IKKβ/NF-κB信号通路与骨骼肌胰岛素抵抗

骨骼肌是胰岛素抵抗发生的主要部位.IκB激酶β(IKKβ)/核因子-κB(NF-κB)信号通路通过干扰正常胰岛素信号转导和诱导机体低水平慢性炎性反应,在骨骼肌胰岛素抵抗中发挥重要作用.通过作用于IKKB/NF-κB信号通路达到治疗2型糖尿病的目的,可成为一个新的研究方向.     

替米沙坦、瑞舒伐他汀对胰岛素抵抗大鼠骨骼肌小窝蛋白1、葡萄糖转运蛋白4表达的影响

目的测定不同饮食喂养大鼠和替米沙坦、瑞舒伐他汀干预后大鼠产生胰岛素抵抗(IR)的情况,观察大鼠骨骼肌中小窝蛋白(Caveolin)1、葡萄糖转运蛋白(GLUT)4表达的变化。方法 4周龄Wistar雄性大鼠48只,以高糖高脂饮食诱导建立IR模型,以高糖高脂给药(替米沙坦、瑞舒伐他汀)诱导建立实验组,通过RT-PCR方法检测IR大鼠骨骼肌组织中Caveolin 1、GLUT4的表达水平。结果高糖高脂喂养组产生IR,给予替米沙坦、瑞舒伐他汀干预后IR明显改善,高糖高脂组Caveolin1 mRNA在骨骼肌中的表达明显高于对照组(P<0.05),高糖高脂组GLUT4 mR-NA在骨骼肌中的表达明显低于对照组(P<0.05),替米沙坦、瑞舒伐他汀可降低Caveolin1 mRNA在IR大鼠骨骼肌中的表达,升高GLUT4 mRNA在IR大鼠骨骼肌中的表达。结论①高糖高脂饲料喂养8 w可诱导大鼠IR。②IR大鼠骨骼肌组织Caveolin 1表达增加,GLUT4表达减少。③通过替米沙坦类、他汀类药物干预,可改善IR,降低Caveolin1表达水平,升高GLUT4表达水平。     

阿托伐他汀对老年早期糖尿病肾病患者外周血NF-κB和胰岛素抵抗的影响

目的观察阿托伐他汀对老年早期糖尿病肾病患者外周血单个核细胞中核因子-κB(NF-κB)P65的磷酸化水平和血清hs-CRP、TNF-α、IL-6、IL-1β炎症因子以及胰岛素抵抗的影响.方法选择66例老年早期2型糖尿病患者随机分为糖尿病常规治疗组(对照组,n=31)及糖尿病常规治疗联合阿托伐他汀干预组(治疗组,n=35),比较两组治疗前后NF-κB、血清hs-CRP、TNF-α、IL-6、IL-1β及胰岛素抵抗指数(HOMA-IR)的变化.结果治疗12周后,治疗组外周血NF-κB水平、血清炎症因子、HOMA-IR显著下降(P<0.05),对照组无明显变化(P>0.05).结论阿托伐他汀可降低糖尿病肾病患者炎症水平,改善胰岛素抵抗.     

辛伐他汀对胰岛素抵抗大鼠脂肪组织脂联素和核因子κB抑制因子激酶mRNA表达的影响

目的探讨辛伐他汀对胰岛素抵抗大鼠脂肪组织脂联素和核因子κB抑制因子激酶mRNA表达的影响。方法采用高脂饲料喂养复制胰岛素抵抗大鼠模型,并用正常血糖—高血浆胰岛素钳夹技术评估。胰岛素抵抗大鼠给予辛伐他汀10mg/(kg.d)治疗。应用逆转录聚合酶链反应检测大鼠脂肪组织中脂联素和核因子κB抑制因子激酶mRNA的表达。结果高脂饲料喂养组大鼠葡萄糖输注率明显低于基础饲料喂养组[0.76±0.28mg/(kg.min)比4.26±0.70mg/(kg.min),P<0.01]。辛伐他汀治疗组和高脂未治疗组大鼠脂肪组织中脂联素mRNA的表达差异无显著性(0.25±0.12比0.29±0.11,P>0.05),但均明显低于基础饲料喂养组(1.18±0.12,P<0.05)。辛伐他汀治疗组大鼠脂肪组织中核因子κB抑制因子激酶mRNA的表达明显低于高脂未治疗组(0.15±0.03比1.21±0.03,P<0.05),与基础饲料喂养组差异无显著性(0.15±0.03,P>0.05)。除外辛伐他汀干预作用后大鼠脂肪组织脂联素与核因子κB抑制因子激酶mRNA的表达负相关(r=-0.97,P=0.000)。结论辛伐他汀不能增加高脂诱导的胰岛素抵抗大鼠脂肪组织脂联素mRNA的表达,但能使升高的核因子κB抑制因子激酶mRNA表达水平得以恢复,这可能得益于辛伐他汀调脂作用外的抗炎作用。     

