Changes in adiponectin receptor expression in muscle and adipose tissue of type 2 diabetic patients during rosiglitazone therapy

Aims/hypothesis Adiponectin is important in the regulation of insulin sensitivity in man. Its receptors, adipoR1 and R2, have recently been identified, but their expression in adipose tissue and their regulation in response to insulin sensitisation of diabetic patients have never been assessed. We therefore explored the regulation of adipoR1/R2 and adiponectin expression in adipose tissue and skeletal muscle, and of adiponectin plasma concentrations in response to insulin sensitisation by rosiglitazone.Methods Patients with type 2 diabetes were studied in a double-blind, placebo-controlled crossover study, using in vivo arteriovenous techniques of measuring adipose tissue and muscle blood flow, combined with measurement of adipose tissue and skeletal muscle gene expression.Results Rosiglitazone treatment increased adiponectin concentrations by 69%. Skeletal muscle adipoR1 expression was down-regulated from 109.0 (70.1–165.7) (median [interquartile range]) to 82.8 (63.6–89.3) relative units (p=0.04), but adipose tissue adipoR1 expression was up-regulated from 5.3 (4.4–9.4) to 11.2 (4.8–15.3) relative units (p=0.02) by rosiglitazone. In contrast to adipoR1 expression, adipoR2 expression was not altered by rosiglitazone in either of the tissues. The increase in adipose tissue adipoR1 expression with rosiglitazone was associated with increased postprandial triglyceride clearance (r=0.67, p=0.05), and increased fasting fatty acid output (r=0.78, p=0.01) measured in subcutaneous adipose tissue.Conclusions/interpretation AdipoR1 expression is up-regulated in adipose tissue but down-regulated in skeletal muscle by rosiglitazone. These data suggest that adipoR1 plays a role in mediating the effects of adiponectin in specific tissues in relation to insulin sensitisation.G. D. Tan, and C. Debard contributed equally to this work.     

吡格列酮对非酒精性脂肪肝病大鼠Kupffer细胞的影响

目的探讨吡格列酮对sD大鼠非酒精性脂肪肝病形成的预防作用及其机制。方法36只雄性SD大鼠按随机数字表法分为正常对照组、高脂饮食组及吡格列酮干预组,饲养8周;正常对照组喂饲普通饲料,剩余两组喂饲高脂饲料;吡格列酮干预组于实验第4—8周予吡格列酮灌胃,其余两组同期予蒸馏水灌胃;测定空腹血清丙氨酸氨基转移酶（ALT）、天门冬氨酸氨基转移酶（AST）、甘油三酯（TG）、总胆固醇（TC）、空腹血糖（FPG）、空腹胰岛素（FINS）水平;计算空腹胰岛素抵抗指数（FIRI）;HE染色分析肝组织切片病理学改变;观察Kupffer细胞形态变化及分泌肿瘤坏死因子-α（TNF-α）、一氧化氮（NO）的水平。结果高脂饮食组大鼠空腹FIRI、TG、TC均高于正常对照组,差异均有统计学意义（P＜0．05）,肝组织呈以大泡性脂肪变性为主的混合性脂肪变性并出现炎症细胞浸润,肝脏Kupffer细胞发生形态改变,其产生的TNF-α、NO水平与肝组织病理学改变呈正相关（P＜0．05）;吡格列酮干预组大鼠空腹FIRI、TG、TC均低于高脂饮食组,差异均有统计学意义（P＜0．05）,肝组织结构基本正常,肝脏Kupffer细胞形态及功能基本正常。结论吡格列酮可预防高脂饮食诱导的非酒精性脂肪肝病发生;其机制可能与改善胰岛素抵抗、降低血脂和调节Kupffer细胞功能有关。     

吡格列酮对2型糖尿病患者护骨素和骨密度的影响

目的探讨噻唑烷二酮类药物吡格列酮对2型糖尿病(T2DM)患者护骨素和骨密度的影响。方法57例T2DM患者,随机分为T2DM对照组24例,T2DM实验组33例,实验组降糖方案中联合吡格列酮(30 mg/d),疗程3个月;正常对照30例。治疗前后分别测定糖尿病患者和健康对照组骨密度、血清护骨素(OPG)水平,并进行比较。结果①T2DM血清护骨素(OPG)水平高于健康对照组(P<0.05);②T2DM实验组经吡格列酮治疗后OPG水平有所升高,但与治疗前比较差异无统计学意义(P>0.05),T2DM对照组治疗前后OPG无显著变化;③T2DM实验组经吡格列酮治疗后髋部及腰椎BMD均有所下降,而T2DM对照组治疗前后髋部及腰椎BMD无显著变化。结论吡格列酮可对2型糖尿病患者骨代谢的不利影响因素可能超过有利因素。     

