罗格列酮对2型糖尿病大鼠主动脉内皮依赖性血管舒张功能的影响

目的观察2型糖尿病（T2DM）大鼠胸主动脉内皮依赖性血管舒张功能和一氧化氮（NO）、一氧化氮合酶（eNOS）的变化及罗格列酮（RSG）治疗对其内皮功能的影响。方法SD大鼠经高糖高脂喂养6周后予小剂量链脲佐菌素腹腔注射建立T2DM大鼠模型，糖尿病大鼠又分为对照（DM）组和RSG治疗组，RSG组用RSG干预8周，另选正常大鼠为正常对照（NC）组。实验终止时用正常葡萄糖高胰岛素钳夹技术的葡萄糖输注率（GIR）评价胰岛素抵抗，观察大鼠离体主动脉内皮依赖性血管舒张反应和主动脉NO、eNOS的变化。结果T2DM大鼠GIR、胸主动脉内皮依赖性血管舒张反应、主动脉NO含量及eNOS阳性表达较NC组显著降低（P〈0、01），RSG治疗后上述指标均显著升高（P〈0．05）。结论T2DM大鼠存在内皮依赖性血管舒张功能紊乱，RSG治疗可改善内皮功能，增强NO水平和eNOS的活性。     

罗格列酮对胰岛素抵抗大鼠β细胞作用形态学观察

目的　研究罗格列酮 (RSG)对胰岛素抵抗 (IR)大鼠 β细胞超微结构病变的作用。 方法高糖饲料喂养SD大鼠 6周复制IR大鼠模型。成模后用药组予RSG 10 μmol·kg-1·d-1,用药 6周。未用药IR大鼠模型为对照 (IR组 )。透射电镜观察胰岛 β细胞超微结构。 结果　与IR组相比 ,RSG组大鼠收缩压、血清甘油三酯、游离脂肪酸、胰岛素降低 (均P <0 .0 1) ,胰岛素敏感指数、血清高密度脂蛋白胆固醇升高 (均P <0 .0 1)。电镜观察IR大鼠 β细胞可见凋亡早期改变 ,细胞浆内脂质沉积以及细胞核和细胞器的病理变化。RSG组 β细胞超微结构病变明显减轻 ,未见凋亡的 β细胞及胞浆内脂质沉积。 结论　罗格列酮可有效防治高糖饲料诱导IR大鼠 β细胞的病理损害     

罗格列酮对胰岛素抵抗大鼠胸主动脉内皮细胞作用的形态学观察

目的　研究罗格列酮对胰岛素抵抗 (IR)大鼠胸主动脉内皮超微结构病变的作用。方法6～ 8周龄SD大鼠高糖饲料喂养 6周复制IR大鼠模型。成模后用药组 (RSG组 )予罗格列酮 10 μmol·kg-1·d-1灌胃 ,用药 6周。未用药IR大鼠模型为对照 (IR组 )。透射电镜观察胸主动脉内皮超微结构。结果　与IR组相比 ,RSG组大鼠收缩压、血清甘油三酯、游离脂肪酸、胰岛素水平降低 (均P <0 .0 1) ,胰岛素敏感指数 (ISI)、血清高密度脂蛋白胆固醇升高 (均P <0 .0 1)。IR组与RSG组空腹血糖及餐后 2h血糖均在正常范围。电镜观察IR大鼠胸主动脉内皮可见内皮细胞和内皮下结构的病理改变。RSG组胸主动脉内皮超微结构接近正常。结论　罗格列酮可有效防治高糖膳食诱导IR大鼠IR早期胸主动脉内皮的病理损害     

罗格列酮对高糖高脂饮食诱导糖尿病大鼠脂肪肝的治疗作用

目的探讨罗格列酮（RSG）对2型糖尿病（T2DM）大鼠合并脂肪肝的治疗作用。方法建立T2DM合并脂肪肝的大鼠模型，以RSG进行干预治疗。18周末留取肝组织及血清，检测比较各组血糖、血脂、胰岛素、谷丙转氨酶、TNF-α、瘦素等指标及肝脏病理变化和TNF-α在肝脏的表达。结果RSG治疗组大鼠肝脏结构较糖尿病对照组明显好转，TNF-α在肝脏的表达水平降低（P〈0.05），TG、TC、瘦素水平均明显下降（P〈0.05，P〈0.01，P〈0.05）。结论RSG对实验性糖尿病大鼠合并脂肪肝具有一定的治疗作用。     

