Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD): study design and protocol

Aims/hypothesis Studies suggest that in addition to blood glucose concentrations, thiazolidinediones such as rosiglitazone improve some cardiovascular (CV) risk factors and surrogate markers, that are abnormal in type 2 diabetes. However, fluid retention might lead to cardiac failure in a minority of people. The aim of the Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD) study is to evaluate the long-term impact of these effects on CV outcomes, as well as on long-term glycaemic control, in people with type 2 diabetes.Materials and methods RECORD is a 6-year, randomised, open-label study in type 2 diabetic patients with inadequate blood glucose control (HbA₁c 7.1–9.0%) on metformin or sulphonylurea alone. The study is being performed in 327 centres in Europe and Australasia. After a 4-week run-in, participants were randomised by current treatment stratum to add-on rosiglitazone, metformin or sulphonylurea, with dose titration to a target HbA₁c of 7.0%. If confirmed HbA₁c rises to 8.5%, either a third glucose-lowering drug is added (rosiglitazone-treated group) or insulin is started (non-rosiglitazone group). The same criterion for failure of triple oral drug therapy in the rosiglitazone-treated group is used for starting insulin in this group. The primary endpoint is the time to first CV hospitalisation or death, blindly adjudicated by a central endpoints committee. The study aim is to evaluate non-inferiority of the rosiglitazone group vs the non-rosiglitazone group with respect to CV outcomes. Safety, tolerability and study conduct are monitored by an independent board. All CV endpoint and safety data are held and analysed by a clinical trials organisation, and are not available to the study investigators while data collection is open.Results Over a 2-year period a total of 7,428 people were screened in 25 countries. Of these, 4,458 were randomised; 2,228 on background metformin, 2,230 on background sulphonylurea. Approximately half of the participants are male (52%) and almost all are Caucasian (99%).Conclusions/interpretation The RECORD study should provide robust data on the extent to which rosiglitazone, in combination with metformin or sulphonylurea therapy, affects CV outcomes and progression of diabetes in the long term.     

Improved insulin sensitivity and adipose tissue dysregulation after short-term treatment with pioglitazone in non-diabetic, insulin-resistant subjects

Aims/hypothesis We examined whether short-term treatment with a thiazolidinedione improves insulin sensitivity in non-obese but insulin-resistant subjects and whether this is associated with an improvement in dysregulated adipose tissue (reduced expression of IRS-1, GLUT4, PPAR co-activator 1 and markers of terminal differentiation) that we have previously documented to be associated with insulin resistance.Methods Ten non-diabetic subjects, identified as having low IRS-1 and GLUT-4 protein in adipose cells as markers of insulin resistance, underwent 3 weeks of treatment with pioglitazone. The euglycaemic–hyperinsulinaemic clamp technique was used to measure insulin sensitivity before and after treatment. Serum samples were analysed for glucose, insulin, lipids, total and high-molecular-weight (HMW) adiponectin levels. Biopsies from abdominal subcutaneous adipose tissue were taken, cell size measured, mRNA and protein extracted and quantified using real-time RT-PCR and Western blot.Results Insulin sensitivity was improved after 3 weeks treatment and circulating total as well as HMW adiponectin increased in all subjects, while no effect was seen on serum lipids. In the adipose cells, gene and protein expression of IRS-1 and PPAR co-activator 1 remained unchanged, while adiponectin, adipocyte P 2, uncoupling protein 2, GLUT4 and liver X receptor- increased. Insulin-stimulated tyrosine phosphorylation and p-ser-PKB/Akt increased, while no significant effect of thiazolidinedione treatment was seen on the inflammatory status of the adipose tissue in these non-obese subjects.Conclusions/interpretation Short-term treatment with pioglitazone improved insulin sensitivity in the absence of any changes in circulating NEFA or lipid levels. Several markers of adipose cell differentiation, previously shown to be reduced in insulin resistance, were augmented, supporting the concept that insulin resistance in these individuals is associated with impaired terminal differentiation of the adipose cells.     

