
[5] Tanji T, Ip YT. Regulators of the Toll and Imd pathways in the Drosophila innateimmune response. Trends Immunol.2005,26(4):193–198.
[6] Kühnlein RP. Drosophila as a lipotoxicity model organism–more than a promise?Biochim Biophys Acta.2010,1801(3):215–221.
[7] Diop SB, Bodmer R. Drosophila as a model to study the genetic mechanisms ofobesity-associated heart dysfunction. J Cell Mol Med.2012,16(5):966–971.
[8] O'Neill LA, Bryant CE, Doyle SL. Therapeutic targeting of Toll-like receptors forinfectious and inflammatory diseases and cancer. Pharmacol Rev.2009,61(2):177–197.
[9] Durmu Tekir S, ümit P, Eren Toku A, et al. Reconstruction of pro tein-proteininteraction network of insulin signaling in Homo sapiens. Journal of Biomedicineand Biotechnology.2010,2010:690925.
[10]Paris M, Bernard-Kargar C, Vilar J, et al. Role of glucose in IRS signaling in ratpancreatic islets: specific e ffects and inter play with insulin. Exp Diabesity Res.2004,5(4):257-263.
[11]Saltiel AR, Kahn CR. Insulin signalling and the regulation of glucose and lipidmetabolism. Nature.2001,414(6865):799-806.
[12]Thong FS, Dugani CB, Klip A. Turning signals on and off: GLUT4traffic in theinsulin-signaling highway. Physiology (Bethesda, Md.).2005,20:271-284.
[13]Liu J, Kimura A, Baumann CA, et al. APS facilitates c-Cbl tyrosinephosphorylation and GLUT4translocation in response to insulin in3T3-L1adipocytes. Mol Cell Biol.2002,22(11):3599-3609.
[14]Mitra P, Zheng X, Czech MP. RNAi-based analysis of CAP, Cbl, and Cr kIIfunction in the regulation of GLUT4by insulin. J Biol Chem.2004,279(36):37431-37435.
[15]Sweeney G, Somwar R, Ramlal T, et al. An inhibitor of p38mitogen-activatedprotein kinase prevents insulin-stimulated glucose transport but not glucosetransporter translocation in3T3-L1adipocytes and L6myotubes. J Biol Chem.1999,274(15):10071-10078.
[16]Murata M, Thanan R, Ma N, et al. Role of nitrative and oxidative DNA damagein inflammation-related carcinogenesis. Journal of Biomedicine andBiotechnology.2012,2012:623019.
[17]Haruta T, Uno T, Kawahara J, et al. A rapamycin-sensitive pathwaydown-regulates insulin signaling via phosphorylation and proteasomaldegradation of insulin receptor substrate-1. Mol Endocrinol.2000,14(6):783-794
[18]Wu F, Liu Y, Lv X, et al. Small interference RNA targeting TLR4gene effectivelyattenuates pulmonary inflammation in a rat model. Journal of Biomedicine andBiotechnology.2012,2012:406435.
[19]Kaneto H, Nakatani Y, Kawamori D, et al. Role of oxidative stress, endoplasmicreticulum stress, and c-Jun N-terminal kinase in pancreatic beta-cell dysfunctionand insulin resistance. International Journal of Biochemistry and Cell Biology.2006,38(5-6):782-793.
[20]H versen L, Danielsson KN, Fogelstrand L, et al. Induction of proinflammatorycytokines by long-chain saturated fatty acids in human macrophages.Atherosclerosis.2009,202(2):382-93.
[21]Coletta DK, Mandarino LJ. Mitochondrial dysfunction and insulin resistancefrom the outside in: extracellular matrix, the cytoskeleton, and mitochondria.American Journal Physiology Endocrinology Metabolism.2011,301(5):E749-755.
[22]Ji C, Chen X, Gao C, et al. IL-6induces lipolysis and mitochondrial dysfunction,but does not affect insulin-mediated glucose transport in3T3-L1a dipocytes. JBioenerg Biomembr.2011,43(4):367-75.
[23]Paquot N, Castillo MJ, Lefèbvre PJ, et al. No increased insulin sensitivity after asingle intravenous administration of a recombinant human tumor necrosis factorreceptor: Fc fusion protein in obese insulin-resistant patients. J Clin EndocrinolMetab.2000,85(3):1316-9.
[24]Gonzalez-Gay MA, Gonzalez-Juanatey C, Vazquez-Rodriguez TR, et al. Insulinresistance in rheumatoid arthritis: the impact of the anti-TNF-alpha therapy.Annals of the New York Academy of Sciences,2010,1193:153-159.
[25]Miranda-Filloy JA, Llorca J, Carnero-López B, et al. TNF-alpha antagonisttherapy improves insulin sensitivity in non-diabetic ankylosing spondylitispatients. Clin Exp Rheumatol.2012,30(6):850-855.
[26]Ridker PM, Thuren T, Zalewski A, et al. Interleukin-1β inhibition and theprevention of recurrent cardiovascular events: rationale and design of theCanakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS).American Heart Journal.2011,162(4):597-605.
[27]Hirabara SM, Gorj o R, Vinolo MA, et al. Molecular targets related toinflammations and insulin resistance and potential interventions. J BiomedBiotechnol.2012:379024.
[28]Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J ClinInvest.2006,116(7):1793–1801.
[29]Prospective Studies Collaboration, Whitlock G, Lewington S, et al. Body-massindex and cause-specific mortality in900000adults: collaborative analyses of57prospective studies. Lancet.2009,373(9669):1083–1096.
[30]Berrington de Gonzalez A, Hartge P, Cerhan JR, et al. Body-mass index andmortality among1.46million white adults. N Engl J Med.2010,363(23):2211–2219.
[31]Koster A, Leitzmann MF, Schatzkin A, et al. Waist circumference and mortality.Am J Epidemiol.2008,167(12):1465–1475.
[32]Pischon T, Boeing H, Hoffmann K, et al. General and abdominal adiposity andrisk of death in Europe. N Engl J Med.2008,359(20):2105–2120.
[33]Czernichow S, Kengne AP, Stamatakis E, et al. Body mass index, waistcircumference and waist–hip ratio: which is the better discriminator ofcardiovascular disease mortality risk?: evidence from an individual-participantmeta-analysis of82864participants from nine cohort studies. Obesity Reviews.2011,12(9):680–687.
[34]Baker AR, Harte AL, Howell N, et al. Epicardial adipose tissue as a source ofnuclear factor-kappaB and c-Jun N-terminal kinase mediated inflammation inpatients with coronary artery disease. Journal of Clinical Endocrinology andMetabolism.2009,94(1):261–267.
[35]Cypess AM, Lehman S, Williams G, et al. Identification and importance of brownadipose tissue in adult humans. N Engl J Med.2009,360(15):1509–1517.
[36]van Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM, et al.Cold-activated brown adipose tissue in healthy men. N Engl J Med.2009,360(15):1500–1508.
[37]Wu J, Bostrom P, Sparks LM, et al. a Beige adipocytes are a distinct type ofthermogenic fat cell in mouse and human. Cell.2012,150(2):366–376.
[38]Peiris AN, Sothmann MS, Hoffmann RG, et al. Adiposity, fat distribution, andcardiovascular risk. Ann Intern Med.1989,110(11):867–872.
[39]Després JP, Moorjani S, Lupien PJ, et al. Regional distribution of body fat,plasma lipoproteins, and cardiovascular disease. Arterio sclerosis.1990,10(4):497–511.
[40]Després JP, Couillard C, Gagnon J, et al. Race, visceral adipose tissue, plasmalipids, and lipoprotein lipase activity in men and women: the Health, Risk Factors,Exercise Training, and Genetics (HERITAGE) family study. Arteriosclerosis,Thrombosis, and Vascular Biology.2000,20(8):1932–1938.
[41]Couillard C, Lamarche B, Tchernof A, et al. Plasma high-density lipoproteincholesterol but not apolipoprotein A-I is a good correlate of the visceralobesity-insulin resistance dyslipidemic syndrome. Metabolism.1996,45(7):882–888.
[42]Wajchenberg BL. Subcutaneous and visceral adipose tissue: their relation to themetabolic syndrome. Endocr Rev.2000,21(6):697–738.
[43]Smith SR, Lovejoy JC, Greenway F, et al. Contributions of total body fat,abdominal subcutaneous adipose tissue compartments, and visceral adiposetissueto the metabolic complications of obesity. Metabolism.2001,50(4):425–435.
[44]Fisher FM, McTernan PG, Valsamakis G, et al. Differences in adiponectin proteinexpression: effect of fat depots and type2diabetic status. Horm Metab Res.2002,34(11-12):650–654.
[45]Harte AL, McTernan PG, McTernan CL, et al. Insulin increases angiotensinogenexpression in human abdominal subcutaneous adipocytes. Diabetes Obes Metab.2003,5(6):462–467.
[46]Harte AL, McTernan PG, McTernan CL, et al. Rosiglitazone inhibits theinsulin-mediated increase in PAI-1secretion in human abdominal subcutaneousadipocytes. Diabetes Obes Metab.2003,5(5):302–310.
[47]McTernan PG, Fisher FM, Valsamakis G, et al. Resistin and type2diabetes:regulation of resistin expression by insulin and rosiglitazone and the effects ofrecombinant resistin on lipid and glucose metabolism in human differentiatedadipocytes. J Clin Endocrinol Metab.2003,88(12):6098–6106.
[48]Kos K, Harte AL, James S, et al. Secretion of neuropeptide Y in human adiposetissue and its role in maintenance of adipose tissue mass. Am J Physiol.Endocrinol. Metab.2007,293(5) E1335–E1340.
[49]Kos K, Harte AL, O'Hare PJ, et al. Ghrelin and the differential regulation ofdes-acyl (DSG) and oct-anoyl ghrelin (OTG) in human adipose tissue (AT). ClinEndocrinol (Oxf).2009,70():383–389.
[50]Jern s M, Olsson B, Arner P, et al. Regulation of carboxylesterase1(CES1) inhuman adipose tissue. Biochem Biophys Res Commun.2009,383(1):63–67.
[51]Saiki A, Olsson M, Jern s M, et al. Tenomodulin is highly expressed in adiposetissue, increased in obesity, and down-regulated during diet-induced weight loss.J Clin Endocrinol Metab.2009,94(10):3987–3994.
[52]Carobbio S, Rodriguez-Cuenca S, Vidal-Puig A. Origins of metaboliccomplications in obesity: ectopic fat accumulation. The importance of thequalitative aspect of lipotoxicity. Curr Opin Clin Nutr Metab Care.2011,14(6):520–526.
[53]McGee KC, Harte AL, da Silva NF, et al. Visfatin is regulated by rosiglitazone intype2diabetes mellitus and influenced by NFkB and JNK in human abdominalsubcutaneous adipocytes. Plos One.2011,6(6): e20287.
[54]Manolopoulos KN, Karpe F, Frayn KN. Gluteofemoral body fat as a determinantof metabolic health. Int J Obes.2010,34(6):949–959.
[55]Youssef-Elabd EM, McGee KC, Tripathi G, et al. Acute and chronic saturatedfatty acid treatment as a key instigator of the TLR-mediated inflammatoryresponse in human adipose tissue, in vitro. J Nutr Biochem.2012,23(1):39–50.
[56]Mlinar B, Marc J. New insights into adipose tissue dysfunction in insulinresistance. Clin Chem Lab Med.2011,49(12):1925–1935.
[57]Pirola L, Johnston AM, Van Obberghen E. Modulation of insulin action.Diabetologia.2004,47(2):170–184.
