ROLE OF PIOGLITAZONE IN THE TREATMENT OF NON-ALCOHOLIC STEATOHEPATITIS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 目的：探讨吡格列酮对糖耐量减低或2型糖尿病(T2 DM)合并非酒精性脂肪性肝炎(NASH)的治疗作用。NASH是一种以血浆转氨酶升高和肝脏组织病理学改变为特征的疾病，其特征是肝细胞脂肪变性、慢性炎症和纤维化。吡格列酮是一种新的噻唑烷二酮(TZD)，已被证明是治疗T2 DM安全有效的药物。NASH影响大约10%-20%的肥胖和2型糖尿病受试者。虽然NASH的发病机制尚不清楚，但已有共识认为胰岛素抵抗及其相关的脂代谢异常在肝脏脂肪堆积的发展中起关键作用，而肿瘤坏死因子-α是肝脏损伤进展的主要介质。目前，NASH还没有令人满意的治疗方法。 研究计划和方法：吡格列酮改善T2 DM患者的胰岛素敏感性和血糖控制，激活与脂肪合成有关的基因，导致血浆游离脂肪酸(FFA)和甘油三酯降低。TZDS还可以减少甘油三酯在肝脏、肌肉和内脏脂肪中的过度蓄积，并拮抗肿瘤坏死因子-α的代谢效应，后者被认为在NASH的发病机制中发挥核心作用。为了评估这一假设，我们计划在一项随机、双盲、安慰剂对照试验中，用吡格列酮治疗糖耐量受损(IGT)或T2 DM患者24周。将测量三个主要终点：(A)肝脏活检评估的组织学反应；(B)肝脏磁共振波谱(MRS)测量的肝脏脂肪含量；以及(C)肝脏胰岛素敏感性和葡萄糖代谢的研究，使用双示踪技术(注射3-3H葡萄糖结合放射性标记的1-14C葡萄糖口服葡萄糖负荷)。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. OBJECTIVE: The purpose of this study is to determine the role of pioglitazone in the treatment of nonalcoholic steatohepatitis (NASH) in patients with glucose intolerance or type 2 diabetes mellitus (T2DM). NASH is a disease characterized by elevated plasma aminotransferases and histopathological changes in liver characterized by hepatocellular steatosis, chronic inflammation and fibrosis. Pioglitazone, a new thiazolidinedione (TZD), has proven to be safe and effective for the treatment of T2DM. NASH affects approximately 10-20% of obese and type 2 diabetic subjects. While the pathogenesis of NASH is poorly understood, there is consensus that insulin resistance and its associated abnormalities in lipid metabolism play a key role in the development of liver fat accumulation, and TNF-alpha is a major mediator in the progression of liver damage. Currently, there is no satisfactory therapy for NASH. RESEARCH PLAN AND METHODS: Pioglitazone improves insulin sensitivity and glycemic control in patients with T2DM activating genes involved in lipid synthesis, causing a reduction in plasma free fatty acid (FFA) and triglycerides. TZDs also decrease excessive triglyceride accumulation in liver, muscle, and visceral fat and antagonize the metabolic effects of TNF-alpha, which is believed to play a central role in the pathogenesis of NASH. In order to evaluate this hypothesis, we plan to treat patients with impaired glucose tolerance (IGT) or T2DM for 24 weeks with pioglitazone in a randomized, double-blinded, placebo-controlled trial. Three major endpoints will be measured: (a) histologic response assessed by liver biopsy; (b) liver fat content, measured by liver magnetic resonance spectroscopy (MRS); and (c) hepatic insulin sensitivity and glucose metabolism, studied using a double-tracer technique (infusion of 3-3H glucose combined with an oral glucose load radiolabeled with 1-14C glucose).