高脂喂养及罗格列酮干预对老年大鼠骨骼肌线粒体功能的影响

目的 观察高脂饮食和罗格列酮干预对老年大鼠骨骼肌过氧化物酶体增生物激活受体γ共激活因子1α(PGC-1α)和线粒体融合蛋白2(Mfn2)表达的影响. 方法 21～23月龄Wistar大鼠分为老年对照组、高脂组和高脂+罗格列酮干预组(干预组),并设4～5月龄Wistar大鼠作为青年对照组.应用正常葡萄糖高胰岛素钳夹技术评价胰岛素敏感性,高脂喂养第8周时,检测骨骼肌PGC-1α和Mfn2的mRNA及蛋白表达.结果高脂喂养8周后,青年对照组、老年对照组和高脂组空腹血游离脂肪酸[(0.68±0.18)mmol/L、(0.82±0.23)mmol/L和(1.53±0.40)mmol/L],三酰甘油[(0.53±0.13)mmol/L、(0.63±0.17)mmol/L和(1.08±0.30)mmol/L],骨骼肌三酰甘油[(1.09±0.17)mmol/L、(1.34±0.20)mmol/L和(2.07±0.30)mmol/L]均升高,葡萄糖输注率((30.4±4.2)mg·kg~(-1)·min~(-1)、(20.9±2.2)mg·kg~(-1)·min~(-1)和(12.0±1.9)mg·kg~(-1)·min~(-1)]下降;经过罗格列酮干预后游离脂肪酸[(0.93±0.29)mmol/L]、三酰甘油[(0.62±0.12)mmol/L]及骨骼肌三酰甘油[(1.68±0.28)mmol/L)]均明显下降,葡萄糖输注率[(16.7±1.7)mg·kg~(-1)·min~(-1)]升高.与青年对照组比较,老年对照组骨骼肌PGC-1α和Mfn2的表达下降,经高脂喂养后PGc-1α和Mfn2的表达进一步下降,干预组上述基因的表达均显著高于高脂组(P<0.05),但仍比老年对照组降低(P<0.05). 结论 高脂饮食可诱导老年大鼠产生IR,推测可能与骨骼肌PGC-1α和Mfn2的表达下降有关;罗格列酮可通过改变骨骼肌PGC-1α和Mfn2的表达增加胰岛素敏感性.     

吡格列酮对高糖培养大鼠肾小球系膜细胞p38丝裂原活化蛋白激酶和转化生长因子β-1的影响

目的观察吡格列酮(PIO)对高糖(HG)培养的肾小球系膜细胞(MCs)p38丝裂原活化蛋白激酶(p38MAPK)和转化生长因子β-1(TGF-β1)表达的影响,探讨PIO肾保护作用及机制。方法体外培养MCs,取对数生长期的细胞以2×105/孔的密度接种于6孔细胞培养板,同步化后随机分为正常对照(NG)组、HG组、p38MAPK抑制剂(S)组及PIO(P)组。Western blot测定磷酸化p38MAPK(p-p38)和总p38MAPK(t-p38)蛋白含量,半定量RT-PCR测定细胞TGF-β1 mRNA表达情况。结果与NG组比较,HG组细胞内p-p38MAPK含量和TGF-β1mRNA表达增强(P0.01);与HG组比较,p38MAPK抑制剂显著抑制HG刺激的细胞内p38MAPK活性和TGF-β1表达(P0.05);与HG组比较,P组细胞内上述变化亦明显降低(P0.05),与S组相似;p38MAPK活性和TGF-β1表达呈正相关(r=0.587,P0.01)。结论 PIO可抑制肾小球系膜p38MAPK通路,降低TGF-β1表达,该作用可能与其肾脏保护部分有关。     

Insulin resistance: a potential new target for therapy in patients with heart failure

There is increasing evidence to suggest that chronic heart failure (CHF) is an insulin resistant (IR) state and that the degree of IR correlates with the severity and mortality of CHF. The pathophysiology of IR in CHF has yet to be fully defined. Additionally, it remains to be determined if IR is merely a marker reflecting the severity of CHF or whether it contributes to the disease in CHF. If IR is truly a culprit that worsens CHF, it will potentially be a new target for therapy as strategies that can reverse IR in CHF may potentially result in an improvement in symptoms and even mortality in these patients. However, there are concerns regarding the use of certain insulin sensitizers, most notably, the thiazolidinediones (TZDs) which have been associated with increased risk of hospitalizations for CHF. Despite previous concerns of lactic acidosis (LA), there is now evidence that metformin may not only be safe but could potentially be useful in the setting of CHF. There are now ongoing prospective studies, including the TAYSIDE study, to determine if reversing IR with metformin will have beneficial effects in patients with CHF.     

