吡格列酮提高肥胖小鼠脂肪组织内脂素的基因表达

目的 观察吡格列酮对营养性肥胖小鼠内脏脂肪和皮下脂肪组织内脂素基因表达的影响.方法 高脂饮食喂养刚断乳雄性c57BL/6小鼠8周,诱导出营养性肥胖模型.8周后,筛选肥胖小鼠,随机分为营养性肥胖组和吡格列酮治疗组[100 mg/(kg·d);治疗两周],普通饲料作为正常对照(正常体质量对照组),实时荧光定量RT-PCR方法检测内脂素的基因表达.结果 吡格列酮治疗组内脏脂肪量、腹部皮下脂肪量虽较正常体质量对照组增加(P<0 01),但较肥胖组降低(P<0 05).以正常体质量组内脂素基因表达为1,吡格列酮治疗组内脏脂肪组织内脂素基因表达比正常体质量对照组和肥胖组明显升高(吡格列酮:7 6 比肥胖组:4.8 比正常体质量组:1,P<0 01),腹部皮下脂肪组织内脂素基因表达也比正常体质量对照组和肥胖组明显升高(吡格列酮:5 4比肥胖组:1.3比正常体质量组:1, P<0 01).结论 吡格列酮能够促进内脏脂肪与皮下脂肪的再分布,上调内脏脂肪组织和皮下脂肪组织内脂素的基因表达.     

吡格列酮提高肥胖小鼠脂肪组织内脂素的基因表达

目的观察吡格列酮对营养性肥胖小鼠内脏脂肪和皮下脂肪组织内脂素基因表达的影响。方法高脂饮食喂养刚断乳雄性 c57BL/6小鼠8周,诱导出营养性肥胖模型。8周后,筛选肥胖小鼠,随机分为营养性肥胖组和吡格列酮治疗组[100 mg/(kg·d);治疗两周],普通饲料作为正常对照(正常体质量对照组),实时荧光定量RT-PCR 方法检测内脂素的基因表达。结果吡格列酮治疗组内脏脂肪量、腹部皮下脂肪量虽较正常体质量对照组增加(P<0.01),但较肥胖组降低(P<0.05)。以正常体质量组内脂素基因表达为1,吡格列酮治疗组内脏脂肪组织内脂素基因表达比正常体质量对照组和肥胖组明显升高(吡格列酮:7.6比肥胖组:4.8比正常体质量组:1,P<0.01),腹部皮下脂肪组织内脂素基因表达也比正常体质量对照组和肥胖组明显升高(吡格列酮:5.4比肥胖组:1.3比正常体质量组:1,P<0.01)。结论吡格列酮能够促进内脏脂肪与皮下脂肪的再分布,上调内脏脂肪组织和皮下脂肪组织内脂素的基因表达。     

吡格列酮与二甲双胍对初诊肥胖2型糖尿病患者血清内脏脂肪素影响的研究

目的观察吡格列酮与二甲双胍对初诊肥胖T2DM患者血清内脏脂肪素（visfatin）水平的影响,探讨visfatin与T2DM发病的关系和药物的治疗机制。方法100例初诊肥胖T2DM患者随机分为吡格列酮组50例,每日口服盐酸吡格列酮片30mg,二甲双胍组50例,每日早晚口服二甲双胍缓释片500mg,疗程24周。结果吡格列酮组空腹血清visfatin、IR、TG较用药前明显降低,B细胞功能有改善（P〈0．05或P〈0．01）。二甲双胍组血清visfatin、TG无统计学改变。两组治疗后比较,吡格列酮组的visfatin、IR、TG降低明显,差异有统计学意义（P〈0．05或〈0．01）,但二甲双胍组的BMI较吡格列酮组下降更明显（P〈0．05）。结论对初诊肥胖T2DM患者吡格列酮与二甲双胍均能较好地控制血糖,吡格列酮还能明显降低血清visfatin的水平,提示吡格列酮通过下调visfatin水平发挥抗炎作用。     

二甲双胍、吡格列酮对初诊糖代谢异常伴腹型肥胖患者血脂及尿酸的影响

目的 探讨二甲双胍、吡格列酮对初诊糖代谢异常伴腹型肥胖患者血脂及尿酸的影响.方法 选择初诊糖代谢异常伴腹型肥胖患者36例,随机分为二甲双胍组20例(1 500 mg/d)、吡格列酮组16例(30 mg/d).治疗3个月后,观察两组治疗前后血糖、胰岛素、糖化血红蛋白、血脂和血尿酸等指标变化.结果 二甲双胍组治疗后LDL-C较治疗前明显下降(P＜0.05);吡格列酮组治疗后TG、血尿酸水平较治疗前明显下降(P均＜0.05).结论 在治疗剂量下,二甲双胍主要降低LDL-C水平,吡格列酮主要降低TG、血尿酸水平.     