罗格列酮对糖尿病大鼠残存胰岛β细胞的保护作用

目的观察罗格列酮（RSG）对糖尿病大鼠残存胰岛β细胞功能的影响。方法SD大鼠48只随机分为3组,正常对照（NC）组8只,糖尿病对照（DM）组20只,罗格列酮干预（RSG）组20只。DM、RSG两组成模糖尿病大鼠,RSG组即以罗格列酮灌胃（5mg&#183;kg^-1&#183;d^-1）,此后1、2、4、7、10周时,分别测定各组的FBG和FIns,DM、RSG两组分别在每个时间点各处死动物4只。透射电镜观察胰岛β细胞超微病变,免疫组化法检测胰岛中胰岛素水平。结果（1）与DM组相比,RSG组血清胰岛素水平逐渐上升,血糖水平逐渐下降。（2）RSG组β细胞数量增加,分泌颗粒增多。（3）RSG组胰岛表达胰岛素水平逐渐增高,并明显大于DM组（P〈0.05）。结论罗格列酮对糖尿病大鼠残存胰岛β细胞具有一定的保护作用。     

罗格列酮对2型糖尿病患者血清脂肪细胞因子的影响

目的观察罗格列酮（RSG）对2型糖尿病（T2DM）患者血清脂肪细胞因子的影响，探讨血清脂肪细胞因子和胰岛素抵抗（IR）的关系及其在T2DM发病机制中的作用。方法38例新诊断T2DM患者（DM组），以RSG每日4mg口服治疗12周；24例年龄和性别匹配的糖耐量正常者为正常对照（NC）组。检测NC组及DM组患者治疗前后的身高、体重、血压、FPG、2hPG、免疫反应胰岛素（IRI）、真胰岛素（TI）、胰岛素原（PI）、血清脂肪细胞因子瘦素（LEP）、抵抗素（RST）、脂联素（APN）、视黄醇结合蛋白4（RBP-4）、尿白蛋白（UAlb）和血脂谱。计算BMI、胰岛素敏感性指数（QUICKI）、胰岛素抵抗指数（HOMA-IR）和FPI／FTI。结果DM组RSG治疗前PG、IRI、FPI、LEP、RST、RBP-4、HOMA-IR和FPI／FTI均较NC组升高，而APN和QUICK下降（P〈0．05）；DM组RSG治疗后，BMI、UAlb、血脂谱和RBP-4无显著变化，其余指标均向正常转化，APN则升高达2倍多（P〈0．01）。LEP与性别、BMI、FIRI、FTI、FPI、HOMA-IR和QUICKI相关；RST与FPI／FTI和TI相关；APN与年龄、BMI、RBP-4、FPI、2hPI、FTI、HOMA-IR和QuICKI相关；RBP-4与BMI、APN、HOMA-IR相关。多元逐步回归分析提示，LEP和APN与IR独立相关。结论新诊断T2DM患者存在IR和血清LEP、RST、RBP-4升高；APN下降；RSG可能通过改善血清脂肪细胞因子谱而发挥降血糖、改善IR和口细胞功能的疗效。     

罗格列酮对2型糖尿病大鼠肾小管的保护作用

目的探讨罗格列酮（rosiglitazone，RSG）对2型糖尿病（T2DM）大鼠肾脏的保护机制及其对肾功能的影响。方法采用组化与流式的方法检测T2DM大鼠肾小管上皮细胞转分化过程中的标志蛋白：α-SMA、Vim、TGF-β1在肾小管上皮细胞中的表达。结果RSG组较同期糖尿病组大鼠血脂、胰岛素、肾功能好转；α-SMA、Vim、TGF-β1表达减少。结论RSG不仅可减轻代谢紊乱；还可通过减少肾小管上皮细胞的表型转化，延缓肾间质纤维化。     

