HIV Protease Inhibitors: Insulin Resistance & Insulysin

HIV 蛋白酶抑制剂：胰岛素抵抗

• 批准号: 7062630
• 负责人: FREDERICK G HAMEL
• 金额: $ 21.48万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7062630
• 关键词: 3T3 cells; adipocytes; amprenavir; antiAIDS agent; disease /disorder etiology; drug adverse effect; endocrine pharmacology; enzyme activity; indinavir; insulin sensitivity /resistance; laboratory rat; lipid metabolism; liver cells; metalloendopeptidases; molecular pathology; pharmacokinetics; protease inhibitor; protein metabolism; ritonavir; saquinavir; stavudine

DESCRIPTION (provided by applicant): HIV protease inhibitors are beneficial to HIV patients, however, lipodystrophy, hyperlipidemia, and diabetes are among the significant clinical problems associated with their use. Human and animal studies indicate that insulin resistance is a key factor in the development of these metabolic sequelae, but the etiology is unknown. An endogenous protease that is known to be involved in insulin action that is also affected by the protease inhibitors would be a likely target candidate. Insulin-degrading enzyme (also called insulysin) is such a protein. Insulin-degrading enzyme is involved in mediating insulin action on protein degradation and peroxisomal fatty acid oxidation. The objective of the studies proposed here is to determine which HIV protease inhibitors inhibit insulin degradation by insulin-degrading enzyme, and how that inhibition affects protein and lipid metabolism. It is hypothesized that HIV protease 1 inhibitors induce insulin resistance and alter protein and lipid metabolism by inhibiting the action of insulin-degrading enzyme. The following four Specific Aims will address this hypothesis: 1) Identify HIV protease inhibitors that inhibit insulin-degrading enzyme in vitro and in cells; 2) Evaluate the capacity of HIV protease inhibitors to alter insulin pharmacokinetics in vivo\ 3) Determine the extent to which HIV protease inhibitors alter the inhibition of protein metabolism by insulin; and 4) Determine the extent to which HIV protease inhibitors alter insulin- induced changes in lipid metabolism. Enzyme preparations will be used to characterize the effect of HIV protease inhibitors on insulin-degrading enzyme and its function. Cell culture will be used to demonstrate these actions in whole cell, and their consequences on insulin action. Animals will be treated with HIV protease inhibitors to extend these studies and verify they are physiologically relevant. Understanding how protease inhibitors cause insulin resistance is key to helping HIV/AIDS patients. If insulin-degrading enzyme is involved, HIV protease inhibitors could be developed or screened for minimal reactivity with IDE.

描述（由申请人提供）：HIV蛋白酶抑制剂对HIV患者有益，但是，脂肪营养不良，高脂血症和糖尿病是与使用相关的重要临床问题之一。人类和动物研究表明，胰岛素抵抗是这些代谢后遗症发展的关键因素，但病因尚不清楚。已知参与胰岛素作用的内源性蛋白酶也可能是蛋白酶抑制剂的影响。胰岛素降解酶（也称为胰岛素）就是这样的蛋白质。胰岛素降解酶参与介导胰岛素对蛋白质降解和过氧化物酶体脂肪酸氧化的作用。这里提出的研究的目的是确定哪些HIV蛋白酶抑制剂通过胰岛素降解酶抑制胰岛素降解，以及该抑制作用如何影响蛋白质和脂质代谢。假设HIV蛋白酶1抑制剂通过抑制胰岛素降解酶的作用来诱导胰岛素抵抗并改变蛋白质和脂质代谢。以下四个特定目的将解决这一假设：1）确定在体外和细胞中抑制胰岛素降解酶的HIV蛋白酶抑制剂； 2）评估HIV蛋白酶抑制剂在体内改变胰岛素药代动力学的能力\ 3）确定HIV蛋白酶抑制剂改变胰岛素对蛋白质代谢的抑制程度； 4）确定HIV蛋白酶抑制剂改变胰岛素诱导的脂质代谢变化的程度。酶制剂将用于表征HIV蛋白酶抑制剂对胰岛素降解酶及其功能的影响。细胞培养将用于在整个细胞中证明这些作用及其对胰岛素作用的后果。动物将接受HIV蛋白酶抑制剂的治疗，以扩展这些研究并验证它们在生理上相关。了解蛋白酶抑制剂如何引起胰岛素抵抗是帮助艾滋病毒/艾滋病患者的关键。如果涉及胰岛素降解酶，则可以开发或筛选HIV蛋白酶抑制剂，以使IDE的反应性最小。