大黄酸对肥胖糖尿病大鼠脂肪组织抵抗素基因表达及血浆游离脂肪酸水平的影响

目的探讨大黄酸对肥胖糖尿病大鼠脂肪组织抵抗素基因表达及血浆FFA的影响。进而验证大黄酸具有改善胰岛素抵抗的作用。方法小剂量链脲佐菌素加高脂饲料诱导建立肥胖糖尿病大鼠模型,成模大鼠随机分为模型组、吡格列酮组和大黄酸组。正常组与模型组分别予生理盐水10ml·kg^-1·d^-1,吡格列酮组予吡格列酮10mg·kg^-1·d^-1,大黄酸组予大黄酸100mg·kg^-1·d^-1,分别灌胃8周。测定各组附睾脂肪垫抵抗素基因的表达、血浆FFA及血脂水平。结果与模型组相比,大黄酸组与吡格列酮组脂肪组织抵抗素的表达均下降,FFA、TC、TG、LDL-C均明显降低（P均〈0．05）。结论大黄酸能降低肥胖糖尿病大鼠脂肪组织抵抗素表达,降低血浆FFA。这可能是大黄酸改善胰岛素抵抗的机制之一。     

吡格列酮和瑞舒伐他汀对血脂紊乱兔模型脂代谢及炎症因子的影响

目的 比较吡格列酮和瑞舒伐他汀对兔血脂紊乱的作用.方法 40只白兔随机分为空白对照组、血脂紊乱组、瑞舒伐他汀组、吡格列酮组,除空白对照组外,其余3组高脂饮食.8 w后,瑞舒伐他汀组、吡格列酮组开始用药,用药量分别为瑞舒伐他汀1.5 mg·kg~(-1)·d~(-1),吡格列酮5 mg·kg~(-1)·d~(-1),用药6 w.取血,检测血脂、血糖、TNF-α等指标.结果 吡格列酮组和瑞舒伐他汀组总胆固醇低于血脂紊乱组(P＜0.05).吡格列酮组TG最低,但与各组比较无统计学差异(P＞0.05).ApoA在瑞舒伐他汀组和吡格列酮组均增高,吡格列酮组高于血脂紊乱组(P＜0.05).瑞舒伐他汀组LDL-C较血脂紊乱组降低40%,与血脂紊乱组和吡格列酮组比较均降低(P＜0.05).二者TNF-α低于血脂紊乱组(P＜0.05).吡格列酮组进食量、血糖较血脂紊乱组减低(P＜0.05),瑞舒伐他汀可降低血糖,与吡格列酮组血糖水平接近(P＞0.05).结论 二者均有降血糖、改善血脂、抗炎症的作用,但在降低甘油三酯的作用上吡格列酮较瑞舒伐他汀强,而瑞舒伐他汀降低低密度脂蛋白最强.     

吡格列酮通过p-CREB蛋白对大鼠缺血再灌注损伤心肌保护机制的研究

目的通过检测大鼠心肌缺血再灌注p-CREB蛋白表达的变化,探讨吡格列酮对大鼠缺血再灌注损伤心肌保护机制。方法将55只SD大鼠随机分为假手术组、缺血再灌注组、吡格列酮组、吡格列酮+GW9662组,左前降支结扎的方法建立缺血再灌注损伤模型,伊文思蓝染色测定心肌梗死面积,Western blot法测定心肌组织p-CREB蛋白表达。结果吡格列酮组梗死面积与缺血再灌注组比较明显减少(P0.05),与吡格列酮组比较,吡格列酮+GW9662组梗死面积差异有统计学意义(P0.05)。与假手术组和缺血再灌注组相比,吡格列酮组p-CREB蛋白表达明显增加(P0.05),吡格列酮+GW9662组p-CREB蛋白表达无明显变化(P0.05);与吡格列酮组相比,吡格列酮+GW9662组p-CREB蛋白表达减少,差异有统计学意义(P0.05)。结论吡格列酮可能上调p-CREB蛋白表达进而抑制缺血再灌注诱导的心肌细胞损伤,GW9662可逆转吡格列酮对心肌细胞的保护作用。     