辛伐他汀对胰岛素抵抗大鼠肝脏NF-κB p65表达的影响

目的探讨辛伐他汀（SV）对胰岛素抵抗（IR）大鼠肝脏NF-κB p65表达的影响。方法采用高脂饲料喂养建立IR大鼠模型，并用正常血糖-高血浆胰岛素钳夹技术评估，IR大鼠给予SV治疗。应用Western blot方法检测大鼠肝脏中NF-κB p65蛋白的表达。结果（1）高脂饲料组的葡萄糖输注率明显低于基础饲料组（P〈0．01）。（2）SV治疗组肝脏NF-κB p65蛋白的表达明显低于高脂未治疗组（P〈0．05），但与基础饲料组无明显差别。（3）与基础饲料组相比，SV治疗组和高脂未治疗组的胰岛素敏感性指数（ISI）明显降低（P〈0．05）；SV治疗组与高脂未治疗组的ISI无明显差别。结论SV能使高脂诱导的IR大鼠肝脏升高的NF-κB p65蛋白表达水平恢复正常，但不能明显改善全身胰岛素抵抗。     

IKKβ/F-kB信号通路与骨骼肌胰岛素抵抗

骨骼肌是胰岛素抵抗发生的主要部位。IkB激酶β（IKKβ）／核因子-kB（NF—kB）信号通路通过干扰正常胰岛素信号转导和诱导机体低水平慢性炎性反应，在骨骼肌胰岛素抵抗中发挥重要作用。通过作用于IKKβ／NF-kB信号通路达到治疗2型糖尿病的目的，可成为一个新的研究方向。     

替米沙坦对胰岛素抵抗大鼠糖脂代谢和抵抗素表达的影响

目的观察替米沙坦对高脂饮食诱导的胰岛素抵抗大鼠糖脂代谢和抵抗素表达的影响。方法选择36只Wistar大鼠分为NC组12只和高脂组24只,6周后高脂组大鼠分为替米沙坦组（T）和高脂对照组（HF）各12只,4周后测定体质量、附睾脂肪重量、FPG、FINS、FFA和血脂;高胰岛素一正常葡萄糖钳夹技术评价胰岛素敏感性;RT—PCR法检测附睾脂肪组织抵抗素mRNA的表达。结果与HF组比较,替米沙坦治疗后大鼠的体质量、附睾脂肪重量、FINS、FPG、TG、FFA、LDL—C明显降低,HDL—C、抵抗素mRNA表达水平和胰岛素敏感性增强（P〈0．05或P〈0．01）。结论替米沙坦能减轻IR大鼠的体质量和内脏脂肪重量,改善糖脂代谢紊乱,上调附睾脂肪组织抵抗素mRNA的表达,提高胰岛素敏感性。     

替米沙坦对原发性高血压胰岛素抵抗的影响

目的观察替米沙坦对高血压病患者胰岛素抵抗的影响。方法选择伴有胰岛素抵抗的高血压患者140例。随机分为替米沙坦80mg／d组与氨氯地平5mg／d＋吡格列酮15mg／d组。治疗前和用药后12周分别检测空腹血糖（FPG）、空腹胰岛素（FINS）、口服葡萄糖耐量试验（OGTT）、餐后2小时血糖（P2hBG）、餐后2小时胰岛素（P2hINS）及24h动态血压，计算胰岛素抵抗指标（HOMA-IR）。结果两组用药后12周P2hBG，FINS，P2hINS显著下降，胰岛素敏感指标（HOMA-IS）升高，HOMA-IR降低。治疗后各项指标在两组间比较差异均无统计学意义（P〉0．05）。两组白昼平均收缩压与舒张压、夜间平均收缩压与舒张压均较治疗前下降明显，差异有统计学意义（P〈0．05）。治疗后两组动态血压变化差异无统计学意义（P〉0．05）。结论替米沙坦在降低血压的同时可明显改善胰岛素抵抗，适用于高血压病伴胰岛素抵抗患者。     