[58]Tilg H, Moschen AR. Inflammatory mechanisms in the regulation of insulinresistance. Mol Med.2008,14(3-4):222–231.
[59]Kalupahana NS, Moustaid-Moussa N, Claycombe KJ. Immunity as a linkbetween obesity and insulin resistance. Mol Aspects Med.2012,33(1):26–34.
[60]Stratton IM, Adler AI, Neil HA, et al. Association of glycaemia withmacrovascular and microvascular complications of type2diabetes (UKPDS35):prospective observational study. BMJ.2000,321(7258):405–412.
[61]Selvin E, Marinopoulos S, Berkenblit G, et al. Meta-analysis: glycosylatedhemoglobin and cardio-vascular disease in diabetes mellitus. Ann Intern Med.2004,141(6):421–431.
[62]Gerstein HC, Pogue J, Mann JF, et al. The relationship between dysglycaemiaand cardiovascular and renal risk in diabetic and non-diabetic participants in theHOPE study: a prospective epidemiological analysis. Diabetologia.2005,48(9):1749–1755.
[63]Ghanim H, Mohanty P, Deopurkar R, et al. Acute modulation of Toll-likereceptors by insulin. Diabetes Care.2008,31(9):1827–1831.
[64]Soop M, Duxbury H, Agwunobi AO, et al. Euglycemic hyperinsulinemiaaugments the cytokine and endocrine responses to endotoxin in humans. Am JPhysiol. Endocrinol Metab.2002,282(6): E1276–E1285.
[65]Dandona P, Chaudhuri A, Ghanim H, et al. Proinflammatory effects of glucoseand anti-inflammatory effect of insulin: relevance tocardiovascular disease. Am JCardiol.2007,99(4A):15B–26B.
[66]Esposito K, Nappo F, Marfella R, et al. Inflammatory cytokine concentrations areacutely increased by hyperglycemia in humans: roleof oxidative stress.Circulation.2002,106(16):2067–2072.
[67]Ruge T, Lockton JA, Renstrom F, et al. Acute hyperinsulinemia raises plasmainterleukin-6in both nondiabetic and type2diabetes mellitus subjects, and thiseffect is inversely associated with body mass index. Metabolism.2009,58(6):860–866.
[68]Morohoshi M, Fujisawa K, Uchimura I, et al. Glucose-dependent interleukin6and tumor necrosis factor production by human peripheral blood monocytes invitro. Diabetes.1996,45(7):954–959.
[69]Dasu MR, Devaraj S, Zhao L, et al. High glucose induces Toll-like receptorexpression in human monocytes: mechanism of activation. Diabetes.2008,57(11):3090–3098.
[70]Bouché C, Rizkalla SW, Luo J, et al. Five-week, low-glycemic index dietdecreases total fat mass and improves plasma lipid profile in moderatelyoverweight nondiabetic men. Diabetes Care.2002,25(5):822–828.
[71]Qi L, van Dam RM, Liu S, et al. Whole-grain, bran, and cereal fiber intakes andmarkers of systemic inflammation in diabetic women. Diabetes Care.2006,29(2):207–211.
[72]de Mello VD, Kolehmainen M, Pulkkinen L, et al. Downregulation of genesinvolved in NFkappaB activation in peripheral blood mononuclear cells afterweight loss is associated with the improvement of insulin sensitivity inindividuals with the metabolic syndrome: the GENOBIN study. Diabetologia.2008,51(11):2060–2067.
[73]Heggen E, Klemsdal TO, Haugen F, et al. Effect of a low-fat versus alow-gycemic-load diet on inflammatory biomarker and adipokine concentrations.Metab Syndr Relat Disord.2012,10(6):437–442.
[74]Neuhouser ML, Schwarz Y, Wang C, et al. A low-glycemic load diet reducesserum C-reactive protein and modestly increases adiponectin in overweight andobese adults. J Nutr.2012,142(2):369–374.
[75]van Schothorst EM, Bunschoten A, Schrauwen P, et al. Effects of a high-fat, low-versus high-glycemic index diet: retardation of insulin resistance involves adiposetissue modulation. FASEB Journal.2009,23(4):1092–1101.
[76]Pedersen TR, Wilhelmsen L, Faergeman O, et al. Follow-up study of patientsrandomized in the Scandinavian simvastatin survival study (4S) of cholesterollowering. American Journal of Cardiology.2000,86(3):257–262.
[77]Hsia J, MacFadyen JG, Monyak J, et al. Cardiovascular event reduction andadverse events among subjects attaining low-density lipoprotein cholesterol <50mg/dl with rosuvastatin. The JUPITER trial (Justification for the Use of Statins inPrevention: an Intervention Trial Evaluating Rosuvastatin). J Am Coll Cardiol.2011,57(16):1666–1675.
[78]Sever PS, Chang CL, Gupta AK, et al. The Anglo-Scandinavian CardiacOutcomes Trial:11-year mortality follow-up of the lipid-lowering arm in the U.K.Eur Heart J.2011,32(20):2525–2532.
[79]Randle PJ, Garland PB, Hales CN, et al. The glucose fatty-acid cycle. Its role ininsulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet.1963,1(7285):785–789.
[80]Morino K, Neschen S, Bilz S, et al. Muscle-specific IRS-1Ser/Ala transgenicmice are protected from fat-induced insulinresistance in skeletal muscle. Diabetes.2008,57(10):2644–2651.
[81]Boden G, She P, Mozzoli M, et al. Free fatty acids produce insulin resistance andactivate the proinflammatory nuclear factor-kappaB pathway in rat liver. Diabetes.2005,54(12):3458–3465.
[82]Kim JK, Kim YJ, Fillmore JJ, et al. Prevention of fat-induced insulin resistanceby salicylate. J Clin Invest.2001,108(3):437–446.
[83]Lee JY, Sohn KH, Rhee SH, et al. Saturated fatty acids, but not unsaturated fattyacids, induce the expression of cyclooxygenase-2mediated through Toll-likereceptor4. J Biol Chem.2001,276(20):16683–16689.
[84]Szabo G, Velayudham A, Romics L, et al. Modulation of non-alcoholicsteatohepatitis by pattern recognition receptors in mice: the role of Toll-likereceptors2and4. Alcohol Clin Exp Res.2005,29(11Suppl)140S–145S.
[85]Poggi M, Bastelica D, Gual P, et al. C3H/HeJ mice carrying a Toll-like receptor4mutation are protected against the development of insulin resistance in whiteadipose tissue in response to a high-fat diet. Diabetologia.2007,50(6):1267–1276.
[86]Kim F, Pham M, Luttrell I, et al. Toll-like receptor-4mediatesvascularinflammation and insulin resistance in diet-induced obesity. Circ Res.2007,100(11):1589–1596.
[87]Wu LH, Huang CC, Adhikarakunnathu S, et al. Loss of Toll-like receptor3function improves glucose tolerance andreduces liver steatosis in obese mice.Metabolism.2012,61(11):1633–1645.
[88]Zhang Y, Proenca R, Maffei M, et al. Positional cloning of the mouse obese geneand its human homologue. Nature.1994,372(6505):425–432.
[89]Pelleymounter MA, Cullen MJ, Baker MB, et al. Effects of the obese geneproduct on body weight regulation in ob/ob mice. Science.1995,269(5223):540–543.
[90]Friedman JM, Halaas JL. Leptin and the regulation of body weight in mammals.Nature.1998,395(6704):763–770.
[91]Martín-Romero C, Santos-Alvarez J, Goberna R, et al. Human leptin enhancesactivation and proliferation of human circulating Tlymphocytes. Cell Immunol.2000,199(1):15–24.
[92]Agrawal S, Gollapudi S, Su H, et al. Leptin activates human B cells to secreteTNF-α, IL-6, and IL-10via JAK2/STAT3and p38MAPK/ERK1/2signalingpathway. J Clin Immunol.2011,31(3):472–478.
[93]Xiao E, Xia-Zhang L, Vulliémoz NR, et al. Leptin modulates inflammatorycytokine and neuroendocrine responses to endotoxin in the primate.Endocrinology.2003,144(10):4350–4353.
[94]Sachot C, Poole S, Luheshi GN. Circulating leptin mediateslipopolysaccharide-induced anorexia and fever in rats. J Physiol (Lond.).2004,561(Pt1):263–272.
[95]Weisberg SP, McCann D, Desai M, et al.2003Obesity is associated withmacrophage accumulation in adipose tissue. J Clin Invest.1121796–1808.
[96]Ziccardi P, Nappo F, Giugliano G, et al. Reduction of inflammatory cytokineconcentrations and improvement of endothelial functions in obese women afterweight loss over one year. Circulation.2002,105(7):804–809.
[97]Hivert MF, Sullivan LM, Fox CS, et al. Associations of adiponectin, resistin, andtumor necrosis factor-a with insulin resistance. Journal of Clinical Endocrinologyand Metabolism.2008,98(3):3165–3172.
[98]Stanley TL, Zanni MV, Johnsen S, et al. TNF-a antagonism with etanerceptdecreases glucose and increases the proportion of high molecular weightadiponectin in obese subjects with features of the metabolic syndrome. J ClinEndocrinol Metab.2011,96(1): E146–E150.
[99]Lagathu C, Yvan-Charvet L, Bastard JP, et al. Long-term treatment withinterleukin-1beta induces insulin resistance in murine and human adipocytes.Diabetologia,2006,49,2162–2173.
[100] Jager J, Gremeaux T, Cormont M, et al. Interleukin-1beta-induced insulinresistance in adipocytes through down-regulation of insulin receptorsubstrate-1expression. Endocrinology,2007,148,241-251.
[101] Stienstra R, Joosten LA, Koenen T, et al. The inflammasome-mediatedcaspase-1activation controls adipocyte differentiation and insulin sensitivity.Cell Metab.2010,12,593-605.
[102] Larsen CM, Faulenbach M, Vaag A, et al. Interleukin-1-receptor antagonist intype2diabetes mellitus. N Engl J Med.2007,356,1517-1526.
[103] Rotter V, Nagaev I, Smith U. Interleukin-6(IL-6) induces insulin resistance in3T3-L1adipocytes and is, like IL-8and tumor necrosis factor-a,overexpressed in human fat cells from insulin-resistant subjects. J Biol Chem.2003,278(46):45777–45784.
[104] Kusminski CM, da Silva NF, Creely SJ, et al. The in vitroeffects of resistin onthe innate immune signaling pathway in isolated human subcutaneousadipocytes. Journal of Clinical Endocrinology and Metabolism.2007,92(1):270–276.
[105] Kloting N, Graham TE, Berndt J, et al. Serum retinol-binding protein is morehighly expressed in visceral than in subcutaneous adipose tissue and is amarker of intra-abdominal fat mass. Cell Metab.2007,6:79–87.
[106] Kotani K, Kim YB, Peroni O, et al. Rosiglitazone treatment normalizesglucose tolerance in adipose-specific GLUT4knockout mice but rendersmuscle-specific GLUT4knockout more diabetic. Diabetes.2001,50:A274.
[107] Qi Q, Yu Z, Ye X, Zhao F, Huang P, Hu FB, et al. Elevated retinol-bindingprotein4levels are associated with metabolic syndrome in Chinese people. JClin Endocrinol Metab.2007,92:4827–34.
[108] Hug C, Lodish HF. The role of the adipocyte hormone adiponectin incardiovascular diseases. Curr Opin Pharmacol.2005,5:129–34.
