ROLE OF PIOGLITAZONE IN THE TREATMENT OF NON-ALCOHOLIC STEATOHEPATITIS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 目的：本研究的目的是确定吡格列酮在治疗葡萄糖耐受不良或2型糖尿病（T2 DM）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变化为特征的疾病，其特征在于肝细胞脂肪变性、慢性炎症和纤维化。 吡格列酮是一种新的噻唑烷二酮（TZD），已被证明是安全和有效的治疗2型糖尿病。 NASH影响大约10-20%的肥胖和2型糖尿病受试者。 虽然NASH的发病机制知之甚少，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蓄积的发展中起关键作用，而TNF-α是肝损伤进展的主要介质。 目前，对于NASH没有令人满意的治疗。 研究方法：吡格列酮可改善T2 DM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）和甘油三酯降低。 TZD还可减少肝脏、肌肉和内脏脂肪中甘油三酯的过度积累，并拮抗TNF-α的代谢作用，TNF-α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）通过肝脏活检评估的组织学缓解;（B）通过肝脏磁共振波谱（MRS）测量的肝脏脂肪含量;和（c）使用双示踪剂技术（输注3- 3 H葡萄糖联合口服1- 14 C葡萄糖放射性标记的葡萄糖负荷）研究的肝脏胰岛素敏感性和葡萄糖代谢。

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).