罗格列酮对血管紧张素Ⅱ诱导高血压大鼠的血压影响及其机制

目的：探讨罗格列酮（RSG）对血管紧张素Ⅱ（AngⅡ）诱导高血压大鼠血压的影响及机制。方法：选择24只SD大鼠随机分为4组：正常对照组、RSG组、AngⅡ组及AngⅡ＋RSG组。每组6只大鼠（n=6）。采用alzet渗透泵持续皮下泵入AngⅡ[300ng／（kg·min）×7d]建立高血压大鼠模型,RSG组和AngⅡ＋RSG组给予RSG灌胃[5mg／（kg·d）]7d,7d后观察各组大鼠的血压、心脏质量指数、空腹血糖变化,测定大鼠主动脉NADPH氧化酶的活性及超氧阴离子的含量。结果：与AngⅡ组对比,AngⅡ＋RSG组血压下降[（136±6）mmHgw．（166±6）mmHg,P〈0．01]及心脏质量指数下降[（3．54±0．04）mg,／kg绑．（3．85±0．08）mg／kg,P〈0．01];NADPH氧化酶活性及血管超氧阴离子含量下降[（288．49±36．19）cpm／μg vs．（584．04±69．67）cpm／μg,P〈0．01;（2792．82．7±726．76）cpm／mg vs．（4765．50±597．34）cpm/mg,P〈0．01]。结论：RSG抑制NADPH氧化酶的活性,降低血管超氧阴离子的含量,拮抗血管AngⅡ诱导的血压升高及心肌肥厚,发挥保护心血管的作用。     

胰岛素抵抗大鼠血糖正常阶段肾皮质血管内皮功能的改变

目的通过检测肾皮质内皮素1（ET-1）、内皮型一氧化氮合酶（eNOS）的表达，研究胰岛素抵抗（IR）大鼠血糖正常阶段肾皮质血管内皮功能的改变。方法以免疫组织化学、RT-PCR方法检测IR大鼠模型肾皮质ET-1、eNOS蛋白和mRNA表达的改变。结果与正常大鼠相比，IR大鼠SBP、TG、FFA、Ins水平升高（P均〈0．01），胰岛素敏感指数、HDL-C降低（P均〈0．01）。FBG、2hBG在正常范围。HE染色IR组大鼠肾皮质出现组织学的异常改变，肾皮质ET-1蛋白及mRNA表达升高，eNOS蛋白和mRNA表达减低。结论IR大鼠模型在血糖正常阶段已存在肾皮质ET-1与eNOS平衡的异常，表明在IR早期已存在肾血管内皮功能的损害。     

糖尿病大鼠血清载脂蛋白A5的表达及罗格列酮干预后的变化

目的观察糖尿病大鼠血清载脂蛋白A5（apoA5）的表达及其在罗格列酮（RSG）干预后的变化,以探讨其在糖脂代谢中的作用及可能的作用机制。方法采用40只雄性SD大鼠进行动物实验,建立对照组、高脂组、糖尿病组和RSG干预组（应用RSG对糖尿病大鼠干预治疗8周）4组动物模型。14周末检测各组大鼠血脂、糖代谢指标等;用ELISA法检测各组大鼠血apoA5水平,并与脂、糖代谢指标进行相关分析。结果与对照组比较,高脂组、糖尿病组和RSG干预组大鼠血清apoA5明显降低,以糖尿病组降低为甚;而RSG干预组大鼠较糖尿病组血清apoA5水平有明显升高（P均〈0.05）。apoA5浓度与TG（r=-0.781,P=0.000）、TC（r=-0.643,P=0.000）、空腹血糖（r=-0.758,P=0.000）、空腹胰岛素（r=-0.578,P=0.001）、胰岛素抵抗指数（r=-0.798,P=0.000）均呈显著负相关,与HDL-C（r=0.469,P=0.010）呈显著正相关。结论 apoA5参与糖、脂代谢,其机制可能与调控过氧化物酶增殖体激活型受体有关。     