[109] Lindsay RS, Funahashi T, Hanson RL, et al. Adiponectin and development oftype2diabetes in Pima Indian population. Lancet.2002,360:57–8.
[110] Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, et al. Thefat-derived hormone adiponectin reverses insulin resistance associated withboth lipoatrophy and obesity. Nat Med.2001,7:941–6.
[111] Berg AH, Combs TP, Du X, et al. The adipocyte-secreted protein Acrp30enhances hepatic insulin action. Nat Med.2001,7:947–53.
[112] Watson RT, Pessin J. Intracellular organization of insulin signaling andGLUT4translocation. Recent Prog Horm Res,2001,56(2):175-193.
[113] Gao Y, Yang MF, Su YP, et al. Ginsenoside Re Reduces Insulin Resistancethrough Activation of PPAR-γ Pathway and Inhibition of TNF-α Production. JEthnopharmacol.2013, S0378-8741(13)00213-4.
[114]刘洪凤,崔荣军,申梅淑,等.黄芪多糖对2型糖尿病大鼠GLUT4蛋白表达的影响.中国食物与营养.2011,17(11):70-72.
[115] Cai D, Yuan M, Frantz DF, et al. Local and systemic insulin resistanceresulting from hepatic activation of IKK-beta and NF-kappaB. Nat Med.2005,11(2):183-190.
[116] Soriano FG, Virág L, Szabó C. Diabetic endothelial dysfunction: role ofreactive oxygen and nitrogen species production and poly(ADP-ribose)polymerase activation. J Mol Med (Berl).2001,79(8):437-448.
[117] Sun X, Han F, Yi J, et al. Effect of aspirin on the expression of hepatocyteNF-κB and serum TNF-α in streptozotocin-induced type2diabetic rats. JKorean Med Sci.2011,26(6):765-770.
[118] Ouchi N, Kihara S, Funahashi T, et al. Reciprocal association of C-reactiveprotein with adiponectin in blood stream and adipose tissue. Circulation.2003,107(5):671-674.
[119]王先令,陆菊明,潘长玉.不同糖耐量水平者血清C反应蛋白水平及阿卡波糖干预的影响.中华内分泌杂志.2003,19(4):254-256.
[120]代玲俐,李晓永,林宁,等.高脂喂养大鼠内脏脂肪组织C反应蛋白的表达.中华内分泌代谢杂志.2009,25(3):323-325.
[121] Kawamori D, Kaneto H, Nakatani Y, et al. The forkhead transcription factorFoxo1bridges the JNK pathway and the transcription factor PDX-1through itsintracellular translocation. J Biol Chem.2006,281(2):1091-1098.
[122] Steinbrecher UP, Parthasarathy S, Leake DS, et al. Modification of low densitylipoprotein by endothelial cells involves lipid peroxidation and degradation oflow density lipoprotein phospholipids. Proc Natl Acad Sci U S A.1984,81(12):3883-3887.
[123] Sears DD, Miles PD, Chapman J, et al.12/15-lipoxygenase is required for theearly onset of high fat diet-induced adipose tissue inflammation and insulinresistance in mice. PLoS One.2009,4(9): e7250.
[124]周兴建,蒋绿芝,杨国铭,等.单核细胞趋化因子与2型糖尿病胰岛素抵抗相关性的研究.中国糖尿病杂志,2008,16(3),152-153.
[125] Attané C, Foussal C, Le Gonidec S, et al. Apelin treatment increases completefatty acid oxidation, mitochondrial oxidative capacity, and biogenesis inmuscle of insulin-resistant mice. Diabetes.2012,61(2):310–320.
[126] Heinonen MV, Laaksonen DE, Karhu T, et al. Effect of diet-induced weightloss on plasma apelin and cytokine levels in individuals with the metabolicsyndrome. Nutrition, Metabolism, and Cardiovascular Diseases.2009,19(9):626–633.
[127] Daviaud D, Boucher J, Gesta S, et al. TNFa up-regulates apelin expression inhuman and mouse adipose tissue. FASEB Journal.2006,20(9):1528–1530.
[128] Lu Y, Zhu X, Liang GX, et al. Apelin-APJ induces ICAM-1, VCAM-1andMCP-1expression via NF-κB/JNK signal pathway in human umbilical veinendothelial cells. Amino Acids.2012,43(5):2125–2136.
[129] Shibata R, Ouchi N, Takahashi R, et al. Omentin as a novel biomarker ofmetabolic risk factors. Diab etology&Metabolic Syndrome2012,4:37.
[130] Zhong X, Li X, Liu F, et al. Omentin inhibits TNF-a-induced expression ofadhesion molecules in endothelial cells via ERK/NF-kappaB pathway.Biochem. Biophys. Res. Commun.2012,425(2):401–406.
[131] Kazama K, Usui T, Okada M, et al. Omentin plays an anti-inflammatory rolethrough inhibition of TNF-α-induced superoxide production in vascularsmooth muscle cells. Eur J Pharmacol.2012,686(1-3):116–123.
[132] Ernst MC, Issa M, Goralski KB, et al. Chemerin exacerbates glucoseintolerance in mouse models of obesity and diabetes. Endocrinology.2010,151(5):1998–2007.
[133] Catalán V, Gómez-Ambrosi J, Rodríguez A, et al. Increased levels of chemerinand its receptor, chemokine-like receptor-1, in obesity are related toinflammation: tumor necrosis factor-a stimulates mRNA levels of chemerin invisceral adipocytes from obese patients. Surgery for Obesity and RelatedDiseases.2013,9(2):306-314.
[134] Hart R, Greaves DR. Chemerin contributes to inflammation by promotingmacrophage adhesion to VCAM-1and fibronectin through clustering ofVLA-4and VLA-5. J Immunol.2010,185(6):3728–3739.
[135] Lehrke M, Becker A, Greif M, et al. Chemerin is associated with markers ofinflammation and components of the metabolic syndrome but does not predictcoronary atherosclerosis. Eur J Endocrinol.2009,161(2):339–344.
[136] Yu S, Zhang Y, Li MZ, et al. Chemerin and apelin are positively correlatedwith inflammation in obese type2diabetic patients. Chin Med J.2012,125(19):3440–3444.
[1]中华医学会糖尿病分会.中国2型糖尿病防治指南(2010版).中国医学前沿杂志(电子版).2011,3(6):54-109
[2] Bailey CJ. Insulin resistance and antidiabetic drugs. Biochem Pharmacol.1999,58:1511-1520.
[3] Slovacek L, Pavlik V, Slovakova B. The effect of sibutramine therapy onoccurance of depression symptoms among abese patients. Nutr MetabCardiovascular Disease.2008,18:43-44.
[4]柴可夫,覃志成,王亚丽.北五味子油对糖尿病小鼠胰岛细胞形态及功能的影响.中国中医药科技,2007,14(3):177-178.
[5] Kanagasabapathy G, Kuppusamy UR, Abd Malek SN, et al. Glucan-richpolysaccharides from Pleurotus sajor-caju (Fr.) Singer prevents glucoseintolerance, insulin resistance and inflammation in C57BL/6J mice fed a high-fatdiet. BMC Complement Altern Med.2012,12(1):261.[Epub ahead of print]
[6]刘彦.磺脲类药物对胰岛β细胞凋亡影响的研究进展.国际内科学杂志.2009,36（4）:189-205.
[7] Ning G, hong J, Bi Y, et al. Progress in diabetes research in China. J Diabetes.2009,1(3):163-172.
[8]范美华.五味子的研究新进展.西北药学杂志.2007,22(5):281-282.
[9]李明珠,王艳杰,徐放.五味子粗多糖抑制肿瘤和突变作用的实验研究.黑龙江中医药.2007,(3):40.
[10]孔华丽,闫亮,段慧娟.五味子醇提取物保肝作用成分分析.解放军药学学报.2010,26(1):27-29.
[11]刘丽,赵春苏,马永全,等.五味子抗氧化和抑菌作用的研究进展.仲恺农业工程学学报,2011,24(3):63-66.
[12]刘丹娜,罗晶.不同剂量五味子多糖灌胃给药镇痛作用的观察.第四军医大学学报,2008,29(12):1115-1117.
[13]袁海波,沈忠明,殷建伟,等.五味子中α-葡萄糖苷酶抑制剂对小鼠的降血糖作用．中国生化药物杂志,2002,23(3):112-125.
[14]Sheetz MJ. Molecular understanding of hyperglycemias adverse effects fordiabetic complications. J Am Med Assoc.2002,288:2579-2588.
[15]Goldstein JL, Schrott HG, Hazzard WR, et al.Hyperlipidemia in coronary heartdisease II. Genetic analysis of lipid levels in176families and delineation of anew inherited disorder, combined hyperlipidemia. J Clin Invest1973,52:1544-1568.
[16]Kaur J, Singh P, Sowers JR. Diabetes and cardiovascular diseases. Am J Ther.2002,9:510-515.
[17]丁雯芳.红景天多糖对链脲佐菌素诱导糖尿病小鼠糖脂代谢的影响.广西中医学院学报.2011,14(2):4-5.
[18]金龙,葛争艳,郭宇洁,等.降糖消脂片对2型糖尿病大鼠降糖降脂作用的研究.中国实验方剂学杂志.2012,21:161-165.
[19]Soop M, Duxbury H, Agwunobi AO, et al. Euglycemic hyperinsulinemiaaugments the cytokine and endocrine responses to endotoxin in humans. Am. J.Physiol. Endocrinol Metab.2002,282(6): E1276–E1285.
[20]Larsen CM, Faulenbach M, Vaag A, et al. Interleukin-1-receptor antagonist intype2diabetes mellitus. N Engl J Med.2007,356(15):1517-1526.
[1] Saeks DB. Amylin-a glucoregulatory hormone involved in hepatho-genesis ofdiabetes mellitus？Clin Chem.1996,42:494.
[2] Abdul-Ghani MA, DeFronzo RA. Pathogenesis of insulin resistance in skeletalmuscle. J Biomed Biotechnol.2010(2010):476279. doi:10.1155/2010/476279.
[3] Di Carlo M, Picone P, Carrotta R, et al. Insulin promotes survival of amyloid-betaoligomers neuroblastoma damaged cells via caspase9inhibition and Hsp70upregulation. J Biomed Biotechnol.2010(2010):147835. doi:10.1155/2010/147835.
[4] Kontrogianni Konstantopoulos A, Benian G, Granzier H. Advances in MusclePhysiology and Pathophysiology2011. J Biomed Biotechnol.2012(2012):930836.doi:10.1155/2012/930836.
[5] Hundal RS, Petersen KF, Mayerson AB, Randhawa PS, et al. Mechanism bywhich high-dose aspirin improves glucose metabolism in type2diabetes. J ClinInvest.2002,109(10):1321-1326.
[6]朱耀国，任叶慧，姜军权．罗格列酮治疗2型糖尿病的机制及临床疗效．中国新药与临床杂志.2003,22(12):751-753．
[7]沈杰符鸿俊.罗格列酮对初发2型糖尿病患者血糖、胰岛β细胞功能和炎症因子的影响.中国现代医生.2012,50(32):69-70.
[8] Gandhi H, Upaganlawar A, Balaraman R. Adipocytokines: The pied pipers. JPharmacol Pharmacother.2010,1(1):9-17.
[9] Zou C, Shao J. Role of adipocytokines in obesity-associated insulin resistance. JNutr Biochem.2008,19:277-286.