吡格列酮对慢性高血压大鼠脑白质病变和空间记忆功能的影响

目的 探讨过氧化物酶体增殖物激活受体γ激动剂吡格列酮对慢性高血压大鼠脑白质病变和空间记忆功能的影响.方法 雄性Sprague-Dawley大鼠36只,随机分为假手术组（n=6）、高血压组（n=15）和吡格列酮组（n=15）.高血压组和吡格列酮组采用双肾双夹法制作易卒中型肾血管性高血压大鼠（stroke-prone renovascular hypertensive rat,RHRSP）模型,术后8周开始灌胃给药.吡格列酮组给予10 mg/（kg＆#183;d）吡格列酮,高血压组给予等量生理盐水,分别于术前、给药前及给药后每隔2周经尾动脉监测血压.连续给药12周后进行Loyez染色观察脑白质疏松程度,水迷宫试验检测空间记忆功能.结果 RHRSP大鼠造模后血压缓慢升高,显著性高于假手术组（P均=0.000）,高血压组与吡格列酮组血压无显著性差异（P =0.897）.水迷宫试验显示,假手术组和吡格列酮组逃避潜伏期显著性短于高血压组（P均＜0.05）,三组大鼠跨越平台次数分别为（5.200＆#177;1.798）次、（4.560＆#177;1.592）次和（2.333＆#177;1.978）次,差异具有统计学意义（F=8.143,P=0.001）,假手术组和吡格列酮组均显著性多于高血压组（P均＜0.05）.Loyez染色显示,假手术组、高血压组和吡格列酮组胼胝体脑白质病变分级分别为0.333＆#177;0.516、2.600＆#177;0.507和0.500＆#177;0.522,三组间差异有统计学意义（F =25.652,P=0.000）,假手术组和吡格列酮组分级均显著性低于高血压组（P均＜0.05）.结论 PPAR-γ激动剂吡格列酮能通过减轻慢性高血压大鼠脑白质病变保护空间记忆功能.     

Avoiding hypoglycaemia while achieving good glycaemic control in type 2 diabetes through optimal use of oral agent therapy

Abstract

Background:

Patients with type 2 diabetes appear to be at relatively low risk of severe hypoglycaemia and hypoglycaemia unawareness in the early stages of disease. However, declining endogenous insulin secretory capacity due to β-cell dysfunction/failure eventually produces vulnerability similar to type 1 diabetes. Severe hypoglycaemia itself is associated with serious morbidity and sometimes mortality, and represents an important barrier to achieving glycaemic goals and thus may reduce the protection from diabetes-related morbidity provided by good glycaemic control. Achieving an optimal balance of good glycaemic control and low risk of hypoglycaemia is key to providing optimum care in individuals with type 2 diabetes. This article discusses the issues related specifically to hypoglycaemia associated with oral agent therapy and how these agents may be best employed to provide an optimal balance between hypoglycaemia and good glycaemic control.     

噻唑烷二酮类药物治疗对2型糖尿病患者血管内皮功能影响

目的探讨噻唑烷二酮类药物（TZDs）对2型糖尿病患者血管内皮功能影响。方法选择TZDs的代表药物吡格列酮（PIO）,对我院2010年7月～2012年6月收治的2型糖尿病患者用PIO进行治疗,治疗前后测定空腹血糖（FPG）、2hPG、空腹胰岛素（Fins）、总胆固醇（TC）、甘油三酯（TG）、高密度脂蛋白胆固醇（HDL-C）、低密度脂蛋白胆固醇（LDL-C）、血管细胞黏附分子（sVCAM-1）、糖化血红蛋白（HbAlc）、炎症因子C反应蛋白（CRP）、纤溶酶原激活物抑制物-I（PAI-1）、脂联素、肿瘤坏死因子（TNFd）、胰岛素抵抗指数（HOMA—IR）、内皮依赖性血管舒张功能（ED-VD）水平的改变。结果治疗后EDVD明显改善,sVCAM-1、血糖、Fins、HbA1c、HOMA-IR、PAI-1、CRP及TNFa水平显著降低,脂联素显著升高（P〈0．05）,血脂情况得到明显改善。结论PIO可明显改善2型糖尿病患者的内皮细胞功能．TZDs对2型糖尿病患者心血管并发症的发生具有很好的预防作用,为临床应用TZDs治疗糖尿病及其并发症提供临床基础。     