Effect of chronic rosiglitazone, metformin and glyburide treatment on beta-cell mass, function and insulin sensitivity in mZDF rats

Here we investigate the effect of rosiglitazone (RSG), metformin (MET) and glyburide (GLIB) on plasma glucose levels, β-cell mass, function and insulin sensitivity in 10-week-old diabetic male Zucker diabetic fatty (mZDF) rats using quantitative morphometry and a mathematical model β-cell mass, insulin and glucose kinetics (βIG). At treatment start, 10-week-old diabetic mZDF rats were severely hyperglycaemic and had very low β-cell function (insulin secretory capacity). RSG treatment significantly lowered plasma glucose levels in 67% of the mZDF rats. MET was effective at lowering plasma glucose levels in 33% of the mZDF rats, while GLIB was completely ineffective at lowering blood glucose levels in 10-week-old mZDF rats. RSG treatment prevented the fall in β-cell mass after 6–8 weeks of treatment accompanied by a significant decrease in β-cell death while MET treatment had no effect on β-cell mass. RSG treatment increased insulin sensitivity 10-fold, increased β-cell function fivefold and modestly increased β-cell mass 1.4-fold. MET treatment increased insulin sensitivity fourfold, with no significant effect on β-cell function or mass. Although RSG treatment was highly successful in lowering plasma glucose levels, the 33% of mZDF rats that did not respond to the treatment had significantly lower β-cell function prior to treatment start compared with the responder group. Thus, the low level of β-cell function at treatment start may explain why none of these agents were completely effective at lowering blood glucose levels in 10-week-old diabetic mZDF rats. Nevertheless, these data suggest that the preservation of β-cell mass and improvement in β-cell function play a role in the overall beneficial effect of RSG in 10-week-old diabetic mZDF rats.     

病灶区灌注罗格列酮对脑出血家兔血肿周围咬合蛋白和闭合小环蛋白1 mRNA表达水平及血-脑屏障通透性的影响

目的观察病灶区灌注罗格列酮(RSG)对家兔脑出血(ICH)模型血肿周围咬合蛋白和闭合小环蛋白1(ZO-1)mRNA表达水平、血-脑屏障(BBB)通透性及神经功能评分的影响。方法选择健康雄性家兔45只,体质量2.0~2.5 kg,按随机数字表法分为对照组、ICH模型组和罗格列酮(RSG)治疗组,每组15只(其中5只用于BBB测定)。对照组模拟制作颅内血肿的过程,穿刺成功后对兔靶点注射等渗盐水0.3 ml,6 h后再次注入等渗盐水0.1 ml;ICH模型组穿刺成功后靶点注射自体非抗凝动脉血0.3 ml,6 h后靶点再次注入等渗盐水0.1 ml;RSG治疗组在ICH模型制作成功后6 h,血肿区灌注RSG 0.5 mg(溶于0.1 ml等渗盐水中)。继续饲养至第7天,对各组家兔进行神经功能缺损评分(Purdy评分)后处死,逆转录聚合酶链反应(RT-PCR)法检测血肿周围脑组织咬合蛋白及ZO-1 mRNA的表达水平;采用甲酰胺方法测量血肿周围脑组织伊文思蓝(EB)含量以评估BBB通透性。结果 (1)神经功能评分:对照组、ICH模型组、RSG治疗组Purdy评分分别为(2.53±0.05)、(8.13±0.06)、(6.67±0.08)分,组间差异有统计学意义(F=459.116,P0.01);与对照组比较,ICH模型组、RSG治疗组的Purdy评分均明显增加(均P0.01);与ICH模型组比较,RSG治疗组的Purdy评分降低(P0.05);(2)咬合蛋白及ZO-1 mRNA表达水平:对照组、ICH模型组、RSG治疗组咬合蛋白及ZO-1 mRNA差异均有统计学意义(每组分别为1.013±0.051、1.001±0.045;0.221±0.017、0.247±0.019;0.498±0.041、0.613±0.045;F值分别为443.924、381.929,均P0.01),与对照组比较,ICH模型组、RSG治疗组咬合蛋白及ZO-1 mRNA表达均显著减少(均P0.01);与ICH模型组比较,RSG治疗组咬合蛋白及ZO-1 mRNA的表达增加(均P0.05);(3)BBB通透性:对照组、ICH模型组、RSG治疗组EB含量分别为(12.0±1.0)、(51.6±0.9)、(36.4±1.0)μg/g,组间差异有统计学意义(F=223.516,P0.01);与对照组比较,ICH模型组、RSG治疗组的EB含量明显增加(均P0.01);与ICH模型组比较,RSG治疗组EB含量明显降低(P0.01)。结论病灶区灌注RSG可明显改善家兔ICH后的神经功能,增加血肿周围脑组织咬合蛋白和ZO-1mRNA的表达水平,降低BBB通透性。     