[10]Kanagasabapathy G, Kuppusamy UR, Abd Malek SN, et al. Glucan-richpolysaccharides from Pleurotus sajor-caju (Fr.) Singer prevents glucoseintolerance, insulin resistance and inflammation in C57BL/6J mice fed a high-fatdiet. BMC Complement Altern Med.2012,12(1):261.[Epub ahead of print]
[11]柴可夫,覃志成,王亚丽.北五味子油对糖尿病小鼠抗氧化及葡萄糖转运蛋白4mRNA表达的影响.中医药学刊.2006,24（7）:1199-1201.
[12]Mohanty P, Aljada A, Ghanim H, et al. Evidence for a potent antiinflammatoryeffect of rosiglitazone. J Clin Endocrinol Metab.2004,89(6):2728-2735.
[13]Hotamisligil GS. Inflammation and metabolic disorders. Nature.2006,444(7121):860–867.
[14]Ouchi N, Parker JL, Lugus JJ, et al. Adipokines in inflammation and metabolicdisease. Nat Rev Immunol.2011,11(2):85–97.
[15]Vozarova B, Weyer C, Hanson K, Tataranni PA, et al. Circulating interleukin-6inrelation to adiposity, insulin action, and insulin secretion. Obes Res.2001,9(7):414-417.
[16]Watson RT, Pessin J. Intracellular organization of insulin signaling and GLUT4translocation. Recent Prog Horm Res,2001,56(2):175-193.
[17]Gao Y, Yang MF, Su YP, et al. Ginsenoside Re Reduces Insulin Resistancethrough Activation of PPAR-γ Pathway and Inhibition of TNF-α Production. JEthnopharmacol.2013, S0378-8741(13)00213-4.
[18]刘洪凤,崔荣军,申梅淑,等.黄芪多糖对2型糖尿病大鼠GLUT4蛋白表达的影响.中国食物与营养.2011,17(11):70-72.
[19]Berg AH, Combs TP, Scherer PE. ACRP30/adiponectin: an adipokine regulatingglucose and lipid metabolism [J]. Trends Endocrinol Metab,2002,13(2):84-89.
[20]Lee L, Alloosh M, Saxena R, et al. Nutritional model of steatohepatitis andmetabolic syndrome in the ossabaw miniature swine [J]. Hepatol,2009,50:56-67.
[21]Graham TE, Yang Q, Bluher M, et al. Retinol-binding protein4and insulinresistance in lean, obese and diabetic subjects [J].Eng J Med,2006,354:2552-2563.
[22]Balagopal P, Graham TE, Kahn BB, et al. Reduction of elevated serumretinol-binding protein4in obese children lifestyle intervention: association withsub-clinical inflammation [J]. J Clinical Endocrinol Metab.2007,7:2006-2012.
[23]张豫文，洪洁.炎症因子与胰岛素抵抗.诊断学理论与实践，2010,9(1):90-94.
[24]Weisberg SP, McCann D, Desai M, et al. Obesity is associated with macrophageaccumulation in adipose tissue. J. Clin. Invest.2003,112,1796–1808.
[25]Lagathu C, Yvan-Charvet L, Bastard JP, et al. Long-term treatment withinterleukin-1beta induces insulin resistance in murine and human adipocytes.Diabetologia.2006,49,2162–2173.
[26]Stienstra R, Joosten LA, Koenen T, et al. The inflammasome-mediated caspase-1activation controls adipocyte differentiation and insulin sensitivity. Cell Metab.2010,12,593-605.
[27]Larsen CM, Faulenbach M, Vaag A, et al. Interleukin-1-receptor antagonist intype2diabetes mellitus. N Engl J Med.2007,356,1517-1526.
[28]Rotter V, Nagaev I, Smith U. Interleukin-6(IL-6) induces insulin resistance in3T3-L1adipocytes and is, like IL-8and tumor necrosis factor-a, overexpressedin human fat cells from insulin-resistant subjects. J Biol Chem.2003,278(46):45777–45784.
[29]Cai D, Yuan M, Frantz DF, et al. Local and systemic insulin resistance resultingfrom hepatic activation of IKK-beta and NF-kappaB. Nat Med.2005,11(2):183-190.
[30]Soriano FG, Virág L, Szabó C. Diabetic endothelial dysfunction: role of reactiveoxygen and nitrogen species production and poly(ADP-ribose) polymeraseactivation. J Mol Med (Berl).2001,79(8):437-448.
[31]Sun X, Han F, Yi J, et al. Effect of aspirin on the expression of hepatocyte NF-κBand serum TNF-α in streptozotocin-induced type2diabetic rats. J Korean MedSci.2011,26(6):765-770.
[32]Ouchi N, Kihara S, Funahashi T, et al. Reciprocal association of C-reactiveprotein with adiponectin in blood stream and adipose tissue. Circulation.2003,107(5):671-674.
[33]王先令,陆菊明,潘长玉.不同糖耐量水平者血清C反应蛋白水平及阿卡波糖干预的影响.中华内分泌杂志.2003,19(4):254-256.
[34]代玲俐,李晓永,林宁,等.高脂喂养大鼠内脏脂肪组织C反应蛋白的表达.中华内分泌代谢杂志,2009,25(3):323-325.
[35]Kawamori D, Kaneto H, Nakatani Y, et al. The forkhead transcription factorFoxo1bridges the JNK pathway and the transcription factor PDX-1through itsintracellular translocation. J Biol Chem.2006,281(2):1091-1098.
[36]Steinbrecher UP, Parthasarathy S, Leake DS, et al. Modification of low densitylipoprotein by endothelial cells involves lipid peroxidation and degradation oflow density lipoprotein phospholipids. Proc Natl Acad Sci U S A.1984,81(12):3883-3887.
[37]Sears DD, Miles PD, Chapman J, et al.12/15-lipoxygenase is required for theearly onset of high fat diet-induced adipose tissue inflammation and insulinresistance in mice. PLoS One.2009,4(9): e7250.
[38]周兴建,蒋绿芝,杨国铭,等.单核细胞趋化因子与2型糖尿病胰岛素抵抗相关性的研究.中国糖尿病杂志,2008,16(3),152-153.
[39]Kotnik P, Keuper M, Wabitsch M et al. Interleukin-1β Downregulates RBP4Secretion in Human Adipocytes. PLoS One.2013,8(2): e57796. doi:10.1371/journal.pone.0057796. Epub2013Feb27.
[1] Kahn SE, The importance of the β-cell in the pathogenesis of type2diabetesmellitus. Am J Med.2000,108(suppl1):S109-S116.
[2] Saeks DB. Amylin-aglue regulatory hormone involved in hepatho-genesis ofdiabetes mellitus? Clin Chem.1996,42:494.
[3]宁光.胰岛β细胞功能异常在2型糖尿病发生中的重要性.中华内分泌代谢杂志.2003,19：附录5-7
[4] Rhodes CJ. Type2diabetes-a matter of beta-cell life and death? Science.2005,307:380-384.
[5] Butler AE, Janson J, Bonner-Weir S, et al. β-cell deficit and increased β-cellapoptosis in humans with type2diabetes. Diabetes.2003,52:102-110.
[6]柴可夫,覃志成,王亚丽.北五味子油对糖尿病小鼠胰岛细胞形态及功能的影响.中国中医药科技.2007,14(3):177-178.
[7] Lin CY, Gurlo T, Haataja L, et al. Activation of peroxisome proliferator-activatedreceptor-gamma by rosiglitazone protects human islet cells against human isletamyloid polypeptide toxicity by a phosphatidylinositol3'-kinase-dependentpathway. J Clin Endocrinol Metab.2005,90(12):6678-86.
[8] The Expert Committee on the Diagnosis and classification of Diabetes Mellitus.Report of the expert committee on the diagnosis and classification of diabetesmellitus. Diabetes Care.2003,26(suppl1):S5-S20.
[9] Cavaghan MK, Ehrmann DA, Polonsky KS. Interactions between insulinresistance and insulin secretion in the development of glucose intolerance. J ClinInvest.2000,106:329-333.
[10]Kahn BB, Type2dibetes: when insulin secretion fails to compensate for insulinresistance. Cell.1998,92:593-596.
[11]Clerk A, Wells CA, Buley ID, et al. Islet amyloid, increased A-cells, reducedB-cells and exocrine fibrosis: quantitative changes in the pancreas in type2diabetes. Diabetes Res.1988,9(4):151-159.
[12]Saito K, Yaginuma N, Takahashi T. Differential volumetry of A, B and D cells inthe pancreas islet of diabetic and nondiabetic subject. Tohoku J Exp Med.1979,129(3):273-283.
[13]Yoon KH, Ko SH, Cho JH, et al. Selective beta-cell loss and alpha-cell expansionin patients with type2diabetes mellitus in Korea. J Clin Endocrinol Metab.2003,88(5):2300–2308.
[14]Kim WH, Lee JW, Sun YH, et al. Exposure to chronic high glucose induces β-cell apootosis through decreased interaction of glucokinase with mitochondria.Diabetes,2005,54(9):2602-2611.
[15]van Gurp M, Festjens N, van Loo G, et al. Mitochondrial intermembrane proteinsin cell death. Biochem Biophys Res Common.2003,304(3):487-497.
[16]张勇,沈佰华,马安伦.用荧光定量法检测Caxpase-3的活性.细胞与分子免疫学杂志.2001,20(2):135-136.
[17]Li JM, Shah AM. ROS generation by nonphagocytic NADPH oxidase: potentialrelevance in diabetic nephropathy. J Am Soc.2003,14:S221-226.
[18]Hu W, Xie J, Zhao J, et al. Involvement of bcl-2family in apoptosis and signalpathways induced by cigarette smoke extract in the human airway smooth musclecells. DNA Cell Biol.2008,17(12):13-22.
[19]Collier JJ, Burke SJ, Eisenhauer ME, et al. Pancreatic β-cell death in response topro-inflammatory cytokines is distinct from genuine apoptosis. Plos One.2011,6(7):e22485. doi:10.1371/journal.pone.0022485. Epub2011Jul29.
[20]柴可夫,覃志成,王亚丽.北五味子油对糖尿病小鼠抗氧化及葡萄糖转运蛋白4mRNA表达的影响.中医药学刊.2006,24（7）:1199-1201.
[21]刘彦.磺脲类药物对胰岛β细胞凋亡影响的研究进展.国际内科学杂志.2009,36（4）:189-205.
[2] Yumuk VD, Hatemi H, Tarakchi T, et al. High prevalence of obesity and diabetesmellitus in Konya, a central Anatolian city in Turkey. Diabetes Res ClinicalPrac.2005,70:151-158
[3] Bailey CJ. Insulin resistance and antidiabetic drugs. Biochem Pharmacol.1999,58:1511-1520.]
[4] Umar AR, Ahmed QU, Muhammad BY, et al. Antiobesity hyperglycemic activityof the leaves of Tetarcera scandens Linn. Merr. In allaxon induced diabetes rats. JEthnopharmacol.2010,131:140-145.
[5] Butler AE, Janson J, Bonner-Weir, et al. B-cell deficit and increased B-cellapootosis in humans with type2diabetes. Diabetes.2003,52(1):102-110.
[6] Weir GC, Laybutt DR, Kaneto H, et al. B-cell adaptation and decompensationduring the progression of diabetes. Diabetes.2001,50(1): s154-159.
[7] Slovacek L, Pavlik V, Slovackova B. The effect of sibutramine therapy onoccurance of depression symptoms among obese patients. Nutr MetabCardiovascular Disease.2008,18:43–44
[8]刘彦。磺脲类药物对胰岛β细胞凋亡影响的研究进展.国际内科学杂志.2009,36（4）:189-205.
