噻唑烷二酮类药物治疗2型糖尿病的有效性及安全性

噻唑烷二酮类药物是一类新型的治疗2型糖尿病的药物,通过提高机体对胰岛素的敏感性来达到良好控制血糖的作用.噻唑烷二酮类药物还可以有效地降低2型糖尿病患者血中低密度脂蛋白胆固醇、C-反应蛋白、基质金属蛋白酶-9、纤溶酶原激活物抑制剂-11的水平等,提高高密度脂蛋白胆固醇水平,改善血管内皮功能,减少2型糖尿病患者发生心血管疾病的风险.噻唑烷二酮类药物不良反应发生率低,安全性良好.     

全面认识噻唑烷二酮的临床治疗价值

噻唑烷二酮类药物是改善胰岛素敏感性的新型口服降糖药物,该类药物既能保护胰岛B细胞功能,又能保护心血管,起到抗炎等作用,因此该类药物在临床上得到大量应用。但是该类药物也存在一定不良反应。在选择噻唑烷二酮类药物之前,充分了解患者心血管方面的情况对该类药物进行遴选,可提高治疗所获得的益处,避免其不良反应。     

噻唑烷二酮类药物治疗2型糖尿病的效果

噻唑烷二酮类药物是目前治疗糖尿病的主要药物之一,该类药物可增强机体胰岛素敏感性,降低胰岛素抵抗,在降糖效果上与磺脲类和二甲双胍类相当,但对胰岛B细胞的保护性远远要好于磺脲类和二甲双胍类,而且对心血管有着良好的保护作用。噻唑烷二酮类药物最主要的副作用是水肿和皮下脂肪增多。     

噻唑烷二酮类药物治疗2型糖尿病的临床应用

2型糖尿病是以胰岛素抵抗和胰腺β细胞渐进性功能障碍为特征的一类糖尿病。目前，口服降血糖药物有二甲双胍和磺酰脲。近年来，出现了一类治疗糖尿病的新药噻唑烷二酮。它可提高病人对胰岛素的敏感性和改善胰腺β细胞的功能。噻唑烷二酮类药物是一种人工合成的配体，能够结合核过氧化物酶体增殖激活受体γ(PPAR-γ)，激活基因的转录，从而调节脂肪细胞的分化和脂肪细胞的形成，以及葡萄糖和油脂的代谢。目前，对噻唑烷二酮作用的确切分子机制还不太清楚。噻唑烷二酮类药物单独给药或与二甲双胍、磺酰脲及胰岛素合用治疗2型糖尿病，通过快速降低膳后血糖水平，从而改善对血糖生成的控制，并能提高对胰岛素的敏感性。     

噻唑烷二酮类药物的临床研究

噻唑烷二酮类药物是20世纪80年代发现有降低血糖和增加胰岛素的敏感性和改善糖代谢作用的化合物,本文对其近年来的生物学特性结构、分布及机制、临床应用、不良反应、循证医学证据的情况进行综述。     

噻唑烷二酮类药物在2型糖尿病中的临床应用

噻唑烷二酮类（TZD）药物作为胰岛素增敏剂近年来在临床上应用非常广泛，该类药物主要是通过增加肝脏和外周胰岛素敏感性来降低空腹血糖（FPG）和糖化血红蛋白（HbA1c）的水平，同时TZD还能保护胰岛B细胞功能。目前在市场上销售的TZD类药物是罗格列酮和吡格列酮，二者自2000年上市以来，总的来说患者的耐受性良好，体重增加和水肿是该类药物最常见的不良反应。     

知名药师解答“三高”用药

（接上期）53．为什么提倡早期使用噻唑烷二酮类降糖药物？噻唑烷二酮类药物使用至今,临床效果显著,可有效降低空腹血糖3．3～4．5mmol／L,降低糖化血红蛋白1．4％～2．6％,与其他降糖药物联合应用可增强其降糖效果,甚至注射胰岛素的2型糖尿病患者联合应用噻唑烷二酮类药物,也会有明显改善血糖控制的功效。此外,它还能调节血脂紊乱,因而具有减少心血管危险因素及延缓疾病进程的作用。因此,在临床治疗中,对于肥胖或超重的2型糖尿病患者,应优先并尽早给予噻唑烷二酮类药物。早期使用本类药物,决不仅仅意味着血糖、糖化血红蛋白水平和血脂水平的下降和达标,更重要的是其潜在益处在于对胰岛B细胞功能的保护和改善,进而延缓糖尿病患者病情进展,改善诸多心血管危险因素,预防慢性并发症及心血管事件的发生及发展。     