Angiographic and clinical outcomes of rosiglitazone in patients with type 2 diabetes mellitus after percutaneous coronary interventions: a single center experience

A beneficial effect of thiazolidinediones includes the reduction of intermediate markers, suggesting a potential for reducing atherosclerosis and restenosis. The objective of this study was to determine if rosiglitazone (RSG) reduced the odds of restenosis and if RSG improved the odds of clinical outcomes after percutaneous coronary intervention (PCI) in type 2 diabetes mellitus (DM) patients. A total of 609 patients with 734 lesions were selected from the period between January 1, 2001 and January 31, 2004. These patients were divided into 2 groups: a "control" group representing patients seen between January 1, 2001 and September 2002 when RSG was not available in our hospital and a "RSG treatment" group representing patients seen between September 2002 and January 31, 2004 when RSG was available in our hospital. Thus, 213 patients with 253 lesions (1.19 L/P) were placed in the RSG group and 396 patients with 481 lesions (1.21 L/P) were placed in the control group. Subgroup analysis based on the PCI received had 88 patients in the RSG arm receiving balloon angioplasty and 125 patients receiving coronary stenting; the control group had 187 and 209 patients, respectively, in the subgroups. Primary endpoint was angiographic restenosis at 6 months, and secondary endpoints were death, myocardial infarction, and target lesion revascularization. More patients in the control group were insulin-requiring, had poorer left ventricular function, but had a larger preprocedural minimal lumen diameter (pre-MLD). At 6 months, restenosis and reocclusion rates were lower in the RSG group (P = .014 and P = .006, respectively). Twenty-nine patients died in the control group versus 1 in the RSG group (P 相似文献   

脂联素降低右侧星状神经节活性抑制心肌梗死后室性心律失常

目的探究脂联素对右侧星状神经节(RSG)功能与神经活性,对右心室电生理状态的影响;探究脂联素对于心肌梗死(心梗)后室性心律失常的防治作用。方法16只成年雄性比格犬随机数字表法分为对照组(n=8)与脂联素组(n=8),分别向RSG中注射生理盐水0.2 ml与0.1 mg/ml脂联素0.2 ml。结扎冠状动脉左前降支进行心梗造模。检测基础状态与心梗后RSG功能与神经活性,右心室有效不应期,记录心梗后30 min心电图分析室性心律失常情况并测量心室颤动(室颤)阈值。实验结束后取RSG进行免疫荧光染色。结果与对照组相比,脂联素抑制心梗后RSG激活(P<0.05),抑制心脏交感神经活性增强(P<0.05)。脂联素改善心梗后右心室各部位有效不应期缩短(P<0.05),减少室性心律失常发生[室性早搏(117.5±7.4)次对(87.0±6.5)次;室性心动过速(室速)(12.0±1.7)阵对(2.3±0.9)阵;室速持续时间(11.1±1.9)s对(3.4±0.9)s,均P<0.05],升高室颤阈值[(5.5±1.3)V对(10.0±1.4)V,P<0.05]。脂联素降低交感神经中即刻早期基因含量[(80.0±5.0)%对(8.8±4.8)%,P<0.05],改善心梗后RSG神经重构。结论脂联素降低心梗后RSG神经活性,抑制室性心律失常发生。     