[9]雷定超,张兰兰,周水平等.中药治疗糖尿病现状与研究进展.中国医药导报.2012,9（21）：8-12
[10]范美华.五味子的研究新进展.西北药学杂志.2007,22(5):281-282.
[11]金祖汉，王香英，毛培江等.治疗糖尿病高频中药的降血糖作用研究.中国现代应用药学杂志.2009,26(4):267-270.
[12]柴可夫,覃志成,王亚丽.北五味子油对糖尿病小鼠胰岛细胞形态及功能的影响.中国中医药科技.2007,14(3):177-178.
[1] Hotamisligil GS. Inflammation and metabolic disorders. Nature.2006,444(7121):860–867.
[2] Ouchi N, Parker JL, Lugus JJ, et al. Adipokines in inflammation and metabolicdisease. Nat Rev Immunol.2011,11(2):85–97.
[3] Nishimura S, Manabe I, Nagasaki M, et al. CD8Ceffector T cells contribute tomacrophage recruitment and adipose tissue inflammation in obesity. Nat Med.2009,15(8):914–920.
[4] Reiter LT, Potocki L, Chien S, et al. A systematic analysis of humandisease-associated gene sequences in Drosophila melanogaster. Genome Res.2001,11(6):1114–1125.
[5] Tanji T, Ip YT. Regulators of the Toll and Imd pathways in the Drosophila innateimmune response. Trends Immunol.2005,26(4):193–198.
[6] Kühnlein RP. Drosophila as a lipotoxicity model organism–more than a promise?Biochim Biophys Acta.2010,1801(3):215–221.
[7] Diop SB, Bodmer R. Drosophila as a model to study the genetic mechanisms ofobesity-associated heart dysfunction. J Cell Mol Med.2012,16(5):966–971.
[8] O'Neill LA, Bryant CE, Doyle SL. Therapeutic targeting of Toll-like receptors forinfectious and inflammatory diseases and cancer. Pharmacol Rev.2009,61(2):177–197.
[9] Durmu Tekir S, ümit P, Eren Toku A, et al. Reconstruction of pro tein-proteininteraction network of insulin signaling in Homo sapiens. Journal of Biomedicineand Biotechnology.2010,2010:690925.
[10]Paris M, Bernard-Kargar C, Vilar J, et al. Role of glucose in IRS signaling in ratpancreatic islets: specific e ffects and inter play with insulin. Exp Diabesity Res.2004,5(4):257-263.
[11]Saltiel AR, Kahn CR. Insulin signalling and the regulation of glucose and lipidmetabolism. Nature.2001,414(6865):799-806.
[12]Thong FS, Dugani CB, Klip A. Turning signals on and off: GLUT4traffic in theinsulin-signaling highway. Physiology (Bethesda, Md.).2005,20:271-284.
[13]Liu J, Kimura A, Baumann CA, et al. APS facilitates c-Cbl tyrosinephosphorylation and GLUT4translocation in response to insulin in3T3-L1adipocytes. Mol Cell Biol.2002,22(11):3599-3609.
[14]Mitra P, Zheng X, Czech MP. RNAi-based analysis of CAP, Cbl, and Cr kIIfunction in the regulation of GLUT4by insulin. J Biol Chem.2004,279(36):37431-37435.
[15]Sweeney G, Somwar R, Ramlal T, et al. An inhibitor of p38mitogen-activatedprotein kinase prevents insulin-stimulated glucose transport but not glucosetransporter translocation in3T3-L1adipocytes and L6myotubes. J Biol Chem.1999,274(15):10071-10078.
[16]Murata M, Thanan R, Ma N, et al. Role of nitrative and oxidative DNA damagein inflammation-related carcinogenesis. Journal of Biomedicine andBiotechnology.2012,2012:623019.
[17]Haruta T, Uno T, Kawahara J, et al. A rapamycin-sensitive pathwaydown-regulates insulin signaling via phosphorylation and proteasomaldegradation of insulin receptor substrate-1. Mol Endocrinol.2000,14(6):783-794
[18]Wu F, Liu Y, Lv X, et al. Small interference RNA targeting TLR4gene effectivelyattenuates pulmonary inflammation in a rat model. Journal of Biomedicine andBiotechnology.2012,2012:406435.
[19]Kaneto H, Nakatani Y, Kawamori D, et al. Role of oxidative stress, endoplasmicreticulum stress, and c-Jun N-terminal kinase in pancreatic beta-cell dysfunctionand insulin resistance. International Journal of Biochemistry and Cell Biology.2006,38(5-6):782-793.
[20]H versen L, Danielsson KN, Fogelstrand L, et al. Induction of proinflammatorycytokines by long-chain saturated fatty acids in human macrophages.Atherosclerosis.2009,202(2):382-93.
[21]Coletta DK, Mandarino LJ. Mitochondrial dysfunction and insulin resistancefrom the outside in: extracellular matrix, the cytoskeleton, and mitochondria.American Journal Physiology Endocrinology Metabolism.2011,301(5):E749-755.
[22]Ji C, Chen X, Gao C, et al. IL-6induces lipolysis and mitochondrial dysfunction,but does not affect insulin-mediated glucose transport in3T3-L1a dipocytes. JBioenerg Biomembr.2011,43(4):367-75.
[23]Paquot N, Castillo MJ, Lefèbvre PJ, et al. No increased insulin sensitivity after asingle intravenous administration of a recombinant human tumor necrosis factorreceptor: Fc fusion protein in obese insulin-resistant patients. J Clin EndocrinolMetab.2000,85(3):1316-9.
[24]Gonzalez-Gay MA, Gonzalez-Juanatey C, Vazquez-Rodriguez TR, et al. Insulinresistance in rheumatoid arthritis: the impact of the anti-TNF-alpha therapy.Annals of the New York Academy of Sciences,2010,1193:153-159.
[25]Miranda-Filloy JA, Llorca J, Carnero-López B, et al. TNF-alpha antagonisttherapy improves insulin sensitivity in non-diabetic ankylosing spondylitispatients. Clin Exp Rheumatol.2012,30(6):850-855.
[26]Ridker PM, Thuren T, Zalewski A, et al. Interleukin-1β inhibition and theprevention of recurrent cardiovascular events: rationale and design of theCanakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS).American Heart Journal.2011,162(4):597-605.
[27]Hirabara SM, Gorj o R, Vinolo MA, et al. Molecular targets related toinflammations and insulin resistance and potential interventions. J BiomedBiotechnol.2012:379024.
[28]Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J ClinInvest.2006,116(7):1793–1801.
[29]Prospective Studies Collaboration, Whitlock G, Lewington S, et al. Body-massindex and cause-specific mortality in900000adults: collaborative analyses of57prospective studies. Lancet.2009,373(9669):1083–1096.
[30]Berrington de Gonzalez A, Hartge P, Cerhan JR, et al. Body-mass index andmortality among1.46million white adults. N Engl J Med.2010,363(23):2211–2219.
[31]Koster A, Leitzmann MF, Schatzkin A, et al. Waist circumference and mortality.Am J Epidemiol.2008,167(12):1465–1475.
[32]Pischon T, Boeing H, Hoffmann K, et al. General and abdominal adiposity andrisk of death in Europe. N Engl J Med.2008,359(20):2105–2120.
[33]Czernichow S, Kengne AP, Stamatakis E, et al. Body mass index, waistcircumference and waist–hip ratio: which is the better discriminator ofcardiovascular disease mortality risk?: evidence from an individual-participantmeta-analysis of82864participants from nine cohort studies. Obesity Reviews.2011,12(9):680–687.
[34]Baker AR, Harte AL, Howell N, et al. Epicardial adipose tissue as a source ofnuclear factor-kappaB and c-Jun N-terminal kinase mediated inflammation inpatients with coronary artery disease. Journal of Clinical Endocrinology andMetabolism.2009,94(1):261–267.
[35]Cypess AM, Lehman S, Williams G, et al. Identification and importance of brownadipose tissue in adult humans. N Engl J Med.2009,360(15):1509–1517.
[36]van Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM, et al.Cold-activated brown adipose tissue in healthy men. N Engl J Med.2009,360(15):1500–1508.
[37]Wu J, Bostrom P, Sparks LM, et al. a Beige adipocytes are a distinct type ofthermogenic fat cell in mouse and human. Cell.2012,150(2):366–376.
[38]Peiris AN, Sothmann MS, Hoffmann RG, et al. Adiposity, fat distribution, andcardiovascular risk. Ann Intern Med.1989,110(11):867–872.
[39]Després JP, Moorjani S, Lupien PJ, et al. Regional distribution of body fat,plasma lipoproteins, and cardiovascular disease. Arterio sclerosis.1990,10(4):497–511.
[40]Després JP, Couillard C, Gagnon J, et al. Race, visceral adipose tissue, plasmalipids, and lipoprotein lipase activity in men and women: the Health, Risk Factors,Exercise Training, and Genetics (HERITAGE) family study. Arteriosclerosis,Thrombosis, and Vascular Biology.2000,20(8):1932–1938.
[41]Couillard C, Lamarche B, Tchernof A, et al. Plasma high-density lipoproteincholesterol but not apolipoprotein A-I is a good correlate of the visceralobesity-insulin resistance dyslipidemic syndrome. Metabolism.1996,45(7):882–888.
[42]Wajchenberg BL. Subcutaneous and visceral adipose tissue: their relation to themetabolic syndrome. Endocr Rev.2000,21(6):697–738.
[43]Smith SR, Lovejoy JC, Greenway F, et al. Contributions of total body fat,abdominal subcutaneous adipose tissue compartments, and visceral adiposetissueto the metabolic complications of obesity. Metabolism.2001,50(4):425–435.
[44]Fisher FM, McTernan PG, Valsamakis G, et al. Differences in adiponectin proteinexpression: effect of fat depots and type2diabetic status. Horm Metab Res.2002,34(11-12):650–654.
[45]Harte AL, McTernan PG, McTernan CL, et al. Insulin increases angiotensinogenexpression in human abdominal subcutaneous adipocytes. Diabetes Obes Metab.2003,5(6):462–467.
[46]Harte AL, McTernan PG, McTernan CL, et al. Rosiglitazone inhibits theinsulin-mediated increase in PAI-1secretion in human abdominal subcutaneousadipocytes. Diabetes Obes Metab.2003,5(5):302–310.
[47]McTernan PG, Fisher FM, Valsamakis G, et al. Resistin and type2diabetes:regulation of resistin expression by insulin and rosiglitazone and the effects ofrecombinant resistin on lipid and glucose metabolism in human differentiatedadipocytes. J Clin Endocrinol Metab.2003,88(12):6098–6106.
[48]Kos K, Harte AL, James S, et al. Secretion of neuropeptide Y in human adiposetissue and its role in maintenance of adipose tissue mass. Am J Physiol.Endocrinol. Metab.2007,293(5) E1335–E1340.
[49]Kos K, Harte AL, O'Hare PJ, et al. Ghrelin and the differential regulation ofdes-acyl (DSG) and oct-anoyl ghrelin (OTG) in human adipose tissue (AT). ClinEndocrinol (Oxf).2009,70():383–389.
[50]Jern s M, Olsson B, Arner P, et al. Regulation of carboxylesterase1(CES1) inhuman adipose tissue. Biochem Biophys Res Commun.2009,383(1):63–67.
[51]Saiki A, Olsson M, Jern s M, et al. Tenomodulin is highly expressed in adiposetissue, increased in obesity, and down-regulated during diet-induced weight loss.J Clin Endocrinol Metab.2009,94(10):3987–3994.
