Mechanism of Fat Induced Hepatic Insulin Resistance

描述（由申请人提供）：在本次K23奖任期内，Samuel博士将研究脂肪诱导的肝脏胰岛素抵抗机制。他将通过教学课程和实践经验来发展体内人体代谢研究的技能。在专家导师的指导下，他将接受核磁共振光谱和GC/MS方法的培训。利用这些技术，他将探索肝脏脂肪积累、胰岛素抵抗和2型糖尿病之间的关系，2型糖尿病在美国越来越普遍。2型糖尿病影响了大约6%的人口，每年花费1000亿美元。虽然肝脏胰岛素抵抗是本病的主要特征，但其机制尚不清楚。越来越多的人认识到，许多2型糖尿病患者有肝脏脂肪堆积。鉴于肌肉脂肪堆积导致外周胰岛素抵抗，我们假设肝脏脂肪堆积导致肝脏胰岛素抵抗。我们预测肝脏脂肪堆积会通过限制IRS2激活PI3激酶的能力而损害胰岛素信号级联。这将削弱胰岛素刺激糖原合成的能力。我们还假设肝脏脂肪堆积会导致糖异生增加，这是丙酮酸羧化酶活性增加和PEP-CK转录增加的结果。两者都是糖异生的关键调控酶。我们将测试这些假设，瘦的受试者吃高脂肪的食物。我们预测脂肪会先于肌肉在肝脏内堆积。用[13C]核磁共振测量糖原分解、糖异生和肝脏胰岛素敏感性。通过一个互补的大鼠肝脂肪变性模型，我们可以检测信号级联，酶活性和基因转录的变化。通过腺病毒将UCP2基因转移到大鼠肝脏，我们将确定是否增加解偶联可以防止饮食诱导的肝脏脂肪变性和胰岛素抵抗。最后，通过一种直接测量糖异生的新方法，我们将确定肝脏脂肪堆积是否会增加肝脏糖异生。

DESCRIPTION (provided by applicant): During the tenure of this K23 Award, Dr. Samuel will pursue the mechanism of fat-induced hepatic insulin resistance. He will develop the skills for in vivo human metabolic studies through didactic classes and practical experience. Under the guidance of expert mentors, he will receive training in NMR spectroscopy and GC/MS metholdogy. With these techniques, he will explore the relationship between hepatic fat accumulation, insulin resistance and type 2 diabetes mellitus, conditions that are increasingly common in American. Type 2 diabetes mellitus affects approximately 6% of the population and costs $100 billion dollars annually. Although hepatic insulin resistance is a cardinal feature of this disease, its mechanism is undetermined. There is growing appreciation that many patients with type 2 diabetes mellitus hae hepatic fat accumulation. Given that muscle fat accumulation causes peripheral insulin reisstance, we hypothesize that hepatic fat accumulation leads to hepatic insulin resistance. We predict that hepatic fat accumulation will impair the insulin signaling cascade by limiting the ability of IRS2 to activate PI3 kinase. This will impair the ability of insulin to stimulate glycogen synthesis. We also hypothesize that hepatic fat accumulation will lead to increased gluconeogenesis as a result of increased pyruvate carboxylase activity and increase transcription of PEP-CK. Both are key regulatory enzymes in gluconeogenesis. We will tests these hypotheses, lean subjects consuming a high fat diet. We predict that fat will accumulate within the liver prior to the muscle. With [13C] NMR measures of glycogenolysis, gluconeogenesis and hepatic insulin sensitivity. Through a complementary rat model of fiet induced hepatic steatosis we can examine changes in the signaling cascade, enzyme activity and gene transcription. Using adenoviral transfer of the UCP2 gene into rat livers, we will determine if increased uncoupling prevents diet induced hepatic steatosis and insulin resistance. Finally, with a novel method to directly measure gluconeogenesis, we will determine if hepatic fat accumulation increases hepatic gluconeogenesis.