Potential benefits of early addition of rosiglitazone in combination with glimepiride in the treatment of type 2 diabetes

Aim: To assess the efficacy and tolerability of early combination therapy with rosiglitazone (RSG) and glimepiride (GLIM) vs. GLIM monotherapy in patients with type 2 diabetes mellitus (T2DM). Methods: Strategies for the addition of RSG in combination with GLIM were evaluated with data from two randomized, double‐blind, placebo (PBO)‐controlled studies. Study A – addition of RSG (4 or 8 mg) or PBO to continued GLIM 3 mg once daily; study B – addition of low‐dose RSG (4 mg) prior to uptitration of GLIM (from 2 to 4 mg) vs. continued uptitration of GLIM (from 2 to 8 mg). Results: Study A reported significant reductions in fasting plasma glucose (FPG) from baseline to week 26 with the addition of both 4 and 8 mg RSG to GLIM 3 mg [?21 mg/dl (?1.2 mmol/l), p = 0.0019 and ?43 mg/dl (?2.4 mmol/l), p < 0.0001, respectively] and in haemoglobin A_1c (HbA_1c) (?0.63%, p = 0.00015 and ?1.17%, p < 0.0001, respectively) from a baseline of 8.2 and 8.1%, respectively. At the end of the study, target HbA_1c <7.0% was achieved in 43 and 68% of patients in the RSG 4 mg + GLIM and RSG 8 mg + GLIM groups, respectively, compared with 32% in the PBO + GLIM (GLIM alone) group. In study B, addition of RSG to GLIM reduced mean FPG and HbA_1c levels at week 24 from baseline [?28 mg/dl (?1.5 mmol/l), p < 0.0001, and ?0.68%, p < 0.0001, respectively]. There were no significant changes with GLIM monotherapy in either study. Favourable effects of RSG + GLIM on insulin sensitivity, β‐cell function and cardiovascular disease biomarkers were also observed. All treatments were similarly well tolerated. Conclusions: Early addition of RSG to GLIM is an effective and well‐tolerated treatment option to improve glycaemic control in sulphonylurea‐treated patients with T2DM.     

罗格列酮对哮喘大鼠引哮喘发作潜伏期的影响

目的 观察过氧化物酶体增殖物活化受体γ(PPARγ)配体罗格列酮(RSG)对支气管哮喘(哮喘)大鼠气道哮喘发作潜伏期的影响.方法 SD大鼠75只,分为正常对照组(A组)、哮喘组(B组)、RSG治疗组(C组),每组25只.制备各组大鼠体外去上皮气管环,比较在0.05 mmol·L-1、0.5 mmol·L-1、5.0 mmol·L-1浓度梯度乙酰胆碱(ACh)激发下,各组大鼠体外气管环收缩张力大小.观察三种浓度0.01 mmol·L-1、0.1 mmol·L-1、1.0 mmol·L-1RSG对A、B两组大鼠体外气管环的ACh量效曲线的影响,比较各组大鼠引喘潜伏期差异.结果 三组大鼠引喘潜伏期分别为A组(121.50±17.44)s,B组(61.50±17.68)s,C组(94.40±21.17)s,差异有统计学意义(P＜0.05,n=20).三组大鼠气管环对三种浓度ACh的反应率,B＞C＞A组,差异有统计学意义(P＜0.05,n=20).RSG可引起A、B两组大鼠体外气管环ACh量效曲线右移.结论 RSG可延长哮喘发作潜伏期,降低气道收缩张力,可能具有减轻气道高反应性、减少哮喘发作的作用.     

