过氧化物酶增殖体活化受体α/γ双重激动剂的研究进展

过氧化物酶增殖体活化受体（PPAR）是治疗2型糖尿病等人类代谢疾病的新靶点。与单一的PPARγ激动剂相比，PPARα/γ双重激动剂可以产生协同作用，更具有开发潜力。现综述α烷氧基苯基丙酸类、苯氧异丁酸类、苄基丙二酸衍生物类及其他类型的PPARα/γ双重激动剂的研究进展，并提出一些研究思路。     

过氧化物酶体增殖物激活受体激动剂安全性研究进展

过氧化物酶体增殖物激活受体（peroxisome proliferator-activated receptors,PPAR）是调控能量代谢、炎症反应、细胞发育和分化相关基因表达的重要核受体。其激动剂已被开发用于治疗糖尿病,血脂异常和动脉粥样硬化等代谢性疾病。PPAR激动剂的不良反应限制了其在临床上的使用以及新型PPAR激动剂的开发。本文对特异性PPAR激动剂相关的毒性类型和毒性机制进行了归纳整理,并介绍了临床试验中双重PPAR激动剂和泛PPAR激动剂的不良反应报道,以期更好地了解PPAR激动剂毒性作用,为设计出安全性更高的PPAR激动剂提供参考。     

PPARγ激动剂的研究进展

过氧化物酶体增殖剂活化受体γ（PPARγ）是一个由配体激活的核转录因子，属于核激素受体（nuclear hormone receptor)超家族。被激动剂激活以后，该受体可以促进葡萄糖的利用以及胰岛素的增敏。因此，PPARγ激动剂有希望成为一类全新的Ⅱ型糖尿病治疗药物。本文对现有的PPARγ天然和合成的激动剂进行一个综述。     

姜黄素通过激活过氧化物酶体增殖子活化受体γ诱导肝星状细胞凋亡

目的研究姜黄素对肝星状细胞(HSC)凋亡的作用,以及与过氧化物酶体增殖子活化受体γ(PPARγ)信号之间的关系。方法肝脏原位灌流酶消化、Nycodenz密度梯度离心方法分离培养大鼠HSC,传代培养并使用药物处理。Ho-echst33258染色检测细胞凋亡,免疫荧光染色检测PPARγ的细胞内分布。收集裂解细胞分别抽提RNA、总蛋白和核蛋白,半定量RT-PCR和Westernblot方法检测目标基因和蛋白表达水平。结果活化HSC几乎没有凋亡发生,而姜黄素处理诱导了HSC凋亡,促进了HSC中PPARγ的核转位和(或)重分布。姜黄素在转录和翻译水平,增强HSC胞核PPARγ表达,抑制了抗凋亡因子Bcl-2的表达,促进了促凋亡因子Bax表达;这些作用能够被PPARγ阻断剂所拮抗。结论姜黄素促进过氧化物酶体增殖因子活化受体γ表达和核转位/重分布,诱导肝星状细胞凋亡。     

过氧化物酶体增殖物活化受体δ及其在代谢综合征中的作用

肥胖与胰岛素抵抗、脂代谢紊乱、高血压及糖耐量降低是代谢综合征的主要特点。过氧化物酶体增殖物活化受体（PPAR）δ是新近发现的PPAR家族的新成员，存在多种配体。激活PPARδ可增强脂肪及肌肉组织中的脂肪酸氧化和能量偶联，抑制巨噬细胞内的炎症反应，同时具有改善血脂和胰岛素抵抗的作用。这些功能提示PPA鼢可用于控制体重、增加胰岛素敏感性，缓减冠心病症状，可能是极具潜力的代谢综合征治疗的新靶点。     

过氧化物酶体增殖物激活受体β/δ激动剂对脂代谢的作用及其机制研究进展

作为过氧化物酶体增殖物激活受体(PPAR)的一个亚型,PPARβ/δ对骨骼肌、心肌、肝脏等组织的脂代谢具有重要调节作用,研究发现PPARδ激动剂对脂代谢紊乱的相关疾病具有潜在治疗作用。本文对PPARβ/δ激动剂对脂代谢的影响及相关机制的研究进展进行了综述。     

