Mechanism of Fat Induced Hepatic Insulin Resistance

脂肪诱导肝胰岛素抵抗的机制

• 批准号: 6754421
• 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/6754421
• 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K23奖任期内，Samuel博士将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NMR光谱学和GC/MS方法学的培训。通过这些技术，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，这些疾病在美国越来越普遍。2型糖尿病影响约6%的人口，每年花费1000亿美元。虽然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。越来越多的人认识到许多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，肝脏脂肪蓄积将通过限制IRS 2激活PI 3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。我们还推测，肝脏脂肪蓄积将导致丙酮酸羧化酶活性增加和PEP-CK转录增加，从而导致肝脏异生增加。两者都是植物异生过程中的关键调控酶。我们将测试这些假设，瘦的受试者消耗高脂肪的饮食。我们预测，脂肪会在肝脏中积累，然后才是肌肉。用[13 C] NMR测量糖原分解、糖原生成和肝胰岛素敏感性。通过一个补充的大鼠脂肪肝模型，我们可以检测信号级联、酶活性和基因转录的变化。使用腺病毒转移UCP 2基因到大鼠肝脏，我们将确定是否增加解偶联预防饮食诱导的肝脂肪变性和胰岛素抵抗。最后，通过一种新的方法来直接测量肝再生，我们将确定肝脏脂肪积累是否会增加肝再生。