Thiazolidinedione use and post-operative atrial fibrillation: a US nested case-control study

ABSTRACT

Background: Previous investigations suggested thiazolidinediones (TZDs) have the ability to suppress inflammation. Since the pathophysiology of atrial fibrillation (AF) after cardiothoracic surgery (CTS) likely involves an inflammatory mechanism, we sought to determine whether preoperative use of TZDs could further reduce the incidence of post-CTS AF in a population treated with beta-blockers and prophylactic amiodarone.

Methods: All diabetic patients over the age of 50 years, not in atrial arrhythmia prior to surgery, who underwent CTS from the Atrial Fibrillation Suppression Trials I, II and III (AFIST I, II and III) were evaluated in this nested case-control study. Patient demographics, surgical character­istics, medication utilization and the incidence of post-CTS AF (AF > 5 minutes duration) were collected as part of AFIST I, II and III. Multivariate logistic regression was used to calculate adjusted odds ratios with 95% confidence intervals (CIs).

Results: One hundred and eighty-four diabetic patients were enrolled in the three trials. Overall, the study population averaged 66.9 ± 7.3 years of age, 71.7% were male, 7.1% underwent valve surgery, 4.9% had prior AF, 17.9% had heart failure and 84.2% and 41.8% received postoperative beta-blockade and prophylactic amiodarone, respectively. Forty patients (21.7%) received a preoperative TZD and 144 (78.3%) did not. In total, 66 patients (35.9%) developed post-CTS AF. Upon multi­variate logistic regression, the preoperative use of TZDs was found to be associated with a 20% non-statistically significant reduction in post-CTS AF (adjusted odds ratio; 0.80, 95% CI 0.32–1.99; p = 0.63).

Limitations: Patients were not randomized to receive TZDs or not. We may not have had adequate power to evaluate our post-CTS AF endpoint.

Conclusions: In a diabetic population treated peri­operatively with beta-blocker and amiodarone, adjunctive TZD use was associated with a non-statistically significant reduction in a patient's odds of developing post-CTS AF. Further research is needed to determine whether TZDs, in fact, do not have anti-fibrillatory effects or whether our study was underpowered to detect a statistically significant benefit with TZDs.     

噻唑烷二酮类药物的抗肿瘤作用

噻唑烷二酮（TZDs）是用于治疗以胰岛素抵抗为特征的2型糖尿病的药物。它主要通过作用于核受体家族中的过氧化物酶增殖体的激活受体γ（PPARγ）来发挥抗糖尿病的作用。近年来,越来越多的实验证据发现其具有一定的抗肿瘤作用,涉及的机制主要有诱导细胞周期的终止,促进细胞的凋亡或分化,抑制肿瘤的转移及血管新生等。     

Clinical effects of antidiabetic drugs on psoriasis: The perspective of evidence-based medicine

Psoriasis and diabetes shared common underlying pathophysiological mechanisms. Emerging data suggested that antidiabetic medications may improve the psoriasis severity in patients with diabetes mellitus. Several hypoglycemic agents including thiazolidinediones, glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, and biguanides have been reported to make a remarkable reduction in the Psoriasis Area and Severity Index score from baseline. This antipsoriatic effect could be mediated not only by the glucoselowering action of these agents but also via inhibition of keratinocyte over proliferation, increase expression of differentiation markers, suppression the immune inflammatory pathway, and blocking the calcium channels and mitogen-activated protein kinase signaling pathways. On the other hand, there was no significant increase in adverse reactions associated with the treatment of pioglitazone or metformin. However, previous studies often had the relatively short duration of the trials, and did not have enough power to assess recurrence of psoriasis. Potential bias in the study and missing data could undermine the reliability of the results. Therefore, the appropriately randomized controlled studies with large sample sizes and long-term durations in various psoriasis patients are warranted for further support.