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).
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