PPARs激动剂在心脑血管疾病中的研究进展

PPARs是一类由配体激活的转录因子,属于Ⅱ型核受体超家族成员。PPARs被激活后,能够改善胰岛素抵抗(IR)、纠正脂质代谢紊乱、逆转心肌肥厚、抑制血管平滑肌细胞(VSMCs)和内皮细胞的增殖与迁移,从而改善心脑血管的病理性重构,并具有降压效应。因此,PPARs激动剂的研究在心脑血管疾病的防治中具有重要的理论意义和临床应用价值。本文对近几年的PPARs激动剂进行综述。     

过氧化物酶体增殖物受体对肿瘤能量代谢调控的研究进展

过氧化物酶体增殖物受体（PPARs）是细胞能量代谢的主要调节因子,PPARs的3种亚型在多种肿瘤细胞中具有不同的转录活性与效应,能量代谢稳态对细胞的命运至关重要,关于肿瘤的能量代谢一直是热点问题。所有细胞活动都强烈依赖于分解代谢和合成代谢途径之间的平衡,破坏能量平衡和微环境,将表现出一系列的代谢改变包括葡萄糖消耗增加,线粒体呼吸的减少,细胞死亡抗性增强,所有这些都是癌症进展的原因。了解癌症中的代谢过程和阐明PPARs的调控机制会产生新的治疗策略。     

过氧化物酶体增殖物激活受体γ在肝脏疾病的研究进展

过氧化物酶体增殖物激活受体γ(PPARγ)属于类固醇受体超家族成员,最早在脂肪代谢的研究中被发现。近年的研究表明,PPARγ作用广泛,在众多病理生理过程中均发挥着重要作用。在肝脏疾病领域,PPARγ参与病毒性肝炎、非酒精性脂肪性肝病、肝硬化、酒精性肝病、肝脏缺血-再灌注损伤和肝癌等多种肝脏疾病的发生、发展。随着对其研究的进一步深入,PPARγ有望成为肝脏疾病防治的新靶点。     

AMPK、PPARs在2型糖尿病中的作用机制及药物研究

2型糖尿病（T2DM）在全球范围内广泛流行,其主要特征为胰岛素抵抗和胰腺β细胞分泌的胰岛素减少,糖脂代谢发生紊乱,其发病原因是多因素的。AMPK和PPARs作为体内代谢过程的关键调节因子,对糖脂代谢平衡有着巨大贡献。本文着重综述两者在2型糖尿病发生发展中的作用机制,以及相应的药物对2型糖尿病的治疗效果和作用机制,以期为2型糖尿病药物的研发提供参考。     

2型糖尿病的胰岛素治疗

糖尿病目前在全球范围内已经成为危害人类健康的重要公共卫生问题之一,大量的研究表明胰岛素治疗糖尿病可以延缓或阻止糖尿病慢性并发症的发生。本文综述2型糖尿病中胰岛素治疗的时机、方法、制剂以及不足等。     

Combination lipid therapy in type 2 diabetes mellitus

Introduction: A significant drop in cardiovascular risk has been seen in patients with type 2 diabetes treated with statins. However, this cardiovascular risk remains high, compared with nondiabetic individuals. This is partly due to the typical abnormalities of diabetic dyslipidemia – hypertriglyceridemia and decreased high-density lipoprotein cholesterol (HDL-C) – that are uncontrolled by statins. For this reason, combination lipid therapy may be considered in patients with type 2 diabetes.

Areas covered: This review presents the main reasons for a combination lipid therapy in type 2 diabetes and the effects of several drugs, including fibrates, pioglitazone, niacin and omega 3, on diabetic dyslipidemia and the prevention of cardiovascular events. The real cardiovascular benefit of fibrates in patients with type 2 diabetes is not totally clear, but they may produce a significant benefit in patients with type 2 diabetes and diabetic dyslipidemia (hypertriglyceridemia, low HDL-C). Pioglitazone, which reduces triglycerides and increases HDL-C, has been shown to reduce the risk for major cardiovascular events in type 2 diabetes. Niacin and omega 3 fatty acids have a positive effect on diabetic dyslipidemia, but warrants clinical trials to demonstrate a clear cardiovascular benefit in type 2 diabetes.