罗格列酮对大鼠胸主动脉球囊损伤后内皮再生和内膜增生的影响

目的探讨罗格列酮(rosiglitazone,RSG)对血管损伤后内皮再生和内膜增生的影响。方法制备大鼠胸主动脉球囊损伤模型,将SD大鼠随机分为RSG组、对照组和假手术组,于术后第7天和第14天处死动物。分别进行伊文思蓝染色观察内皮覆盖情况,细胞核增殖抗原(PCNA)免疫组化染色和组织形态学定量分析,并测量损伤后14 d时各组血清一氧化氮(NO)含量。结果RSG 7 d组和14 d组的再生内皮覆盖率分别为38.2%和75.2%,均较对照组(32.4%和60.4%)显著增加(P<0.05和P<0.01),且RSG 14 d组血清中的NO含量较对照组升高。球囊损伤后7 d内膜开始有少量增生,14 d时形成明显的新生内膜。RSG使损伤后14 d形成的新生内膜显著减少,内膜面积与中膜面积的比值(IA/MA)较对照组降低60.9%。与对照组比较,RSG 7 d组和14 d组新生内膜内的PCNA阳性表达指数均显著减少。结论RSG可以促进大鼠胸主动脉球囊损伤处的内皮再生,并减少新生内膜的形成。     

Initial treatment with fixed-dose combination rosiglitazone/glimepiride in patients with previously untreated type 2 diabetes

Aim: This study assessed the efficacy and safety of two different dosing regimens of fixed‐dose combination (FDC) rosiglitazone (RSG) plus glimepiride (GLIM) compared with RSG or GLIM monotherapy in drug‐naive subjects with type 2 diabetes mellitus (T2DM). Methods: Drug‐naive subjects (n = 901) were enrolled into this 28‐week, double‐blind, parallel‐group study if their glycosylated haemoglobin A_1c (HbA_1c) was >7.5% but ≤12%. Subjects were randomized to receive either GLIM [4 mg once daily (OD) maximal], RSG (8 mg OD maximal) or RSG/GLIM FDC regimen A (4 mg/4 mg OD maximal) or RSG/GLIM FDC regimen B (8 mg/4 mg OD maximal). Patients were assessed for efficacy and safety every 4 weeks for the first 12 weeks of the study, and at weeks 20 and 28. The primary efficacy endpoint was change in HbA_1c from baseline. Key secondary endpoints included the proportion of patients achieving recommended HbA_1c and fasting plasma glucose (FPG) targets; change from baseline in FPG, insulin, C‐reactive protein (CRP), adiponectin, free fatty acids and lipids; and percentage change in homeostasis model assessment‐estimated insulin sensitivity and β‐cell function. Safety evaluations included adverse‐event (AE) monitoring and clinical laboratory evaluations. Results: At week 28, both RSG/GLIM FDC regimens significantly reduced HbA_1c (mean ± s.d.: ?2.4 ± 1.4% FDC regimen A; ?2.5 ± 1.4% FDC regimen B) to a greater extent than RSG (?1.8 ± 1.5%) or GLIM (?1.7 ± 1.4%) monotherapy (model‐adjusted mean treatment difference, p < 0.0001 vs. both RSG and GLIM). Significantly more subjects achieved HbA_1c target levels of ≤6.5 and <7% with either RSG/GLIM FDC regimen compared with RSG or GLIM alone (model‐adjusted odds ratio, p < 0.0001 for both comparisons). Similarly, a significantly greater reduction in FPG levels was observed in subjects treated with the RSG/GLIM FDC [mean ± s.d. (mg/dl): ?69.5 ± 57.5 FDC regimen A; ?79.9 ± 56.8 FDC regimen B) compared with RSG (?56.6 ± 58.1) or GLIM (?42.2 ± 66.1) monotherapy (model‐adjusted mean treatment difference, p < 0.0001 for both comparisons). Improvement in CRP was also observed in subjects who were treated with a RSG/GLIM FDC or RSG monotherapy compared with GLIM monotherapy. RSG/GLIM FDC was generally well tolerated, with no new safety or tolerability issues identified from its monotherapy components, and a similar AE profile was observed across FDC regimens. The most commonly reported AE was hypoglycaemia, and the incidence of confirmed symptomatic hypoglycaemia (3.6–5.5%) was comparable among subjects treated with an RSG/GLIM FDC and GLIM monotherapy. Conclusions: Compared with RSG or GLIM monotherapy, the RSG/GLIM FDC improved glycaemic control with no significant increased risk of hypoglycaemia. RSG/GLIM FDC provides an effective and well‐tolerated treatment option for drug‐naive individuals with T2DM.     

