ROLE OF PIOGLITAZONE IN THE TREATMENT OF NONALCOHOLIC STEATOHEPATITIS

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。目的：本研究的目的是确定吡格列酮在治疗糖耐受不良或2型糖尿病（T2DM）患者的非酒精性脂肪性肝炎（NASH）中的作用。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，以肝细胞脂肪变性、慢性炎症和纤维化为特征。吡格列酮是一种新的噻唑烷二酮（TZD），已被证明是治疗2型糖尿病的安全有效的药物。NASH影响约10-20%的肥胖和2型糖尿病患者。虽然NASH的发病机制尚不清楚，但人们一致认为，胰岛素抵抗及其相关的脂质代谢异常在肝脏脂肪积累的发展中起着关键作用，而tnf - α是肝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T2DM患者的胰岛素敏感性和血糖控制，激活参与脂质合成的基因，导致血浆游离脂肪酸（FFA）和甘油三酯的降低。TZDs还可以减少肝脏、肌肉和内脏脂肪中过多的甘油三酯积累，并拮抗tnf - α的代谢作用，这被认为在NASH的发病机制中起核心作用。为了评估这一假设，我们计划在一项随机、双盲、安慰剂对照试验中使用吡格列酮治疗糖耐量受损（IGT）或T2DM患者24周。将测量三个主要终点：(a)通过肝活检评估组织学反应；(b)肝脏脂肪含量，采用肝脏磁共振波谱法（MRS）测定；(c)肝脏胰岛素敏感性和葡萄糖代谢，采用双示踪技术（3-3H葡萄糖输注与1-14C葡萄糖放射性标记的口服葡萄糖负荷联合）进行研究。

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).