替米沙坦对原发性高血压胰岛素抵抗的影响

目的 观察替米沙坦对高血压病患者胰岛素抵抗的影响.方法 选择伴有胰岛素抵抗的高血压患者140例.随机分为替米沙坦80 mg/d组与氨氯地平5 mg/d 吡格列酮15 mg/d组.治疗前和用药后12周分别检测空腹血糖(FPG)、空腹胰岛素(FINS)、口服葡萄糖耐量试验(OGTT)、餐后2小时血糖(P2hBG)、餐后2小时胰岛素(P2hINS)及24 h动态血压,计算胰岛素抵抗指标(HOMA-IR).结果两组用药后12周P2hBG,FINS,P2hINS显著下降,胰岛素敏感指标(HOMA-IS)升高,HOMA-IR降低.治疗后各项指标在两组间比较差异均无统计学意义(P＞0.05).两组白昼平均收缩压与舒张压、夜间平均收缩压与舒张压均较治疗前下降明显,差异有统计学意义(P＜0.05).治疗后两组动态血压变化差异无统计学意义(P＞0.05).结论 替米沙坦在降低血压的同时可明显改善胰岛素抵抗,适用于高血压病伴胰岛素抵抗患者.     

瑞舒伐他汀预处理对大鼠脑缺血再灌注损伤模型NF-κB表达的影响

目的探讨预防性应用瑞舒伐他汀对大鼠脑缺血再灌注损伤脑组织NF-κB表达的影响。方法 48只SD大鼠按随机化原理分成三组:假手术组、缺血再灌注组(简称对照组)、瑞舒伐他汀组。瑞舒伐他汀组大鼠术前10天予瑞舒伐他汀(5mg/kg)行灌胃治疗,每天一次;假手术组和对照组给予等容积0.9%氯化钠溶液,每天一次。采用改良的Longa氏法制备大鼠大脑中动脉缺血再灌注模型,缺血2h再灌注24h以后行神经功能缺损评分,HE染色法观察大鼠脑组织病理形态;免疫组织化学方法观察核转录因子NF-κB(nuclear factor-ΚB)的表达。结果瑞舒伐他汀组较对照组神经功能缺损评分降低(P0.05)。瑞舒伐他汀组与对照组比较,缺血区变性坏死的神经元数量,空泡化改变及组织间水肿均明显减轻。瑞舒伐他汀组较对照组NF-κB阳性表达细胞数明显减少(P0.01)。结论预防性应用瑞舒伐他汀对大鼠脑缺血再灌注损伤有神经保护作用,其机制可能与抑制炎症反应有关。     

肝SOCS-3和SREBP—1c基因表达在大鼠胰岛素抵抗及非酒精性脂肪肝中的作用

目的探讨胰岛素抵抗（IR）和非酒精性脂肪肝（NAFL）联系的可能分子机制。方法用高脂喂养建立NAFL大鼠模型,对部分大鼠限食干预,RT-PCR检测肝脏细胞因子信号抑制物3（SOCS-3）及固醇调节成分结合蛋白1c（SREBP-1c）的表达,并观察肝脏病理改变。结果与正常对照组比,高脂组TC、TG、HOMA-IR水平升高（P〈0．01）,肝脏SOCS-3、SREBP-1cmRNA表达增加（P〈0．05）,高脂限食组相关指标下降。结论IR和NAFL可通过一系列因子相互联系。饮食对大鼠IR和NAFL有一定的影响。     

Effects of telmisartan on hypertensive patients with dyslipidemia and insulin resistance

The benefits of angiotensin converting enzyme inhibi-tor (ACEI) and angiotensin receptor blocker (ARB) beyondblood pressure reduction have been proven through manylarge studies (HOPE, LIFE) in high risk CVD patients;1 posthoc studies have shown reductions in new onset type 2 dia-betes mellitus (DM). However, there are no studies whichrevealed a strong correlation between impaired fasting glu-cose (IFG) and cardiovascular disease (CVD); instead, therewere correlations with post challenge glucose and post chal-lenge insulin levels. Insulin resistance (IR) is fundamental tohigh risk CVD situations and high fasting and post challengeinsulin levels are surrogate markers for IR, albeit inconsistently.A logical approach to the prevention of type 2 DM and CVDmust be therapeutic insulin reduction. Type 2 DM clearly in-fluences the incidence of poor outcomes in CVD patients, andfor any level of risk factors analyzed, a mechanism or mecha-     

Angiotensin II type 1 receptor-independent beneficial effects of telmisartan on dietary-induced obesity, insulin resistance and fatty liver in mice

Aims/hypothesis  

Evidence suggests that telmisartan, an angiotensin II type 1 receptor (AT1) blocker and peroxisome proliferator-activated receptor-γ partial agonist, has beneficial actions that limit development of the metabolic syndrome and diabetes. However, the role played by AT1 inhibition in metabolic effects elicited by telmisartan remains uncertain. Here we isolated the metabolic effects of telmisartan from AT1 antagonism.     