吡格列酮和罗格列酮对兔血脂异常的作用

目的 比较吡格列酮和罗格列酮对兔血脂异常的作用.方法 40只白兔随机分为4组:空白对照组、血脂异常组、罗格列酮组、吡格列酮组.除空白对照组外,其余3组高脂饮食.8 w后,罗格列酮组、吡格列酮组开始用药,用药最分别为罗格列酮1.5 mg/(kg·d),吡格列酮5mg/(kg·d),用药6 w.取血,检测血脂、血糖、瘦素、TNF-α等指标.结果 血清总胆固醇吡格列酮组[(6.68±1.89)mmol/L)]低于罗格列酮组[(8.40±0.18)mmol/L](P＜0.05),吡格列酮组甘油三酯较罗格列酮组降低39.4%,高密度脂蛋白罗格列酮组[(4.73±2.27)mmol/L]高于吡格列酮组[(2.30±1.52)mmol/L](P＜0.05).二者TNF-α低于血脂异常组(P＜0.05)、瘦素高于血脂异常组(p＜0.05).吡格列酮组进食量、血糖较血脂异常组减低(P＜0.05).载脂蛋白A较血脂异常组增高(p＜0.05);罗格列酮亦有上述作用,但与血脂异常组比较无统计学差异.结论 二者均有降血糖、改善血脂、抗炎症、促进瘦素分泌的作用,但在降低胆固醇和甘油三酯的作用上吡格列酮较罗格列酮强,而罗格列酮升高高密度脂蛋白的作用最强.     

吡格列酮干预对糖尿病肾病患者尿单核细胞趋化蛋白-1的影响

目的 探讨吡格列酮对糖尿病肾病(DN)患者尿单核细胞趋化蛋白-1(MCP-1)的影响.方法 80例患者随机分为吡格列酮组和对照组(完成71例).吡格列酮组加服吡格列酮15 mg/d连续6个月.服药前、服药后3个月、6个月分别留取空腹血测定血糖、糖化血红蛋白(HbA1c);留取晨尿液测定MCP-1、微量白蛋白/肌酐(Alb/Cr).结果 吡格列酮组血糖、HbA1c较治疗前有所下降,但无统计学意义(P＞0.05),尿MCP -1、Alb/Cr显著降低(均P＜ 0.05).结论 吡格列酮除具备降糖作用外对肾脏还有保护作用.     

吡格列酮预防非肥胖糖尿病鼠胰岛β细胞凋亡的机制研究

目的 探讨吡格列酮预防非肥胖糖尿病小鼠胰岛β细胞凋亡的机制.方法 (1)将4周龄NOD雌鼠分为吡格列酮(21只)及对照(21只)组,分别摄食含0.02％吡格列酮的混合饲料和普通营养饲料.观察52周龄的累积糖尿病发病率.(2)各组取12周龄未发病NOD鼠(n=15)胰腺,HE染色观察胰岛炎;TUNEL+SABC法检测胰岛β细胞凋亡.(3)ELISA法测定血清、脾细胞培养上清IFN-γ和IL-4水平及培养脾细胞核因子PPARγ、NF-κB活性.结果 (1)30、52周龄时,吡格列酮及对照组发病率分别为57.1％和76.2％ 、76.2％和90.5％(均P＞0.05);15周龄时,吡格列酮及对照组发病率分别为4.8％和33.3％(P=0.045).(2) 12周龄时,吡格列酮组正常胰岛和胰岛周围炎比例(14.73％,26.02％)高于对照组(5.69％,15.72％;均P＜0.01),胰岛内炎比例(59.25％)则低于对照组(78.59％,P＜0.01);吡格列酮组胰岛β细胞凋亡率(6.17％±3.62％)低于对照组( 10.62％±4.43％,P=0.008).(3)12周龄NOD鼠吡格列酮组血清IFN-γ水平[(561.05 ±78.61) pg/ml]显著低于对照组[(666.43±28.42) pg/ml,P=0.045];在培养的脾细胞上清中,吡格列酮组IFN-γ水平[(605.84±65.60) pg/ml]显著低于对照组[(692.20±44.98)pg/ml,P=0.041].(4)在培养的脾细胞中,吡格列酮组PPARγ活性(0.06±0.01)高于对照组(0.03±0.01,P=0.013),NF-κB活性(0.03±0.01)较对照显著降低(0.08±0.01,P=0.001).结论 吡格列酮活化PPARγ,抑制NF-κB活性,血清和脾细胞上清IFN-γ下降,Th细胞向Th1方向分化减少,NOD鼠胰岛炎减轻、胰岛β细胞凋亡减少.     