[52]Carobbio S, Rodriguez-Cuenca S, Vidal-Puig A. Origins of metaboliccomplications in obesity: ectopic fat accumulation. The importance of thequalitative aspect of lipotoxicity. Curr Opin Clin Nutr Metab Care.2011,14(6):520–526.
[53]McGee KC, Harte AL, da Silva NF, et al. Visfatin is regulated by rosiglitazone intype2diabetes mellitus and influenced by NFkB and JNK in human abdominalsubcutaneous adipocytes. Plos One.2011,6(6): e20287.
[54]Manolopoulos KN, Karpe F, Frayn KN. Gluteofemoral body fat as a determinantof metabolic health. Int J Obes.2010,34(6):949–959.
[55]Youssef-Elabd EM, McGee KC, Tripathi G, et al. Acute and chronic saturatedfatty acid treatment as a key instigator of the TLR-mediated inflammatoryresponse in human adipose tissue, in vitro. J Nutr Biochem.2012,23(1):39–50.
[56]Mlinar B, Marc J. New insights into adipose tissue dysfunction in insulinresistance. Clin Chem Lab Med.2011,49(12):1925–1935.
[57]Pirola L, Johnston AM, Van Obberghen E. Modulation of insulin action.Diabetologia.2004,47(2):170–184.
[58]Tilg H, Moschen AR. Inflammatory mechanisms in the regulation of insulinresistance. Mol Med.2008,14(3-4):222–231.
[59]Kalupahana NS, Moustaid-Moussa N, Claycombe KJ. Immunity as a linkbetween obesity and insulin resistance. Mol Aspects Med.2012,33(1):26–34.
[60]Stratton IM, Adler AI, Neil HA, et al. Association of glycaemia withmacrovascular and microvascular complications of type2diabetes (UKPDS35):prospective observational study. BMJ.2000,321(7258):405–412.
[61]Selvin E, Marinopoulos S, Berkenblit G, et al. Meta-analysis: glycosylatedhemoglobin and cardio-vascular disease in diabetes mellitus. Ann Intern Med.2004,141(6):421–431.
[62]Gerstein HC, Pogue J, Mann JF, et al. The relationship between dysglycaemiaand cardiovascular and renal risk in diabetic and non-diabetic participants in theHOPE study: a prospective epidemiological analysis. Diabetologia.2005,48(9):1749–1755.
[63]Ghanim H, Mohanty P, Deopurkar R, et al. Acute modulation of Toll-likereceptors by insulin. Diabetes Care.2008,31(9):1827–1831.
[64]Soop M, Duxbury H, Agwunobi AO, et al. Euglycemic hyperinsulinemiaaugments the cytokine and endocrine responses to endotoxin in humans. Am JPhysiol. Endocrinol Metab.2002,282(6): E1276–E1285.
[65]Dandona P, Chaudhuri A, Ghanim H, et al. Proinflammatory effects of glucoseand anti-inflammatory effect of insulin: relevance tocardiovascular disease. Am JCardiol.2007,99(4A):15B–26B.
[66]Esposito K, Nappo F, Marfella R, et al. Inflammatory cytokine concentrations areacutely increased by hyperglycemia in humans: roleof oxidative stress.Circulation.2002,106(16):2067–2072.
[67]Ruge T, Lockton JA, Renstrom F, et al. Acute hyperinsulinemia raises plasmainterleukin-6in both nondiabetic and type2diabetes mellitus subjects, and thiseffect is inversely associated with body mass index. Metabolism.2009,58(6):860–866.
[68]Morohoshi M, Fujisawa K, Uchimura I, et al. Glucose-dependent interleukin6and tumor necrosis factor production by human peripheral blood monocytes invitro. Diabetes.1996,45(7):954–959.
[69]Dasu MR, Devaraj S, Zhao L, et al. High glucose induces Toll-like receptorexpression in human monocytes: mechanism of activation. Diabetes.2008,57(11):3090–3098.
[70]Bouché C, Rizkalla SW, Luo J, et al. Five-week, low-glycemic index dietdecreases total fat mass and improves plasma lipid profile in moderatelyoverweight nondiabetic men. Diabetes Care.2002,25(5):822–828.
[71]Qi L, van Dam RM, Liu S, et al. Whole-grain, bran, and cereal fiber intakes andmarkers of systemic inflammation in diabetic women. Diabetes Care.2006,29(2):207–211.
[72]de Mello VD, Kolehmainen M, Pulkkinen L, et al. Downregulation of genesinvolved in NFkappaB activation in peripheral blood mononuclear cells afterweight loss is associated with the improvement of insulin sensitivity inindividuals with the metabolic syndrome: the GENOBIN study. Diabetologia.2008,51(11):2060–2067.
[73]Heggen E, Klemsdal TO, Haugen F, et al. Effect of a low-fat versus alow-gycemic-load diet on inflammatory biomarker and adipokine concentrations.Metab Syndr Relat Disord.2012,10(6):437–442.
[74]Neuhouser ML, Schwarz Y, Wang C, et al. A low-glycemic load diet reducesserum C-reactive protein and modestly increases adiponectin in overweight andobese adults. J Nutr.2012,142(2):369–374.
[75]van Schothorst EM, Bunschoten A, Schrauwen P, et al. Effects of a high-fat, low-versus high-glycemic index diet: retardation of insulin resistance involves adiposetissue modulation. FASEB Journal.2009,23(4):1092–1101.
[76]Pedersen TR, Wilhelmsen L, Faergeman O, et al. Follow-up study of patientsrandomized in the Scandinavian simvastatin survival study (4S) of cholesterollowering. American Journal of Cardiology.2000,86(3):257–262.
[77]Hsia J, MacFadyen JG, Monyak J, et al. Cardiovascular event reduction andadverse events among subjects attaining low-density lipoprotein cholesterol <50mg/dl with rosuvastatin. The JUPITER trial (Justification for the Use of Statins inPrevention: an Intervention Trial Evaluating Rosuvastatin). J Am Coll Cardiol.2011,57(16):1666–1675.
[78]Sever PS, Chang CL, Gupta AK, et al. The Anglo-Scandinavian CardiacOutcomes Trial:11-year mortality follow-up of the lipid-lowering arm in the U.K.Eur Heart J.2011,32(20):2525–2532.
[79]Randle PJ, Garland PB, Hales CN, et al. The glucose fatty-acid cycle. Its role ininsulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet.1963,1(7285):785–789.
[80]Morino K, Neschen S, Bilz S, et al. Muscle-specific IRS-1Ser/Ala transgenicmice are protected from fat-induced insulinresistance in skeletal muscle. Diabetes.2008,57(10):2644–2651.
[81]Boden G, She P, Mozzoli M, et al. Free fatty acids produce insulin resistance andactivate the proinflammatory nuclear factor-kappaB pathway in rat liver. Diabetes.2005,54(12):3458–3465.
[82]Kim JK, Kim YJ, Fillmore JJ, et al. Prevention of fat-induced insulin resistanceby salicylate. J Clin Invest.2001,108(3):437–446.
[83]Lee JY, Sohn KH, Rhee SH, et al. Saturated fatty acids, but not unsaturated fattyacids, induce the expression of cyclooxygenase-2mediated through Toll-likereceptor4. J Biol Chem.2001,276(20):16683–16689.
[84]Szabo G, Velayudham A, Romics L, et al. Modulation of non-alcoholicsteatohepatitis by pattern recognition receptors in mice: the role of Toll-likereceptors2and4. Alcohol Clin Exp Res.2005,29(11Suppl)140S–145S.
[85]Poggi M, Bastelica D, Gual P, et al. C3H/HeJ mice carrying a Toll-like receptor4mutation are protected against the development of insulin resistance in whiteadipose tissue in response to a high-fat diet. Diabetologia.2007,50(6):1267–1276.
[86]Kim F, Pham M, Luttrell I, et al. Toll-like receptor-4mediatesvascularinflammation and insulin resistance in diet-induced obesity. Circ Res.2007,100(11):1589–1596.
[87]Wu LH, Huang CC, Adhikarakunnathu S, et al. Loss of Toll-like receptor3function improves glucose tolerance andreduces liver steatosis in obese mice.Metabolism.2012,61(11):1633–1645.
[88]Zhang Y, Proenca R, Maffei M, et al. Positional cloning of the mouse obese geneand its human homologue. Nature.1994,372(6505):425–432.
[89]Pelleymounter MA, Cullen MJ, Baker MB, et al. Effects of the obese geneproduct on body weight regulation in ob/ob mice. Science.1995,269(5223):540–543.
[90]Friedman JM, Halaas JL. Leptin and the regulation of body weight in mammals.Nature.1998,395(6704):763–770.
[91]Martín-Romero C, Santos-Alvarez J, Goberna R, et al. Human leptin enhancesactivation and proliferation of human circulating Tlymphocytes. Cell Immunol.2000,199(1):15–24.
[92]Agrawal S, Gollapudi S, Su H, et al. Leptin activates human B cells to secreteTNF-α, IL-6, and IL-10via JAK2/STAT3and p38MAPK/ERK1/2signalingpathway. J Clin Immunol.2011,31(3):472–478.
[93]Xiao E, Xia-Zhang L, Vulliémoz NR, et al. Leptin modulates inflammatorycytokine and neuroendocrine responses to endotoxin in the primate.Endocrinology.2003,144(10):4350–4353.
[94]Sachot C, Poole S, Luheshi GN. Circulating leptin mediateslipopolysaccharide-induced anorexia and fever in rats. J Physiol (Lond.).2004,561(Pt1):263–272.
[95]Weisberg SP, McCann D, Desai M, et al.2003Obesity is associated withmacrophage accumulation in adipose tissue. J Clin Invest.1121796–1808.
[96]Ziccardi P, Nappo F, Giugliano G, et al. Reduction of inflammatory cytokineconcentrations and improvement of endothelial functions in obese women afterweight loss over one year. Circulation.2002,105(7):804–809.
[97]Hivert MF, Sullivan LM, Fox CS, et al. Associations of adiponectin, resistin, andtumor necrosis factor-a with insulin resistance. Journal of Clinical Endocrinologyand Metabolism.2008,98(3):3165–3172.
[98]Stanley TL, Zanni MV, Johnsen S, et al. TNF-a antagonism with etanerceptdecreases glucose and increases the proportion of high molecular weightadiponectin in obese subjects with features of the metabolic syndrome. J ClinEndocrinol Metab.2011,96(1): E146–E150.
[99]Lagathu C, Yvan-Charvet L, Bastard JP, et al. Long-term treatment withinterleukin-1beta induces insulin resistance in murine and human adipocytes.Diabetologia,2006,49,2162–2173.
[100] Jager J, Gremeaux T, Cormont M, et al. Interleukin-1beta-induced insulinresistance in adipocytes through down-regulation of insulin receptorsubstrate-1expression. Endocrinology,2007,148,241-251.
[101] Stienstra R, Joosten LA, Koenen T, et al. The inflammasome-mediatedcaspase-1activation controls adipocyte differentiation and insulin sensitivity.Cell Metab.2010,12,593-605.
[102] Larsen CM, Faulenbach M, Vaag A, et al. Interleukin-1-receptor antagonist intype2diabetes mellitus. N Engl J Med.2007,356,1517-1526.
[103] Rotter V, Nagaev I, Smith U. Interleukin-6(IL-6) induces insulin resistance in3T3-L1adipocytes and is, like IL-8and tumor necrosis factor-a,overexpressed in human fat cells from insulin-resistant subjects. J Biol Chem.2003,278(46):45777–45784.