Differential effects of rosiglitazone and insulin glargine on inflammatory markers, glycemic control, and lipids in type 2 diabetes

Type 2 diabetes remains a difficult clinical challenge characterized by progressive insulin deficiency and frequent cardiovascular events requiring multiple therapeutic decisions. In this randomized clinical trial, we assessed the comparative effects of rosiglitazone (RSG) and insulin glargine (IG) on inflammatory biomarkers, glycemic control, and lipids. Forty subjects with type 2 diabetes and inadequate glycemic control on sulfonylurea and metformin therapy received 24 weeks of add-on therapy with either RSG 4mg daily or IG 10 units daily. Subjects on RSG with fasting glucose values >120mg/dl at 12 weeks were increased from 4 to 8mg. Subjects on IG increased insulin doses until fasting glucose was <120mg/dl. Markers of glycemic control and inflammation including HbA1c, hsCRP, PAI-1, plasma F2-isoprostanes, and lipids were measured at baseline, 12, 18, and 24 weeks. RSG and IG demonstrated similar efficacy in reducing HbA1c levels by 1.5 and 1.4%, respectively, with greater weight gain with RSG. Hypoglycemic events occurred with equal frequency. IG did not reduce hsCRP, but RSG reduced hsCRP levels 45% from baseline. Both IG and RSG reduced F2-isoprostanes similarly. IG did not affect PAI-1 levels, but did reduce total, LDL, and non-HDL cholesterol levels. Despite similar HbA1c reductions with RSG and IG, differential effects were found on inflammatory biomarkers and lipids that deserve consideration in the clinical decision process of selecting a therapeutic agent.     

Augmentation of nitric oxide is crucial for the time-dependent effects of rosiglitazone on blood pressure and baroreflex function in rats

OBJECTIVES: To determine the time-dependent effects of rosiglitazone (RSG) on blood pressure (MAP) and baroreflex sensitivity (BRS) and the involvement of nitric oxide (NO) in these effects. METHODS: Male Sprague-Dawley rats were treated with RSG (8 mg/kg per day, orally) or saline for 4, 8 and 12 weeks. BRS was determined by linear regression method with bolus injections of phenylephrine (PE-BRS) or sodium nitroprusside (NP-BRS). Insulin sensitivity (M value) was determined by euglycemic hyperinsulinemic clamp study. Vascular and cardiac responsiveness to isoproterenol, acetylcholine and NP were determined after ganglionic blockade. Effects of endogenous NO were examined by Nomega-nitro-L-arginine-methyl ester (L-NAME) administration. RESULTS: RSG treatment time-dependently decreased circulating lipids, insulin, glucose levels and insulin resistance (HOMA-IR) but increased plasma NOx levels. M values were progressively decreased in control rats, but remained unchanged in RSG-treated rats. Chronic RSG treatment progressively lowered MAP but reciprocally increased heart rate (HR). In addition, chronic RSG treatment significantly attenuated HR changes to methylatropine but enhanced HR changes to propranolol. Twelve-week RSG treatment enhanced PE-BRS which was suppressed by methylatropine but not propranolol, and attenuated NP-BRS which was sustained after methylatropine or propranolol. Moreover, 12-week RSG treatment also diminished cardiac responsiveness to isoproterenol and augmented vascular responsiveness to acetylcholine, but not to NP. L-NAME eliminated the differences in MAP and HR between groups, and reversed both RSG-induced enhanced PE-BRS and attenuated NP-BRS. Plasma NOx levels were highly correlated with RSG-mediated changes in the baseline MAP, HR and BRS. CONCLUSION: These data suggest that RSG-induced NO production is important for the time-dependent effects of RSG on MAP and BRS in rats.