两种方法治疗多囊卵巢综合征胰岛素抵抗患者的临床效果比较

目的比较两种方法治疗多囊卵巢综合征胰岛素抵抗患者的临床效果,探讨临床有效治疗多囊卵巢综合征胰岛素抵抗的有效方案。方法选择2012年1月至2013年12月在信阳市妇幼保健院妇科门诊就诊的80例多囊卵巢综合征胰岛素抵抗患者随机分为两组,其中PCOSⅠ组40例采用二甲双胍治疗;PCOSⅡ组40例采用噻唑烷二酮类药物治疗,观察两组治疗前后胰岛素(HI)水平、体质量指数(BMI)、血清黄体生成素(LH)与卵泡刺激素(FSH)比值及葡萄糖耐量试验(OGTT)的变化。结果两组在治疗前后体质量指数(BMI)、HI水平、LH/FSH值及OGTT改善方面比较差异有显著性(P<0.05)。PCOSⅠ组与PCOSⅡ组治疗后比较,差异有显著性(P<0.01)。结论二甲双胍和噻唑烷二酮类药物在改善胰岛素敏感性、高雄激素上具有相似作用,但二甲双胍的使用更加显著地降低了体内胰岛素水平和雄激素水平,只有在二甲双胍治疗效果不佳时可采用噻唑烷二酮类药物。     

“胰岛素增敏剂”如何降糖

所谓“胰岛素增敏剂”,就是可以改善胰岛素信号通路、增强胰岛素作用的药物。噻唑烷二酮类药物是临床上广泛应用的胰岛素增敏剂类降糖药。那么,噻唑烷二酮类是如何提高胰岛素敏感性从而达到降糖目的的呢？     

噻唑烷二酮类药物致不良反应文献分析

目的：分析噻唑烷二酮类药物不良反应的发生情况及临床特点,为合理用药提供参考。方法：检索噻唑烷二酮类在中国上市以来CNKI、VIP数据库收载的不良反应文献进行统计分析。结果：噻唑烷二酮类不良反应的文献报道共24例次;年龄60岁以上发生率较高(16例,66.7％);多发生在用药1月后(11例,45.8%);分别涉及红细胞异常、心血管系统一般损害、代谢和营养障碍、肝胆系统损害等多个系统/器官。结论：临床合理使用噻唑烷二酮类药物的同时,加强用药监测,以减少不良反应的发生。     

Insulin resistance and PPAR insulin sensitizers

Drugs that reverse insulin resistance are of importance as insulin resistance is frequently associated with type 2 diabetes. The three peroxisome proliferator-activated receptors (PPARs) PPARalpha, PPAR90 and PPARgamma are essential for the actions of the many insulin sensitizers. PPARalpha activation enhances free fatty acid oxidation and potentiates anti-inflammatory effects, while PPARgamma is essential for normal adipocyte differentiation and proliferation, as well as fatty acid uptake and storage. Thiazolidinediones (TZDs) are selective ligands of PPARgamma and act as insulin sensitizers. TZDs also suppress free fatty acids via the inhibition of lipolysis in adipose tissue. Insulin sensitizers currently under development include partial PPARgamma agonists and antagonists, and dual PPARalpha/PPARgamma agonists. Given that TZDs show anti-inflammatory, anti-oxidant and antiprocoagulant properties in addition to their insulin sensitizing and antilipotoxic properties, a case may be made for initiating TZD therapy early in the treatment of type 2 diabetes, particularly in those patients at risk of cardiovascular disease. TZDs may also be an important therapeutic option in the treatment of metabolic syndrome.     

Thiazolidinediones: effects on insulin resistance and the cardiovascular system

Thiazolidinediones (TZDs) have been used for the treatment of hyperglycaemia in type 2 diabetes for the past 10 years. They may delay the development of type 2 diabetes in individuals at high risk of developing the condition, and have been shown to have potentially beneficial effects on cardiovascular risk factors. TZDs act as agonists of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) primarily in adipose tissue. PPAR-gamma receptor activation by TZDs improves insulin sensitivity by promoting fatty acid uptake into adipose tissue, increasing production of adiponectin and reducing levels of inflammatory mediators such as tumour necrosis factor-alpha (TNF-alpha), plasminogen activator inhibitor-1(PAI-1) and interleukin-6 (IL-6). Clinically, TZDs have been shown to reduce measures of atherosclerosis such as carotid intima-media thickness (CIMT). However, in spite of beneficial effects on markers of cardiovascular risk, TZDs have not been definitively shown to reduce cardiovascular events in patients, and the safety of rosiglitazone in this respect has recently been called into question. Dual PPAR-alpha/gamma agonists may offer superior treatment of insulin resistance and cardioprotection, but their safety has not yet been assured.     