Fatty liver,insulin resistance,and dyslipidemia

After recently being recognized as a feature of the metabolic syndrome, fatty liver has evolved as a key player in the pathogenesis of dyslipidemia. Development of nonalcoholic fatty liver disease comes from an imbalance between the influx and production of fatty acids and the use of fatty acids for oxidation or secretion as very low density lipoprotein (VLDL) triglycerides. Previously, we have shown a strong relationship between increased liver fat and overproduction of large VLDL particles. We observed recently that in patients with high liver fat, insulin was unable to regulate VLDL production. The result is increased concentrations of VLDL particles in the circulation. Consequently, changes are seen in the metabolism of other lipoproteins that interact with VLDL particles, the net result being decreased high-density lipoprotein cholesterol and increased formation of small, dense low-density lipoprotein. In this article, we review recent findings on the development of fatty liver and its role in the diabetic dyslipidemia pathogenesis.     

替米沙坦对肥胖性高血压患者体脂、血脂及胰岛素抵抗的影响

目的探讨替米沙坦对肥胖性高血压患者体脂、血脂、胰岛素抵抗的影响。方法 BMI≥25 kg/m2的原发性高血压患者60例,随机分成观察组和对照组,并分别给予替米沙坦和硝苯地平缓释片干预,观察干预前后BP、BMI、腰臀比（W/H）、TC、LDL-C、TG、胰岛素抵抗指数（IRI）、高敏C反应蛋白（hsCRP）等指标变化。结果与干预前比较,干预后12、24周两组BP均下降（P〈0.01）,干预后24周观察组W/H、TGI、RI、hsCRP下降（P〈0.01或P〈0.05）。观察组IRI、hsCRP的变化与SBP、DBP、BMI、W/H、TG等呈直线相关。结论替米沙坦除良好的降压外,有一定的减轻腹型肥胖、控制TG和改善胰岛素抵抗的作用。     

Impact of mitochondrial ROS production in the pathogenesis of insulin resistance

Tumor necrosis factor-alpha (TNF-alpha) inhibits insulin action, in part, by activating c-jun NH(2)-terminal kinases (JNK). However, the precise mechanisms by which TNF-alpha activates JNK are unknown. Recently, we confirmed that hyperglycemia increased mitochondrial reactive oxygen species (ROS) production, and which can associate with the pathogenesis of diabetic vascular complications. In addition, apoptosis signal-regulating kinase 1 (ASK1) was reported to activate the JNK and p38 signaling pathways and is required for TNF-alpha-induced apoptosis. Here we demonstrate that TNF-alpha increases mitochondrial ROS production and ASK1 activity, and that these TNF-alpha-induced phenomena associate with JNK activation, increase in Ser(307) phosphorylation of IRS-1 and decrease in insulin-stimulated tyrosine phosphorylation of IRS-1, all of which are believed to be the molecular basis of TNF-alpha-induced insulin resistance. We claim that mitochondrial ROS production may be a key factor not only in diabetic vascular complications, but also in the development of type 2 diabetes. This integrating paradigm could provide a new conceptual framework for further research and therapies for the treatment of type 2 diabetes.     

替米沙坦对非酒精性脂肪性肝炎大鼠肝纤维化基质金属蛋白酶-13及其抑制因子-1的表达和胰岛素抵抗的影响

目的观察替米沙坦对非酒精性脂肪性肝炎（NASH）大鼠肝纤维化的疗效和对基质金属蛋白酶-13（MMP-13）及其抑制因子-1（TIMP-1）的表达和胰岛素抵抗的影响。方法30只雄性SD大鼠随机分为正常对照组、模型组和替米沙坦干预组。模型组和干预组给予高脂饲料喂养16周诱发脂肪性肝炎,其中干预组于高脂喂养12周后,给予替米沙坦[5mg／（kg·d）】灌胃治疗4周。16周末处死所有动物。检测血清丙氨酸转氨酶（ALT）、天冬氨酸转氨酶（AST）及空腹胰岛素（FINS）、空腹血糖（FPG）,并计算胰岛素抵抗指数（HOMA—IR）,RT—PCR和Westernblot法检测肝组织TIMP-1、MMP-13mRNA和蛋白的表达水平。病理切片观察组织学改变,免疫组织化学法检测a-平滑肌肌动蛋白（α-SMA）的表达情况。结果模型组血清ALT,AST,FPG,FINS及HOMA—IR较正常组均显著升高（均P〈0．01）。与模型组相比,干预组血清ALT,FPG,FINS及HOMA—IR均明显下降,差异具有统计学意义（均P〈0．01）。AST与干预组相比存在下降趋势,但差异无统计学意义（P〉0．05）。与模型组相比,替米沙坦可显著改善肝脏炎症活动度及肝纤维化程度（均P〈0．01）。干预组HOMA-IR较模型组明显降低【（3．59±0．29）VS（6．23±0．19）,P〈0．01]。干预组肝组织α—SMA的表达明显减少,肝组织MMP．13mRNA和蛋白的表达均增加,TIMP-1mRNA和蛋白的表达均降低（均P〈0．01）。结论替米沙坦对NASH大鼠具有改善胰岛素抵抗和抗肝纤维化的作用。     