吡格列酮对体外培养大鼠破骨细胞样细胞分化及活性的影响

目的 观察吡格列酮对大鼠破骨细胞样细胞(OLC)分化及活性的影响,探讨PPARγ2活化与破骨细胞之间的关系.方法 用NF-кB受体活化因子配体(RANKL)及巨噬细胞集落刺激因子(M-CSF)协同诱导大鼠骨髓单个核细胞(BMC)向OLC分化,同时加入1、5、10μmol/L盐酸吡格列酮干预.应用RT-PCR分析OLC分化过程中PPARγ2及NF-кB受体活化因子(RANK)mRNA的表达,结合细胞染色及抗酒石酸酸性磷酸酶(TRAP)活性观察吡格列酮对OLC分化的影响,通过骨吸收陷窝分析及整合素β3(CD61)平均荧光强度的检测比较吡格列酮对OLC活性的影响.结果 (1)对OLC分化的影响:培养7 d时10μmol/L吡格列酮组与其它组相比OLC数量及TRAP活性明显减少(P<0.01或P<0.05),表明吡格列酮部分抑制OLC分化且此作用与剂量相关;RT-PCR结果显示在诱导分化早期,不同浓度吡格列酮呈剂量依赖性上调PPARγ2的表达水平,但随OLC的成熟其表达渐减弱,而RANK表达在5及10 p,mol/L吡格列酮干预组培养的各时间点均明显下调,与对照及1μmol/L干预组相比有显著差异(P<0.05或P<0.01);(2)对OLC活性的影响:骨吸收陷窝数量及吸收面积在吡格列酮5、10μmol/L组明显减少,与另两组相比差异显著(P<0.05或P<0.01),培养早期这两组细胞CD61平均荧光强度均明显下调(P<0.05或P<0.01).结论 吡格列酮激活PPAR田γ2转录活性可部分抑制大鼠骨髓OLC的分化及活性.     

TNF-α和吡格列酮对3T3-L1脂肪细胞adiponutrin mRNA表达的影响

目的探讨肿瘤坏死因子α（TNF-α）和吡格列酮（PIO）对3T3-L1脂肪细胞中，脂肪滋养蛋白（adiponutrinADPN） mRNA表达的影响及时间效应。方法用100Fmol／L的PIO和100ng／ml的TNE-α处理不同阶段的3T3-L1脂肪细胞，RT-PCR检测ADPN的表达水平。结果在分化过程中和分化成熟的3T3-L1细胞中，TNF-α均增加ADPN的表达，PIO则可明显抑制其mRNA的表达。结论PIO和TNF-α可影响3T3-L1脂肪细胞的ADPN的表达。     

Effect of pioglitazone on biochemical indices of non-alcoholic fatty liver disease in upper body obesity.

BACKGROUND & AIMS: The aim of our study is to report our observations on the change in liver function tests of volunteers receiving pioglitazone as part of a study of its effects on fatty acid metabolism. Treatment with other thiazolidinediones has been reported to ameliorate non-alcoholic fatty liver disease (NAFLD) in obese and diabetic humans, but whether pioglitazone has similar effects has not been reported. METHODS: Five of 20 upper body obese volunteers (10 men, 10 premenopausal women) had abnormal baseline liver enzymes (3 had ultrasonographic evidence of hepatic steatosis). All volunteers were treated with 30 mg pioglitazone per day for 18 +/- 0.4 weeks. Body composition, blood lipids, and insulin sensitivity (intravenous glucose tolerance test) were assessed at baseline and after pioglitazone treatment. RESULTS: During pioglitazone treatment, the liver enzyme abnormalities uniformly improved in subjects with evidence of NAFLD, primarily during the first 2 months. Some parameters of insulin sensitivity improved when measured after 18 weeks of pioglitazone treatment. Liver function tests remained normal in the 15 volunteers without evidence of NAFLD. CONCLUSIONS: Liver function studies improved in obese volunteers with NAFLD during pioglitazone treatment. Although the nature of our observations does not prove a cause and effect relationship between pioglitazone treatment and improvement in liver enzymes, the time course and magnitude of improvement we observed may facilitate future research into thiazolidinedione treatment of NAFLD.     

