Genetic and Cellular Mechanisms of NAFLD and Hepatic Insulin Resistance

描述(由申请人提供)：2型糖尿病(T2 DM)、非酒精性脂肪性肝病(NAFLD)及其相关的并存疾病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证实，NAFLD在成人和儿童肝脏胰岛素抵抗和T2 DM的发病机制中发挥了关键作用。本课题组在转基因和基因敲除小鼠中的补充研究阐明了与NAFLD相关的肝脏胰岛素抵抗的分子机制。在这笔R-24赠款中，一组跨学科和独立的调查人员，他们有既定的合作记录，将解决关于这两种日益普遍的疾病之间关系的基本问题。具体地说，这个跨学科的科学家团队将研究以下复杂和相关的问题：谁会患上NAFLD，NAFLD是如何导致肝脏胰岛素抵抗的，是什么触发了T2 DM患者肝脏糖异生的增加，以及这些变化中的许多是如何在Roux-en-Y胃分流术(RYGB)后，甚至在体重大幅下降之前迅速解决的？具体地说，我们将研究：1)与NAFLD和T2 DM相关的肝脏胰岛素抵抗和肝脏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机制中的作用。3)Roux-en-Y胃旁路术后逆转胰岛素抵抗和T2 DM的细胞和分子机制。这项建议建立在研究人员之间跨学科合作的既定记录以及开发和实施新的最先进的MRS/MRI和稳定同位素方法以非侵入性评估人类肝脏葡萄糖和脂肪代谢的25年历史的基础上。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T2 DM发病机制的理解。 公共卫生相关性：这一跨学科的团队科学计划将研究2型糖尿病和非酒精性脂肪性肝病的发病机制，这两种疾病正迅速成为21世纪成人和儿童面临的最大全球健康挑战。

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. PUBLIC HEALTH RELEVANCE: This interdisciplinary team science program will examine the pathogenesis of type 2 diabetes mellitus and non alcoholic fatty liver disease, which are rapidly emerging as the greatest global health challenges of the twenty-first century in both adults and children.