Effects of telmisartan and losartan on insulin resistance in hypertensive patients with metabolic syndrome.

Partial peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists are known to decrease insulin resistance. Experimental studies have shown that the angiotensin type 1 receptor blocker (ARB) telmisartan has a PPAR-gamma-activating property, but there does not appear to be a class effect. To test telmisartan's clinical importance, we here investigated its effect on insulin resistance in hypertensive patients with metabolic syndrome (MetS) in comparison with another ARB, losartan. A total of 42 hypertensive MetS patients (29 female, 13 male) were included (mean age: 50+/-9, range: 20-70 years). NCEP-ATP III criteria were used for the diagnosis of MetS. Patients were randomized to receive either telmisartan 80 mg/day (n=21) or losartan 50 mg/day (n=21) for 8 weeks. Biochemical assessments were made at baseline and at the end of the 8 weeks. Insulin resistance was evaluated by using homeostasis model assessment of insulin resistance (HOMA-IR). Both groups had similar reductions in systolic and diastolic pressures (p>0.05). HOMA-IR did not change significantly in either group throughout the study. In the telmisartan group, the mean HOMA-IR at baseline and at the end of the study were 1.9+/-07 and 1.9+/-0.5, respectively. The figures for the losartan group were 1.8+/-0.6 and 1.8+/-0.6, corresponding. In conclusion, in contrast with the reports that telmisartan may decrease insulin resistance by an effect associated with its molecular structure, 8 weeks of telmisartan treatment in the present study had a neutral effect on insulin resistance in hypertensive MetS patients, and similar results were obtained for losartan.     

Effect of rosuvastatin on insulin sensitivity in an animal model of insulin resistance: evidence for statin-induced hepatic insulin sensitization

Statin-treatment of fructose-fed/insulin resistant hamsters was recently shown to ameliorate metabolic dyslipidemia and hepatic VLDL overproduction. Here, we provide evidence that rosuvastatin treatment of insulin resistant hamsters can induce improvements in hepatic and whole body insulin sensitivity. Treatment with 10 mg/kg/day rosuvastatin for 10 days significantly reduced fasting insulin (−59%) and triglyceride (−50%) levels in fructose-fed hamsters (p < 0.05). Following an intraperitoneal (IP) glucose challenge, rosuvastatin-treated hamsters exhibited enhanced glucose clearance compared to untreated hamsters maintained on the high-fructose diet (area under curve (AUC) = 1772 ± 223 mM min vs. 2413 ± 253 mM min, respectively; p < 0.002) with a significant reduction in 2 h post-challenge glucose (n = 5, p < 0.02). Rosuvastatin-treatment also significantly improved sensitivity to an IP insulin challenge (AUC = 314 ± 39 mM min vs. 195 ± 22 mM min for rosuvastatin-treated and fructose-fed hamsters, respectively; p < 0.04, n = 3). At the molecular level, significant increases in tyrosine-phosphorylation of the hepatic insulin receptor and IRS-1 were observed for rosuvastatin-treated hamsters (+37% and +58%, respectively) compared to fructose-fed controls following an intravenous (IV) bolus of insulin (p < 0.05). Increases in insulin receptor and IRS-1 phosphorylation were also observed in muscle and adipose tissue. Analysis of hepatic Akt phosphorylation and mass revealed a small (25%) increase in serine phosphorylation of Akt with no significant change in Akt mass, although serine-phosphorylation and mass of Akt2 were significantly increased (+32%, p = 0.03, and +42%, p = 0.01, respectively). Interestingly, expression of PTP-1B, a key negative regulator of insulin signaling, showed a non-significant trend toward reduction in liver and was significantly reduced in adipose tissue (−20% and −37%, respectively). Taken together, these data suggest that statin-treatment increases whole body and peripheral tissue insulin sensitivity via improved cellular insulin signal transduction.