Pioglitazone-induced increase of insulin sensitivity in the muscles of the obese Zucker fa/fa rat cannot be explained by local adipocyte differentiation

Summary Thiazolidinediones are potent antidiabetic compounds, which act by enhancing peripheral insulin sensitivity. They are also activators of the peroxisome proliferator activated receptor γ in adipose tissue. Pioglitazone induces in vivo adipocyte differentiation in the obese Zucker fa/fa rat and hence the capacity of adipose tissue to utilize glucose. Nevertheless, muscles are the major site for insulin-mediated glucose disposal. The increase of muscle glucose utilization under thiazolidinedione treatment could be secondary to local adipose tissue differentiation. This possibility is supported by the fact that a thiazolidinedione-induced myoblast conversion into adipocytes has been described in vitro. To address this problem, we have studied the in vivo effect of a pioglitazone treatment on insulin-induced glucose utilization and the expression of genes exclusively expressed in mature adipocytes in three muscles differing by their fibre composition in Zucker (fa/fa) rats. Whereas pioglitazone treatment increased insulin-stimulated glucose utilization to the same extent in all muscle types, an adipocyte differentiation was only present in the oxidative muscle, the soleus. Soleus muscle was also the only one in which the presence of genes specific for adipose tissue could be detected before the pioglitazone treatment. There was no detectable expression of adipocyte specific genes in the extensor digitorum longus or in the epitrochlearis muscles before or after the drug treatment. We conclude that pioglitazone effects on muscle glucose metabolism cannot be due to a local adipocyte differentiation, and that the conversion of myoblasts into adipocytes under thiazolidinedione stimulation observed in vitro is, if it exists, a marginal phenomenon in vivo. [Diabetologia (1998) 41: 963–968] Received: 22 December 1997 and in final revised form: 9 March 1998     

Influence of glucose control and improvement of insulin resistance on microvascular blood flow and endothelial function in patients with diabetes mellitus type 2

OBJECTIVE: The study was performed to investigate the effect of improving metabolic control with pioglitazone in comparison to glimepiride on microvascular function in patients with diabetes mellitus type 2. METHODS: A total of 179 patients were recruited and randomly assigned to one treatment group. Metabolic control (HbA1c), insulin resistance (HOMA index), and microvascular function (laser Doppler fluxmetry) were observed at baseline and after 3 and 6 months. RESULTS: HbA1c improved in both treatment arms (pioglitazone: 7.52 +/- 0.85% to 6.71 +/- 0.89%, p < .0001; glimepiride: 7.44 +/- 0.89% to 6.83 +/- 0.85%, p < .0001). Insulin-resistance decreased significantly in the pioglitazone group (6.15 +/- 4.05 to 3.85 +/- 1.92, p < .0001) and remained unchanged in the glimepiride group. The microvascular response to heat significantly improved in both treatment groups (pioglitazone 48.5 [15.2; 91.8] to 88.8 [57.6; 124.1] arbitrary units [AU], p < .0001; glimepiride 53.7 [14.1; 91.9] to 87.9 [52.9, 131.0] AU, p < .0001, median [lower and upper quartile]). Endothelial function as measured with the acetylcholine response improved in the pioglitazone group (38.5 [22.2; 68.0] to 60.2 [36.9; 82.8], p = .0427) and remained unchanged in the glimepiride group. CONCLUSIONS: Improving metabolic control has beneficial effects in microvascular function in type 2 diabetic patients. Treatment of type 2 diabetic patients with pioglitazone exerts additional effects on endothelial function beyond metabolic control.     