PPAR- γ agonist in treatment of diabetes: cardiovascular safety considerations

The peroxisome proliferator-activated receptors (PPARs) are nuclear fatty acid receptors, which contain a type II zinc finger DNA binding motif and a hydrophobic ligand binding pocket. These receptors are thought to play an important role in metabolic diseases such as obesity, insulin resistance, and coronary artery disease. Three subtypes of PPAR receptors have been described: PPARα, PPARδ/β, and PPARγ. PPARα is found in the liver, muscle, kidney, and heart. In the liver, its role is to up-regulate genes involved in fatty acid uptake, binding, β-oxidation and electron transport, and oxidative phosphorylation in subcutaneous fat but not in skeletal muscle. PPARδ/β is expressed in many tissues but markedly in brain, adipose tissue, and skin. PPARγ has high expression in fat, low expression in the liver, and very low expression in the muscle. The thiazolidinediones (TZD) are synthetic ligands of PPARγ. By activating a number of genes in tissues, PPARγ increases glucose and lipid uptake, increases glucose oxidation, decreases free fatty acid concentration, and decreases insulin resistance. Although, there is a rationale for the use of TZDs in patients with type 2 diabetes mellitus, clinical studies have produced conflicting data. While currently used TZDs are clearly associated with heart failure (HF) worsening; with regards to cardiovascular outcomes, pioglitazone seems to be related to a trend toward reduction in cardiovascular morbidity and mortality, whereas rosiglitazone may actually increase risk of cardiovascular events. We review the existing literature on TZDs and discuss role and cardiovascular safety of these agents for the contemporary treatment of diabetes. Other side effects of these agents i.e. increase in osteoporosis and possible risk of bladder cancer is also discussed.     

The role of metformin and thiazolidinediones in the regulation of hepatic glucose metabolism and its clinical impact

Fasting hyperglycemia in type 2 diabetes mellitus (T2DM) results from elevated endogenous glucose production (EGP), which is mostly due to augmented hepatic gluconeogenesis. Insulin-resistant humans exhibit impaired insulin-dependent suppression of EGP and excessive hepatic lipid storage (steatosis), which relates to abnormal supply of free fatty acids (FFA) and energy metabolism. Only two glucose-lowering drug classes, the biguanide metformin and the thiazolidendiones (TZDs), exert insulin- and glucagon-independent hepatic effects. Preclinical studies suggest that metformin inhibits mitochondrial complex I. TZDs, as peroxisome proliferator-activated receptor (PPAR) γ-agonists, predominantly reduce the flux of FFA and cytokines from adipose tissue to the liver, but could also directly inhibit mitochondrial complex I. Although both metformin and TZDs improve fasting hyperglycemia and EGP in clinical trials, only TZDs decrease steatosis and peripheral insulin resistance. More studies are required to address their effects on hepatocellular energy metabolism with a view to identifying novel targets for the treatment of T2DM.     

Thiazolidinediones and type 2 diabetes: from cellular targets to cardiovascular benefit

The prevalence of type 2 diabetes is evolving globally at an alarming rate. This fact is mainly the result of our global lifestyle "modernization" that has resulted in overweight and obesity. Dysfunction of peroxisome proliferator activated receptor-gamma (PPAR-gamma) has been implicated in the development of insulin resistance, while a reduce expression of many PPAR-gamma regulated genes has been observed in an obese diabetic state. Thiazolidinediones (TZDs) are potent exogenous agonists of PPAR-gamma, which augment the effects of insulin to its cellular targets and mainly at the level of adipose tissue. Preclinical and clinical studies have demonstrated that apart from their glucose-lowering activity, these drugs also regulate the production of inflammatory mediators by cells that play a pivotal role in the pathogenesis of atherosclerosis. This paper summarizes the evolving changes observed in an enlarged adipose tissue and examines the activity of TZDs in their main cellular targets. It also discusses whether these cellular pleiotropic effects can result in a clinically meaningful outcome, in terms of cardiovascular benefit, in this population.     

Differential effects of rexinoids and thiazolidinediones on metabolic gene expression in diabetic rodents

Both retinoid X receptor (RXR)-selective agonists (rexinoids) and thiazolidinediones (TZDs), PPAR (peroxisome proliferator-activated receptor)-gamma-specific ligands, produce insulin sensitization in diabetic rodents. In vitro studies have demonstrated that TZDs mediate their effects via the RXR/PPAR-gamma complex. To determine whether rexinoids lower hyperglycemia by activating the RXR/PPAR-gamma heterodimer in vivo, we compared the effects of a rexinoid (LG100268) and a TZD (rosiglitazone) on gene expression in white adipose tissue, skeletal muscle, and liver of Zucker diabetic fatty rats (ZDFs). In adipose tissue, rosiglitazone decreased tumor necrosis factor-alpha (TNF-alpha) mRNA and induced glucose transporter 4 (GLUT4), muscle carnitine palmitoyl-transferase (MCPT), stearoyl CoA desaturase (SCD1), and fatty acid translocase (CD36). In contrast, LG100268 increased TNF-alpha and had no effect or suppressed the expression of GLUT4, MCPT, SCD1, and CD36. In liver, the rexinoid increased MCPT, SCD1, and CD36 mRNAs, whereas rosiglitazone induced only a small increase in CD36. In skeletal muscle, rosiglitazone and LG100268 have similar effects; both increased SCD1 and CD36 mRNAs. The differences in the pattern of genes induced by the rexinoids and the TZDs in diabetic animals found in these studies suggests that these compounds may have independent and tissue-specific effects on metabolic control in vivo.     