[104] Kusminski CM, da Silva NF, Creely SJ, et al. The in vitroeffects of resistin onthe innate immune signaling pathway in isolated human subcutaneousadipocytes. Journal of Clinical Endocrinology and Metabolism.2007,92(1):270–276.
[105] Kloting N, Graham TE, Berndt J, et al. Serum retinol-binding protein is morehighly expressed in visceral than in subcutaneous adipose tissue and is amarker of intra-abdominal fat mass. Cell Metab.2007,6:79–87.
[106] Kotani K, Kim YB, Peroni O, et al. Rosiglitazone treatment normalizesglucose tolerance in adipose-specific GLUT4knockout mice but rendersmuscle-specific GLUT4knockout more diabetic. Diabetes.2001,50:A274.
[107] Qi Q, Yu Z, Ye X, Zhao F, Huang P, Hu FB, et al. Elevated retinol-bindingprotein4levels are associated with metabolic syndrome in Chinese people. JClin Endocrinol Metab.2007,92:4827–34.
[108] Hug C, Lodish HF. The role of the adipocyte hormone adiponectin incardiovascular diseases. Curr Opin Pharmacol.2005,5:129–34.
[109] Lindsay RS, Funahashi T, Hanson RL, et al. Adiponectin and development oftype2diabetes in Pima Indian population. Lancet.2002,360:57–8.
[110] Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, et al. Thefat-derived hormone adiponectin reverses insulin resistance associated withboth lipoatrophy and obesity. Nat Med.2001,7:941–6.
[111] Berg AH, Combs TP, Du X, et al. The adipocyte-secreted protein Acrp30enhances hepatic insulin action. Nat Med.2001,7:947–53.
[112] Watson RT, Pessin J. Intracellular organization of insulin signaling andGLUT4translocation. Recent Prog Horm Res,2001,56(2):175-193.
[113] Gao Y, Yang MF, Su YP, et al. Ginsenoside Re Reduces Insulin Resistancethrough Activation of PPAR-γ Pathway and Inhibition of TNF-α Production. JEthnopharmacol.2013, S0378-8741(13)00213-4.
[114]刘洪凤,崔荣军,申梅淑,等.黄芪多糖对2型糖尿病大鼠GLUT4蛋白表达的影响.中国食物与营养.2011,17(11):70-72.
[115] Cai D, Yuan M, Frantz DF, et al. Local and systemic insulin resistanceresulting from hepatic activation of IKK-beta and NF-kappaB. Nat Med.2005,11(2):183-190.
[116] Soriano FG, Virág L, Szabó C. Diabetic endothelial dysfunction: role ofreactive oxygen and nitrogen species production and poly(ADP-ribose)polymerase activation. J Mol Med (Berl).2001,79(8):437-448.
[117] Sun X, Han F, Yi J, et al. Effect of aspirin on the expression of hepatocyteNF-κB and serum TNF-α in streptozotocin-induced type2diabetic rats. JKorean Med Sci.2011,26(6):765-770.
[118] Ouchi N, Kihara S, Funahashi T, et al. Reciprocal association of C-reactiveprotein with adiponectin in blood stream and adipose tissue. Circulation.2003,107(5):671-674.
[119]王先令,陆菊明,潘长玉.不同糖耐量水平者血清C反应蛋白水平及阿卡波糖干预的影响.中华内分泌杂志.2003,19(4):254-256.
[120]代玲俐,李晓永,林宁,等.高脂喂养大鼠内脏脂肪组织C反应蛋白的表达.中华内分泌代谢杂志.2009,25(3):323-325.
[121] Kawamori D, Kaneto H, Nakatani Y, et al. The forkhead transcription factorFoxo1bridges the JNK pathway and the transcription factor PDX-1through itsintracellular translocation. J Biol Chem.2006,281(2):1091-1098.
[122] Steinbrecher UP, Parthasarathy S, Leake DS, et al. Modification of low densitylipoprotein by endothelial cells involves lipid peroxidation and degradation oflow density lipoprotein phospholipids. Proc Natl Acad Sci U S A.1984,81(12):3883-3887.
[123] Sears DD, Miles PD, Chapman J, et al.12/15-lipoxygenase is required for theearly onset of high fat diet-induced adipose tissue inflammation and insulinresistance in mice. PLoS One.2009,4(9): e7250.
[124]周兴建,蒋绿芝,杨国铭,等.单核细胞趋化因子与2型糖尿病胰岛素抵抗相关性的研究.中国糖尿病杂志,2008,16(3),152-153.
[125] Attané C, Foussal C, Le Gonidec S, et al. Apelin treatment increases completefatty acid oxidation, mitochondrial oxidative capacity, and biogenesis inmuscle of insulin-resistant mice. Diabetes.2012,61(2):310–320.
[126] Heinonen MV, Laaksonen DE, Karhu T, et al. Effect of diet-induced weightloss on plasma apelin and cytokine levels in individuals with the metabolicsyndrome. Nutrition, Metabolism, and Cardiovascular Diseases.2009,19(9):626–633.
[127] Daviaud D, Boucher J, Gesta S, et al. TNFa up-regulates apelin expression inhuman and mouse adipose tissue. FASEB Journal.2006,20(9):1528–1530.
[128] Lu Y, Zhu X, Liang GX, et al. Apelin-APJ induces ICAM-1, VCAM-1andMCP-1expression via NF-κB/JNK signal pathway in human umbilical veinendothelial cells. Amino Acids.2012,43(5):2125–2136.
[129] Shibata R, Ouchi N, Takahashi R, et al. Omentin as a novel biomarker ofmetabolic risk factors. Diab etology&Metabolic Syndrome2012,4:37.
[130] Zhong X, Li X, Liu F, et al. Omentin inhibits TNF-a-induced expression ofadhesion molecules in endothelial cells via ERK/NF-kappaB pathway.Biochem. Biophys. Res. Commun.2012,425(2):401–406.
[131] Kazama K, Usui T, Okada M, et al. Omentin plays an anti-inflammatory rolethrough inhibition of TNF-α-induced superoxide production in vascularsmooth muscle cells. Eur J Pharmacol.2012,686(1-3):116–123.
[132] Ernst MC, Issa M, Goralski KB, et al. Chemerin exacerbates glucoseintolerance in mouse models of obesity and diabetes. Endocrinology.2010,151(5):1998–2007.
[133] Catalán V, Gómez-Ambrosi J, Rodríguez A, et al. Increased levels of chemerinand its receptor, chemokine-like receptor-1, in obesity are related toinflammation: tumor necrosis factor-a stimulates mRNA levels of chemerin invisceral adipocytes from obese patients. Surgery for Obesity and RelatedDiseases.2013,9(2):306-314.
[134] Hart R, Greaves DR. Chemerin contributes to inflammation by promotingmacrophage adhesion to VCAM-1and fibronectin through clustering ofVLA-4and VLA-5. J Immunol.2010,185(6):3728–3739.
[135] Lehrke M, Becker A, Greif M, et al. Chemerin is associated with markers ofinflammation and components of the metabolic syndrome but does not predictcoronary atherosclerosis. Eur J Endocrinol.2009,161(2):339–344.
[136] Yu S, Zhang Y, Li MZ, et al. Chemerin and apelin are positively correlatedwith inflammation in obese type2diabetic patients. Chin Med J.2012,125(19):3440–3444.
[1]中华医学会糖尿病分会.中国2型糖尿病防治指南(2010版).中国医学前沿杂志(电子版).2011,3(6):54-109
[2] Bailey CJ. Insulin resistance and antidiabetic drugs. Biochem Pharmacol.1999,58:1511-1520.
[3] Slovacek L, Pavlik V, Slovakova B. The effect of sibutramine therapy onoccurance of depression symptoms among abese patients. Nutr MetabCardiovascular Disease.2008,18:43-44.
[4]柴可夫,覃志成,王亚丽.北五味子油对糖尿病小鼠胰岛细胞形态及功能的影响.中国中医药科技,2007,14(3):177-178.
[5] Kanagasabapathy G, Kuppusamy UR, Abd Malek SN, et al. Glucan-richpolysaccharides from Pleurotus sajor-caju (Fr.) Singer prevents glucoseintolerance, insulin resistance and inflammation in C57BL/6J mice fed a high-fatdiet. BMC Complement Altern Med.2012,12(1):261.[Epub ahead of print]
[6]刘彦.磺脲类药物对胰岛β细胞凋亡影响的研究进展.国际内科学杂志.2009,36（4）:189-205.
[7] Ning G, hong J, Bi Y, et al. Progress in diabetes research in China. J Diabetes.2009,1(3):163-172.
[8]范美华.五味子的研究新进展.西北药学杂志.2007,22(5):281-282.
[9]李明珠,王艳杰,徐放.五味子粗多糖抑制肿瘤和突变作用的实验研究.黑龙江中医药.2007,(3):40.
[10]孔华丽,闫亮,段慧娟.五味子醇提取物保肝作用成分分析.解放军药学学报.2010,26(1):27-29.
[11]刘丽,赵春苏,马永全,等.五味子抗氧化和抑菌作用的研究进展.仲恺农业工程学学报,2011,24(3):63-66.
[12]刘丹娜,罗晶.不同剂量五味子多糖灌胃给药镇痛作用的观察.第四军医大学学报,2008,29(12):1115-1117.
[13]袁海波,沈忠明,殷建伟,等.五味子中α-葡萄糖苷酶抑制剂对小鼠的降血糖作用．中国生化药物杂志,2002,23(3):112-125.
[14]Sheetz MJ. Molecular understanding of hyperglycemias adverse effects fordiabetic complications. J Am Med Assoc.2002,288:2579-2588.
[15]Goldstein JL, Schrott HG, Hazzard WR, et al.Hyperlipidemia in coronary heartdisease II. Genetic analysis of lipid levels in176families and delineation of anew inherited disorder, combined hyperlipidemia. J Clin Invest1973,52:1544-1568.
[16]Kaur J, Singh P, Sowers JR. Diabetes and cardiovascular diseases. Am J Ther.2002,9:510-515.
[17]丁雯芳.红景天多糖对链脲佐菌素诱导糖尿病小鼠糖脂代谢的影响.广西中医学院学报.2011,14(2):4-5.
[18]金龙,葛争艳,郭宇洁,等.降糖消脂片对2型糖尿病大鼠降糖降脂作用的研究.中国实验方剂学杂志.2012,21:161-165.
[19]Soop M, Duxbury H, Agwunobi AO, et al. Euglycemic hyperinsulinemiaaugments the cytokine and endocrine responses to endotoxin in humans. Am. J.Physiol. Endocrinol Metab.2002,282(6): E1276–E1285.
[20]Larsen CM, Faulenbach M, Vaag A, et al. Interleukin-1-receptor antagonist intype2diabetes mellitus. N Engl J Med.2007,356(15):1517-1526.
[1] Saeks DB. Amylin-a glucoregulatory hormone involved in hepatho-genesis ofdiabetes mellitus？Clin Chem.1996,42:494.
[2] Abdul-Ghani MA, DeFronzo RA. Pathogenesis of insulin resistance in skeletalmuscle. J Biomed Biotechnol.2010(2010):476279. doi:10.1155/2010/476279.
[3] Di Carlo M, Picone P, Carrotta R, et al. Insulin promotes survival of amyloid-betaoligomers neuroblastoma damaged cells via caspase9inhibition and Hsp70upregulation. J Biomed Biotechnol.2010(2010):147835. doi:10.1155/2010/147835.
