Genetic and Cellular Mechanisms of NAFLD and Hepatic Insulin Resistance

描述（由申请人提供）：2型糖尿病（T2DM），非酒精性脂肪性肝病（NAFLD）及其相关的合并症，正在成为美国最重要的医疗保健问题。我们小组最近的研究已经确定了NAFLD在成人和儿童肝脏胰岛素抵抗和T2DM发病机制中的关键作用。本小组在转基因小鼠和基因敲除小鼠的补充研究阐明了NAFLD相关肝脏胰岛素抵抗的分子机制。在这项R-24拨款中，一个由跨学科和独立的研究人员组成的团队，他们有良好的合作记录，将解决有关这两种日益普遍的疾病之间关系的基本问题。具体来说，这个跨学科的科学家团队将研究复杂的相关问题，NAFLD是谁发展的，NAFLD是如何引起肝脏胰岛素抵抗的，是什么触发了T2DM患者肝脏糖异生的增加，以及这些变化是如何在Roux-en-Y胃旁路手术（RYGB）后迅速解决的，甚至在体重显著减轻之前。具体来说，我们将研究：1)与NAFLD和T2DM相关的肝脏胰岛素抵抗和肝糖异生增加的分子机制。2)载脂蛋白C3特异性基因变异在NAFLD和肝脏胰岛素抵抗发病中的作用。3) Roux-en-Y胃旁路术后胰岛素抵抗和T2DM逆转的细胞和分子机制。该提案建立在研究者之间跨学科合作的既定记录以及25年开发和实施新型最先进的MRS/MRI和稳定同位素方法的历史上，用于无创评估人类肝脏葡萄糖和脂质代谢。预计这些研究的结果将改变我们目前对NAFLD、肝脏胰岛素抵抗和T2DM发病机制的理解范式。

DESCRIPTION (provided by applicant): Type 2 diabetes mellitus (T2DM), Non Alcoholic Fatty Liver Disease (NAFLD), and their associated co- morbidities, are emerging as the most important health care problems in the USA. Recent studies by our group have established a key role for NAFLD in the pathogenesis of hepatic insulin resistance and T2DM in both adults and children. Complementary studies in transgenic and gene knockout mice by our group have elucidated the molecular mechanism for hepatic insulin resistance associated with NAFLD. In this R-24 grant a team of interdisciplinary and independent investigators, who have an established track record of collaboration, will address fundamental questions regarding the relationship between these two increasingly prevalent conditions. Specifically, this team of interdisciplinary scientists will examine the complex and related problems of who develops NAFLD, how does NAFLD cause hepatic insulin resistance, what triggers the increased hepatic gluconeogenesis in T2DM, and how do many of these changes rapidly resolve following Roux-en-Y gastric bypass (RYGB), even before substantial weight loss? Specifically we will examine: 1) The molecular mechanisms of hepatic insulin resistance and increased hepatic gluconeogenesis associated with NAFLD and T2DM. 2) The role of specific gene variants in apolipoprotein C3 in the pathogenesis of NAFLD and hepatic insulin resistance. 3) The cellular and molecular mechanisms responsible for the reversal of insulin resistance and T2DM following Roux-en-Y gastric bypass. This proposal builds on an established track record of interdisciplinary collaboration among the investigators as well as a 25-year history of developing and implementing novel state-of-the-art MRS/MRI and stable isotope methodologies for noninvasively assessing hepatic glucose and lipid metabolism in humans. It is anticipated that the results from the proposed studies will shift the current paradigm in our understanding of the pathogenesis of NAFLD, hepatic insulin resistance and T2DM.