Mechanism of Fat Induced Hepatic Insulin Resistance

脂肪诱导肝胰岛素抵抗的机制

• 批准号: 6637759
• 负责人: VARMAN T SAMUEL
• 金额: $ 12.56万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6637759
• 关键词: Adenoviridae; acetyl coA; biological signal transduction; clinical research; dietary lipid; enzyme activity; gas chromatography mass spectrometry; genetic transcription; gluconeogenesis; glucose clamp technique; glucose transport; glycogen synthase; glycogenesis; human subject; hyperinsulinism; insulin receptor; insulin sensitivity /resistance; laboratory rat; liver metabolism; noninsulin dependent diabetes mellitus; nuclear magnetic resonance spectroscopy; pathologic process; patient oriented research; phosphatidylinositol 3 kinase; pyruvate carboxylase; striated muscles; transfection /expression vector

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.

描述（由申请人提供）：在本次 K23 奖任职期间，Samuel 博士将致力于研究脂肪诱导的肝脏胰岛素抵抗的机制。 他将通过教学课程和实践经验培养人体体内代谢研究的技能。 在专家导师的指导下，他将接受核磁共振波谱学和GC/MS方法学方面的培训。通过这些技术，他将探索肝脏脂肪堆积、胰岛素抵抗和 2 型糖尿病（这种疾病在美国人中越来越常见）之间的关系。 2 型糖尿病影响大约 6% 的人口，每年造成 1000 亿美元的损失。尽管肝脏胰岛素抵抗是这种疾病的主要特征，但其机制尚未确定。人们越来越认识到许多2型糖尿病患者存在肝脏脂肪堆积。鉴于肌肉脂肪积累导致外周胰岛素抵抗，我们假设肝脏脂肪积累导致肝脏胰岛素抵抗。我们预测肝脏脂肪积累将通过限制 IRS2 激活 PI3 激酶的能力来损害胰岛素信号级联。这将损害胰岛素刺激糖原合成的能力。我们还假设，由于丙酮酸羧化酶活性增加和 PEP-CK 转录增加，肝脏脂肪积累将导致糖异生增加。两者都是糖异生中的关键调节酶。我们将测试这些假设，瘦受试者食用高脂肪饮食。我们预测脂肪会先于肌肉在肝脏内积聚。通过 [13C] NMR 测量糖原分解、糖异生和肝脏胰岛素敏感性。通过 fiet 诱导的肝脂肪变性的补充大鼠模型，我们可以检查信号级联、酶活性和基因转录的变化。利用腺病毒将 UCP2 基因转移到大鼠肝脏中，我们将确定增加的解偶联是否可以预防饮食诱导的肝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积累是否会增加肝脏糖异生。