Recent findings concerning thiazolidinediones in the treatment of diabetes

Thiazolidinediones (TZDs) are peroxisomal proliferator-activated receptor (PPAR)-gamma agonists. They increase insulin action through several mechanisms including: stimulation of the expression of genes that increase fat oxidation and lower plasma free fatty acid levels; increased expression, synthesis and release of adiponectin; and stimulation of adipocyte differentiation resulting in more and smaller fat cells. TZDs lower blood sugar comparably to sulfonylureas and metformin. The clinical use of TZDs is limited due to the long duration of time required before they reach their full blood sugar-lowering action (3-4 months) and adverse effects such as fluid retention, resulting in excessive weight gain and occasionally in peripheral and/or pulmonary oedema and congestive heart failure. Troglitazone, a TZD that has since been removed from the market because of hepatoxicity, has been demonstrated to decrease the progression from normal or impaired glucose tolerance to overt Type 2 diabetes mellitus. Pioglitazone, another TZD, marginally decreased the incidence of cardiovascular complications in patients with Type 2 diabetes mellitus (PROactive trial). Other, as yet, unapproved uses of TZDs include: non-alcoholic fatty liver disease, in which TZDs reduced hepatic fat accumulation and improved liver function tests; polycystic ovary syndrome, where TZDs improved ovulation, hirsutism and endothelial dysfunction; and lipodystrophies, where TZDs increased body fat (marginally) and decrease liver size. Lastly, because PPAR-alpha and -gamma agonists improve atherosclerotic vascular disease and insulin sensitivity, respectively, dual PPAR-alpha/gamma agonists, which are currently undergoing clinical trials, may be useful in treating patients with the metabolic syndrome.     

Thiazolidinediones in the treatment of Type 2 diabetes

In the last few years there has been an explosion of research that has improved our understanding of the pathogenesis of Type 2 diabetes mellitus (DM-2) and has led to the development of new oral antidiabetic drugs. Thiazolidinediones (TZDs) are the newest of these antidiabetic agents. TZDs are insulin sensitisers that depend on the presence of insulin for their action. They target insulin resistance, which is thought to play a central role in DM-2 and the associated metabolic syndrome characterised by central obesity, hypertension, dyslipidemia and hypercoagulability, all leading to increased cardiovascular morbidity and mortality. As a result, TZDs have the potential to improve other conditions associated with the metabolic syndrome, in addition to their glycaemic action. TZDs act by activating peroxisome proliferator-activated receptor (PPAR) γ, a nuclear receptor implicated not only in lipid and glucose metabolism but other physiological functions as well. TZDs may have wide clinical applications beyond DM-2, as they can potentially be used to treat other conditions associated with insulin resistance and PPAR-γ receptors, such as impaired glucose tolerance, polycystic ovarian syndrome and HIV lipodystrophy.     

New solutions for type 2 diabetes mellitus: the role of pioglitazone

Type 2 diabetes mellitus remains a significant burden to the Canadian healthcare system. Over 2 million Canadians have diabetes, with 85 to 90% having type 2 diabetes. Insulin resistance is a major pathophysiological mechanism in the development of type 2 diabetes. Insulin resistance can be defined as an impaired biological response to the metabolic and/or mitogenic effects of either exogenous or endogenous insulin. As a consequence of insulin resistance, type 2 diabetes is characterised by decreased glucose transport and utilisation at the level of muscle and adipose tissue and increased glucose production by the liver. The traditional oral agents used to treat type 2 diabetes clearly do not address the underlying insulin resistance responsible for the development of diabetes. Thiazolidinediones (TZDs) represent a relatively new class of oral hypoglycaemic medications that have been shown to reverse some of the metabolic processes believed responsible for the development of insulin resistance and, ultimately, type 2 diabetes. Research has demonstrated that TZDs activate peroxisome proliferator activator receptors, in particular, the gamma-receptor isoform. Pioglitazone is a TZD that reduces plasma glucose levels by increasing peripheral glucose utilisation and decreasing hepatic glucose production. Clinical studies with pioglitazone have demonstrated the following: absolute reductions in glycosylated haemoglobin of 0.8 to 2.6%; reductions in fasting plasma glucose of 1.7 to 4.4 mmol/L; an increase in high density lipoprotein cholesterol of 8.7 to 12.6%; and a decrease in triglycerides of 18.2 to 26.0%, with no significant effects on low density lipoprotein or total cholesterol.