Pioglitazone restores endothelial function in patients with type 2 diabetes treated with insulin

The primary aim of this study was to evaluate the effect of pioglitazone on endothelial function, as assessed by flow-mediated dilatation (FMD) nitroglycerine-induced dilatation (NID) in patients with type 2 diabetes mellitus treated with insulin. A randomized double-blind placebo-controlled trial involved 20 patients with insulin-treated type 2 diabetes. Patients received either pioglitazone 30 mg or placebo for 4 months. FMD, NID, and HbA1c were measured before and after 4 months of treatment. HbA1c decreased from 10.0 (+/- 2.3) to 8.4 (+/- 2.0) in the pioglitazone group, a statistically significant improvement in glycemic control (p = 0.018). HbA1c was unchanged in the placebo group (p = 0.477). Endothelial function as assessed by FMD significantly improved from 10.1 (+/- 4.0)% to 14.6 (+/- 6.2)% in the pioglitazone group (p = 0.036) as compared to the placebo group (p = 0.705). There was a trend towards improvement in the NID in the pioglitazone group (from 13.3 +/- 8.0% to 18.9 +/- 5.4%; p = 0.056). In insulin-treated patients with type 2 diabetes, the addition of pioglitazone improves endothelial function, as measured by FMD. Addition of pioglitazone to insulin in type 2 diabetes patients may favorably impact vascular function in diabetes, even after many years of insulin resistance and hyperglycemia.     

Coefficient of beta-cell failure in patients with type 2 diabetes treated with pioglitazone or acarbose.

AIM: A new method of assessing the coefficient of failure of pancreatic beta-cells from any index of glycaemia has been proposed. This method of analysis has been used to assess data on HbA1c and fasting glucose concentrations from a randomised study comparing pioglitazone with acarbose. METHODS: Patients were treated for 26 weeks with either pioglitazone 45 mg once daily or acarbose 300 mg/day as 3 equal doses. Plasma HbA1c concentration was measured every two months and fasting glucose was measured monthly. The coefficient of failure was determined for each patient from the slope of the least squares regression line over time. RESULTS: The coefficient of failure from HbA1c was - 2.65 +/- 2.13 %/year with pioglitazone and - 1.25 +/- 3.11 %/year with acarbose, indicating improved beta-cell function in each case. The coefficient of failure was improved to a significantly greater extent with pioglitazone ( P < 0.001). Coefficient of failure from fasting blood glucose also showed a greater improvement with pioglitazone (- 53.1 +/- 95.0 mg/dl/year) than with acarbose (- 29.9 +/- 142.5 mg/dl/year; p = 0.049). CONCLUSION: The coefficient of failure showed a significantly greater improvement of beta-cell function with pioglitazone than with acarbose during 26 weeks of treatment.     

Comparison of pioglitazone and metformin efficacy using homeostasis model assessment.

AIMS: To compare clinical efficacy of two different insulin sensitizers, pioglitazone and metformin, and to reveal factors that influence the clinical efficacy. METHODS: Seventy-eight Japanese subjects with Type 2 diabetes mellitus poorly controlled with sulphonylureas [38 men and 40 women, aged 57 +/- 9 years, body mass index 25.2 +/- 1.4 kg/m2, and HbA1c 8.3 +/- 0.6% (means +/- SD)] were randomly assigned to groups for the addition of either pioglitazone or metformin and followed up for 4 months. A decrease in HbA1c levels was compared with baseline factors including homeostasis model assessment of insulin sensitivity (HOMA-R) and beta-cell function (HOMA-beta) with 71 subjects who completed the study. RESULTS: The overall decrease in HbA1c levels was similar for the pioglitazone (-1.2 +/- 0.2%) and metformin (-1.3 +/- 0.1%) groups. In the pioglitazone group, the decrease in HbA1c levels was negatively correlated with baseline HOMA-R (r=-0.698, P<0.0001) and HOMA-beta (r=-0.680, P<0.0001). In contrast, the decrease was positively correlated with baseline HOMA-beta (r=0.556, P=0.0004) in the metformin group. Multivariate analysis revealed that either HOMA-R or HOMA-beta was a main determinant of the decrease in HbA1c levels in the pioglitazone group. In the metformin group, baseline levels of fasting glucose were also included as an independent determinant in addition to HOMA-beta. The subjects with greater HOMA-R (> or =4.0) or HOMA-beta (> or =40%) displayed better response to pioglitazone than to metformin, and vice versa. CONCLUSIONS: In Type 2 diabetic subjects poorly controlled with sulphonylureas, addition of pioglitazone or metformin resulted in a comparable reduction in HbA1c levels. Subjects with greater insulin resistance or preserved beta-cell function displayed better response to pioglitazone, whereas subjects with reduced beta-cell function displayed better response to metformin.