Thiazolidinediones reduce the LDL binding affinity of non-human primate vascular cell proteoglycans

Aims/hypothesis Retention of atherogenic lipoproteins in the artery wall by proteoglycans is a key step in the development of atherosclerosis. Thiazolidinediones have been shown to reduce atherosclerosis in mouse models. The aim of this study was to determine whether thiazolidinediones modify vascular proteoglycan synthesis in a way that decreases LDL binding.Methods Primate aortic smooth muscle cells were exposed to troglitazone or rosiglitazone, or no stimulus at all for a 24-hour steady-state labelling period. Sulphate incorporation, size and LDL binding affinity of proteoglycans were determined. Proteoglycans secreted by cells in the presence or absence of troglitazone were separated into large and small classes by size exclusion chromatography, and LDL binding affinity was determined.Results Proteoglycans synthesised by cells exposed to troglitazone or rosiglitazone were smaller, with decreased sulphate incorporation and decreased LDL binding affinity. However, troglitazone had a greater effect than rosiglitazone. Troglitazone reduced the LDL binding affinities of both the large and small proteoglycans compared with control. The binding differences persisted when glycosaminoglycan chains released from proteoglycans were incubated with LDL, indicating that troglitazone affects the glycosaminoglycan synthetic machinery of these cells.Conclusions/interpretation Thiazolidinediones decrease the LDL binding affinity of the proteoglycans synthesised by primate aortic smooth muscle cells. This could, in part, account for the reduced atherosclerosis observed in animal models.Abbreviations PPAR peroxisome proliferator-activated receptor - K_d binding constantPresented in part at the 3rd Annual Conference on Arteriosclerosis, Thrombosis and Vascular Biology, Salt Lake City, Utah, USA, 6 April 2002     

吡格列酮对急性坏死性胰腺炎大鼠胰腺细胞凋亡的作用

目的 探讨吡格列酮在重症急性胰腺炎发病机制中与凋亡激活的关系.方法 将80只SD大鼠按随机表法分为急性坏死性胰腺炎组（ANP组）、假手术组、二甲基亚砜溶剂对照组（DMSO组）、吡格列酮干预组（吡格列酮组）,每组20只.采用胰胆管逆行注射5％牛磺胆酸钠1 ml/kg体质量的方法制作ANP模型,吡格列酮组在造模前30 min腹腔注射吡格列酮40 mg/kg体质量.术后1、3、6、12 h分批处死大鼠,收集胰腺组织.采用常规HE染色进行胰腺组织病理评分,采用TUNEL染色方法检测大鼠胰腺细胞凋亡,免疫组化法和蛋白质印迹法检测胰腺组织PPARγ的表达变化,同时检测胰腺组织caspase3的表达变化.结果 吡格列酮干预后大鼠胰腺组织病理损伤较ANP组大鼠有所减轻,差异有统计学意义（P＜0.05）.吡格列酮组胰腺组织PPARγ表达水平为2.69 ±0.46,显著高于ANP组的0.75 ±0.05,差异有统计学意义（P＜0.05）.吡格列酮3h组大鼠胰腺细胞凋亡指数为8.35 ±0.95,显著高于同时点ANP组的4.37±1.22;caspase 3的活性为9.24±1.78,显著高于ANP组的5.04±0.86,差异均有统计学意义（P值均＜0.05）.结论 吡格列酮干预后大鼠胰腺炎症减轻,PPARγ和caspase 3表达升高,胰腺细胞凋亡率升高.