Expert opinion: Although combination lipid therapy seems to be useful to control diabetic dyslipidemia, the efficacy of such combined therapies on significantly reducing cardiovascular risk has still to be confirmed by additional clinical trials.     

Combination lipid therapy in type 2 diabetes mellitus

INTRODUCTION: A significant drop in cardiovascular risk has been seen in patients with type 2 diabetes treated with statins. However, this cardiovascular risk remains high, compared with nondiabetic individuals. This is partly due to the typical abnormalities of diabetic dyslipidemia - hypertriglyceridemia and decreased high-density lipoprotein cholesterol (HDL-C) - that are uncontrolled by statins. For this reason, combination lipid therapy may be considered in patients with type 2 diabetes. AREAS COVERED: This review presents the main reasons for a combination lipid therapy in type 2 diabetes and the effects of several drugs, including fibrates, pioglitazone, niacin and omega 3, on diabetic dyslipidemia and the prevention of cardiovascular events. The real cardiovascular benefit of fibrates in patients with type 2 diabetes is not totally clear, but they may produce a significant benefit in patients with type 2 diabetes and diabetic dyslipidemia (hypertriglyceridemia, low HDL-C). Pioglitazone, which reduces triglycerides and increases HDL-C, has been shown to reduce the risk for major cardiovascular events in type 2 diabetes. Niacin and omega 3 fatty acids have a positive effect on diabetic dyslipidemia, but warrants clinical trials to demonstrate a clear cardiovascular benefit in type 2 diabetes. EXPERT OPINION: Although combination lipid therapy seems to be useful to control diabetic dyslipidemia, the efficacy of such combined therapies on significantly reducing cardiovascular risk has still to be confirmed by additional clinical trials.     

Optimising therapy for insulin-treated type 2 diabetes mellitus

The purpose of this article is to provide a guide to the optimal use of insulin in type 2 (non-insulin-dependent) diabetes mellitus. Based on pathophysiological considerations and a knowledge of drug actions, an individualised, targeted strategy is selected for obtaining good metabolic control without compromising well-being and quality of life. The treatment should target hyperglycaemia along with other risk factors. Insulin is indicated when adequate glycaemia can no longer be obtained with diet and oral antihyperglycaemic agents. Commonly, the oral drugs are replaced by insulin, but preferably they should be used in combination with insulin. This approach can lead to improved glycaemic control, a reduced insulin dose and counteraction of insulin-associated bodyweight gain. There may also be less hypoglycaemia with combination insulin/oral therapy as compared with insulin monotherapy, as well as other benefits. Optimisation of oral drug therapy should be attempted before initiating insulin. A combination of insulin with a sulphonylurea agent is commonly used: the adjunctive effect of the sulphonylurea is dependent on pancreatic beta cell function. The combination of insulin with metformin or a thiazolidinedione is more logical as insulin resistance is targeted directly. Bedtime insulin plus metformin conferred the most benefits among several options investigated in a randomised 1-year study. The combination of insulin with acarbose is a further option when there is significant postprandial hyperglycaemia. It is recommended to start with a medium- to long-acting insulin preparation at bedtime or premixed insulin before the evening meal. Changes in insulin administration can be subsequently introduced as needed, e.g. use of twice-daily premixed insulin, multiple injections of rapid-acting insulin or insulin analogues. There are many options, but limited clinical data are available to support a number of the regimens.     