[4] Kontrogianni Konstantopoulos A, Benian G, Granzier H. Advances in MusclePhysiology and Pathophysiology2011. J Biomed Biotechnol.2012(2012):930836.doi:10.1155/2012/930836.
[5] Hundal RS, Petersen KF, Mayerson AB, Randhawa PS, et al. Mechanism bywhich high-dose aspirin improves glucose metabolism in type2diabetes. J ClinInvest.2002,109(10):1321-1326.
[6]朱耀国，任叶慧，姜军权．罗格列酮治疗2型糖尿病的机制及临床疗效．中国新药与临床杂志.2003,22(12):751-753．
[7]沈杰符鸿俊.罗格列酮对初发2型糖尿病患者血糖、胰岛β细胞功能和炎症因子的影响.中国现代医生.2012,50(32):69-70.
[8] Gandhi H, Upaganlawar A, Balaraman R. Adipocytokines: The pied pipers. JPharmacol Pharmacother.2010,1(1):9-17.
[9] Zou C, Shao J. Role of adipocytokines in obesity-associated insulin resistance. JNutr Biochem.2008,19:277-286.
[10]Kanagasabapathy G, Kuppusamy UR, Abd Malek SN, et al. Glucan-richpolysaccharides from Pleurotus sajor-caju (Fr.) Singer prevents glucoseintolerance, insulin resistance and inflammation in C57BL/6J mice fed a high-fatdiet. BMC Complement Altern Med.2012,12(1):261.[Epub ahead of print]
[11]柴可夫,覃志成,王亚丽.北五味子油对糖尿病小鼠抗氧化及葡萄糖转运蛋白4mRNA表达的影响.中医药学刊.2006,24（7）:1199-1201.
[12]Mohanty P, Aljada A, Ghanim H, et al. Evidence for a potent antiinflammatoryeffect of rosiglitazone. J Clin Endocrinol Metab.2004,89(6):2728-2735.
[13]Hotamisligil GS. Inflammation and metabolic disorders. Nature.2006,444(7121):860–867.
[14]Ouchi N, Parker JL, Lugus JJ, et al. Adipokines in inflammation and metabolicdisease. Nat Rev Immunol.2011,11(2):85–97.
[15]Vozarova B, Weyer C, Hanson K, Tataranni PA, et al. Circulating interleukin-6inrelation to adiposity, insulin action, and insulin secretion. Obes Res.2001,9(7):414-417.
[16]Watson RT, Pessin J. Intracellular organization of insulin signaling and GLUT4translocation. Recent Prog Horm Res,2001,56(2):175-193.
[17]Gao Y, Yang MF, Su YP, et al. Ginsenoside Re Reduces Insulin Resistancethrough Activation of PPAR-γ Pathway and Inhibition of TNF-α Production. JEthnopharmacol.2013, S0378-8741(13)00213-4.
[18]刘洪凤,崔荣军,申梅淑,等.黄芪多糖对2型糖尿病大鼠GLUT4蛋白表达的影响.中国食物与营养.2011,17(11):70-72.
[19]Berg AH, Combs TP, Scherer PE. ACRP30/adiponectin: an adipokine regulatingglucose and lipid metabolism [J]. Trends Endocrinol Metab,2002,13(2):84-89.
[20]Lee L, Alloosh M, Saxena R, et al. Nutritional model of steatohepatitis andmetabolic syndrome in the ossabaw miniature swine [J]. Hepatol,2009,50:56-67.
[21]Graham TE, Yang Q, Bluher M, et al. Retinol-binding protein4and insulinresistance in lean, obese and diabetic subjects [J].Eng J Med,2006,354:2552-2563.
[22]Balagopal P, Graham TE, Kahn BB, et al. Reduction of elevated serumretinol-binding protein4in obese children lifestyle intervention: association withsub-clinical inflammation [J]. J Clinical Endocrinol Metab.2007,7:2006-2012.
[23]张豫文，洪洁.炎症因子与胰岛素抵抗.诊断学理论与实践，2010,9(1):90-94.
[24]Weisberg SP, McCann D, Desai M, et al. Obesity is associated with macrophageaccumulation in adipose tissue. J. Clin. Invest.2003,112,1796–1808.
[25]Lagathu C, Yvan-Charvet L, Bastard JP, et al. Long-term treatment withinterleukin-1beta induces insulin resistance in murine and human adipocytes.Diabetologia.2006,49,2162–2173.
[26]Stienstra R, Joosten LA, Koenen T, et al. The inflammasome-mediated caspase-1activation controls adipocyte differentiation and insulin sensitivity. Cell Metab.2010,12,593-605.
[27]Larsen CM, Faulenbach M, Vaag A, et al. Interleukin-1-receptor antagonist intype2diabetes mellitus. N Engl J Med.2007,356,1517-1526.
[28]Rotter V, Nagaev I, Smith U. Interleukin-6(IL-6) induces insulin resistance in3T3-L1adipocytes and is, like IL-8and tumor necrosis factor-a, overexpressedin human fat cells from insulin-resistant subjects. J Biol Chem.2003,278(46):45777–45784.
[29]Cai D, Yuan M, Frantz DF, et al. Local and systemic insulin resistance resultingfrom hepatic activation of IKK-beta and NF-kappaB. Nat Med.2005,11(2):183-190.
[30]Soriano FG, Virág L, Szabó C. Diabetic endothelial dysfunction: role of reactiveoxygen and nitrogen species production and poly(ADP-ribose) polymeraseactivation. J Mol Med (Berl).2001,79(8):437-448.
[31]Sun X, Han F, Yi J, et al. Effect of aspirin on the expression of hepatocyte NF-κBand serum TNF-α in streptozotocin-induced type2diabetic rats. J Korean MedSci.2011,26(6):765-770.
[32]Ouchi N, Kihara S, Funahashi T, et al. Reciprocal association of C-reactiveprotein with adiponectin in blood stream and adipose tissue. Circulation.2003,107(5):671-674.
[33]王先令,陆菊明,潘长玉.不同糖耐量水平者血清C反应蛋白水平及阿卡波糖干预的影响.中华内分泌杂志.2003,19(4):254-256.
[34]代玲俐,李晓永,林宁,等.高脂喂养大鼠内脏脂肪组织C反应蛋白的表达.中华内分泌代谢杂志,2009,25(3):323-325.
[35]Kawamori D, Kaneto H, Nakatani Y, et al. The forkhead transcription factorFoxo1bridges the JNK pathway and the transcription factor PDX-1through itsintracellular translocation. J Biol Chem.2006,281(2):1091-1098.
[36]Steinbrecher UP, Parthasarathy S, Leake DS, et al. Modification of low densitylipoprotein by endothelial cells involves lipid peroxidation and degradation oflow density lipoprotein phospholipids. Proc Natl Acad Sci U S A.1984,81(12):3883-3887.
[37]Sears DD, Miles PD, Chapman J, et al.12/15-lipoxygenase is required for theearly onset of high fat diet-induced adipose tissue inflammation and insulinresistance in mice. PLoS One.2009,4(9): e7250.
[38]周兴建,蒋绿芝,杨国铭,等.单核细胞趋化因子与2型糖尿病胰岛素抵抗相关性的研究.中国糖尿病杂志,2008,16(3),152-153.
[39]Kotnik P, Keuper M, Wabitsch M et al. Interleukin-1β Downregulates RBP4Secretion in Human Adipocytes. PLoS One.2013,8(2): e57796. doi:10.1371/journal.pone.0057796. Epub2013Feb27.
[1] Kahn SE, The importance of the β-cell in the pathogenesis of type2diabetesmellitus. Am J Med.2000,108(suppl1):S109-S116.
[2] Saeks DB. Amylin-aglue regulatory hormone involved in hepatho-genesis ofdiabetes mellitus? Clin Chem.1996,42:494.
[3]宁光.胰岛β细胞功能异常在2型糖尿病发生中的重要性.中华内分泌代谢杂志.2003,19：附录5-7
[4] Rhodes CJ. Type2diabetes-a matter of beta-cell life and death? Science.2005,307:380-384.
[5] Butler AE, Janson J, Bonner-Weir S, et al. β-cell deficit and increased β-cellapoptosis in humans with type2diabetes. Diabetes.2003,52:102-110.
[6]柴可夫,覃志成,王亚丽.北五味子油对糖尿病小鼠胰岛细胞形态及功能的影响.中国中医药科技.2007,14(3):177-178.
[7] Lin CY, Gurlo T, Haataja L, et al. Activation of peroxisome proliferator-activatedreceptor-gamma by rosiglitazone protects human islet cells against human isletamyloid polypeptide toxicity by a phosphatidylinositol3'-kinase-dependentpathway. J Clin Endocrinol Metab.2005,90(12):6678-86.
[8] The Expert Committee on the Diagnosis and classification of Diabetes Mellitus.Report of the expert committee on the diagnosis and classification of diabetesmellitus. Diabetes Care.2003,26(suppl1):S5-S20.
[9] Cavaghan MK, Ehrmann DA, Polonsky KS. Interactions between insulinresistance and insulin secretion in the development of glucose intolerance. J ClinInvest.2000,106:329-333.
[10]Kahn BB, Type2dibetes: when insulin secretion fails to compensate for insulinresistance. Cell.1998,92:593-596.
[11]Clerk A, Wells CA, Buley ID, et al. Islet amyloid, increased A-cells, reducedB-cells and exocrine fibrosis: quantitative changes in the pancreas in type2diabetes. Diabetes Res.1988,9(4):151-159.
[12]Saito K, Yaginuma N, Takahashi T. Differential volumetry of A, B and D cells inthe pancreas islet of diabetic and nondiabetic subject. Tohoku J Exp Med.1979,129(3):273-283.
[13]Yoon KH, Ko SH, Cho JH, et al. Selective beta-cell loss and alpha-cell expansionin patients with type2diabetes mellitus in Korea. J Clin Endocrinol Metab.2003,88(5):2300–2308.
[14]Kim WH, Lee JW, Sun YH, et al. Exposure to chronic high glucose induces β-cell apootosis through decreased interaction of glucokinase with mitochondria.Diabetes,2005,54(9):2602-2611.
[15]van Gurp M, Festjens N, van Loo G, et al. Mitochondrial intermembrane proteinsin cell death. Biochem Biophys Res Common.2003,304(3):487-497.
[16]张勇,沈佰华,马安伦.用荧光定量法检测Caxpase-3的活性.细胞与分子免疫学杂志.2001,20(2):135-136.
[17]Li JM, Shah AM. ROS generation by nonphagocytic NADPH oxidase: potentialrelevance in diabetic nephropathy. J Am Soc.2003,14:S221-226.
[18]Hu W, Xie J, Zhao J, et al. Involvement of bcl-2family in apoptosis and signalpathways induced by cigarette smoke extract in the human airway smooth musclecells. DNA Cell Biol.2008,17(12):13-22.
[19]Collier JJ, Burke SJ, Eisenhauer ME, et al. Pancreatic β-cell death in response topro-inflammatory cytokines is distinct from genuine apoptosis. Plos One.2011,6(7):e22485. doi:10.1371/journal.pone.0022485. Epub2011Jul29.
[20]柴可夫,覃志成,王亚丽.北五味子油对糖尿病小鼠抗氧化及葡萄糖转运蛋白4mRNA表达的影响.中医药学刊.2006,24（7）:1199-1201.
[21]刘彦.磺脲类药物对胰岛β细胞凋亡影响的研究进展.国际内科学杂志.2009,36（4）:189-205.
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