Contraindications to metformin therapy among patients with type 2 diabetes mellitus

Objective The biguanide, metformin, is a commonly prescribed oral antihyperglycemic agent. However, there are several clinical conditions that are considered as contraindications to the use of metformin among patients with type 2 diabetes mellitus. The aim of this study was to investigate the presence and nature of contraindications to metformin therapy among patients with type 2 diabetes mellitus. Method A retrospective study of the medical files of diabetic patients available at Alwosta clinic, north Palestine was carried out. Information about disease and medication profile of the patients was retrieved and analyzed using SPSS during the study period in 2004/2005. Focus was on metformin users who have contraindications to metfromin therapy. Main outcome measure Presence and number of contraindications to metformin therapy. Results Two hundred and seventy-two type 2 diabetic patients were identified. One hundred and twenty four of those diabetic patients were metformin users. Approximately, 60% of patients in the metformin group had a least one contraindication. Congestive heart failure and renal impairment were the most quantitatively present contraindications. Conclusion Contraindications to metformin therapy are common among type 2 diabetic patients and mostly disregarded. Patients have to be critically assessed before starting therapy and in case of metformin prescribing; dose should be adjusted based on the presence of risk factors for metformin adverse effects.     

A rational approach to drug therapy of type 2 diabetes mellitus

Several new pharmacological agents have recently been developed to optimise the management of type 2 (non-insulin-dependent) diabetes mellitus. The aim of this article is to briefly review the various therapeutic agents available for management of patients with type 2 diabetes mellitus and to suggest a potential approach to drug selection. There are three general therapeutic modalities relevant to diabetes care. The first modality is lifestyle adjustments aimed at improving endogenous insulin sensitivity or insulin effect. This can be achieved by increased physical activity and bodyweight reduction with diet and behavioural modification, and the use of pharmacological agents or surgery. This first modality is not discussed in depth in this article. The second modality involves increasing insulin availability by the administration of exogenous insulin, insulin analogues, sulphonylureas and the new insulin secretagogue, repaglinide. The most frequently encountered adverse effect of these agents is hypoglycaemia. Bodyweight gain can also be a concern, especially in patients who are obese. The association between hyperinsulinaemia and premature atherosclerosis is still a debatable question. The third modality consists of agents such as biguanides and thiazolidinediones which enhance insulin sensitivity, or agents that decrease insulin requirements like the alpha-glucosidase inhibitors. Type 2 diabetes mellitus is a heterogeneous disease with multiple underlying pathophysiological processes. Therapy should be individualised based on the degree of hyperglycaemia, hyperinsulinaemia or insulin deficiency. In addition, several factors have to be considered when prescribing a specific therapeutic agent. These factors include efficacy, safety, affordability and ease of administration.     

肥胖2型糖尿病药物研究进展

肥胖与糖尿病发病率密切相关，是糖尿病发病率上升的重要原因。如今上市的大部分降糖药物如胰岛素及其类似物、胰岛素促泌剂、胰岛素增敏剂等都会不同程度的增加患者体重，从而加重胰岛素抵抗，增加降糖药物剂量，形成恶性循环，降糖兼具减肥是当今糖尿病新药研发重要趋势。本文概述了肥胖2型糖尿病的流行病学以及目前上市的降糖药物对体重发展的影响，并重点概述了兼具减肥效应的降糖药物的最新靶点，为肥胖2型糖尿病患者的治疗提供潜在新方法。     

胰高血糖素样肽1受体激动剂在2型糖尿病治疗中的研究进展

胰高血糖素样肽1受体激动剂（glucagon‐like peptide‐1 receptor agonist ，GLP‐1RA）是近年来2型糖尿病药物开发领域的研究热点。作为一种降血糖药物，GLP‐1RA 在增强患者血糖调控能力的同时，还能降低患者低血糖风险，减轻体重，保护心血管系统。此文对已上市和部分正处于临床试验阶段的 GLP‐1RA 的疗效及安全性做一综述，并对 GLP‐1RA 药物的发展趋势进行探讨。     

2型糖尿病候选基因的研究进展

2型糖尿病是一种多基因遗传性疾病,每一种基因变异都对疾病有温和的致病风险,并增加个体对2型糖尿病的遗传易感性.对2型糖尿病遗传发病机制的研究一直是内分泌领域的研究热点之一,迄今已发现了200多种与2型糖尿病发生有关的候选基因.本文就2型糖尿病的7个热点候选基因的研究进展进行综述.