HIV Protease Inhibitors and Glucose Transport

HIV 蛋白酶抑制剂和葡萄糖转运

• 批准号: 6448798
• 负责人: MIKE M MUECKLER
• 金额: $ 27.1万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-01-15 至 2004-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6448798
• 关键词: AIDS therapy; Xenopus oocyte; drug adverse effect; drug interactions; glucose metabolism; glucose transport; glucose transporter; human immunodeficiency virus; indinavir; insulin sensitivity /resistance; medical complication; protease inhibitor; protein binding; protein protein interaction; protein structure function; reverse transcriptase inhibitors; striated muscles

DESCRIPTION (Provided by the applicant): The advent of HIV protease inhibitor (PI) therapy was a major advance in the treatment of HIV infection. Combined treatment of HIV-infected patients with reverse transcriptase inhibitors and PIs (intensive antiretroviral therapy, IART) has been shown to delay the onset of overt disease and to prolong survival. Current guidelines recommend the use of IART for the treatment of all newly diagnosed cases of HIV infection. Unfortunately, IART is associated with the development of numerous metabolic abnormalities, including peripheral lypodystrophy, hyperlipemia, insulin resistance, glucose intolerance, and type 2 diabetes. The reported incidence of type 2 diabetes in PI-treated patients is at least 10- fold greater than that in the general age- and sex-matched population and is particularly alarming considering the relatively young age of the patient populations and the rapidity of diabetes onset after the start of therapy. PIs have recently been shown to rapidly and selectively suppress the activity of Glut4, the insulin-responsive glucose transporter, an effect that can directly account for the insulin resistance and increased incidence of diabetes associated with PI therapy. The long-term goal of this proposal is to elucidate the relationship between the effect of PIs on Glut4 and the metabolic abnormalities associated with IART and to determine the mechanism of the effect of PIs on Glut4 activity. To accomplish these goals, the following specific aims will be pursued: 1) To determine the acute effect of PIs on whole body glucose disposal and glucose transport in skeletal muscle. This aim will directly test the hypothesis that Pls acutely induce whole-body insulin resistance via the inhibition of skeletal muscle Glut4. 2) To determine whether PIs suppress insulin-stimulated glucose transport by direct binding to Glut4. This aim will ascertain whether the PI effect is due to competitive or noncompetitive binding to Glut4 or binding to a molecule involved in the regulation of Glut4 activity in the plasma membrane. 3) To determine whether PIs suppress the activity of Glut isoforms other than Glut4. This aim will address a potentially important clinical issue: whether PIs, as a result of the inhibition of one or more of the other 8 known Glut isoforms, may have iatrogenic effects that have not yet been detected. 4) To determine the structural determinants of Glut4 interaction with PIs. This aim will identify specific Glut4 domains and amino acid residues involved in its predicted binding to PIs.

描述（由申请人提供）：HIV蛋白酶抑制剂的出现 （PI）治疗是艾滋病毒感染治疗的重大进步。合并 用逆转录酶抑制剂和 PIS（强化抗逆转录病毒疗法，IART）已显示出延迟发作 明显的疾病并延长生存。当前指南建议使用 IART治疗所有新诊断的HIV感染病例。 不幸的是，IART与众多代谢的发展有关 异常，包括外周脂肪营养不良，高脂症，胰岛素 电阻，葡萄糖不耐症和2型糖尿病。报告的发生率 PI-PI-治疗患者的2型糖尿病至少10倍 在一般年龄和性别匹配的人口中，特别令人震惊 考虑到患者人群的年龄相对年轻的年龄和 开始治疗后糖尿病发作的速度。 PI最近是 证明可以快速，有选择地抑制GLUT4的活性， 胰岛素反应性葡萄糖转运蛋白，可以直接考虑的效果 与PI相关的胰岛素抵抗和糖尿病的发生率增加 治疗。该提议的长期目标是阐明关系 PI对GLUT4的影响与相关的代谢异常之间 使用IART并确定PI对GLUT4的影响的机理 活动。为了实现这些目标，以下具体目标将是 追捕： 1）确定PI对全身葡萄糖处置的急性影响和 骨骼肌中的葡萄糖转运。这个目标将直接测试 急性通过急性诱导全身胰岛素抵抗的假设 抑制骨骼肌GLUT4。 2）确定PI是否抑制胰岛素刺激的葡萄糖转运 直接结合到Glut4。此目标将确定PI效应是否到期 与竞争性或非竞争性结合与GLUT4或与分子结合 参与质膜中GLUT4活性的调节。 3）确定PI是否抑制除了其他同工型的活性 glut4。这个目标将解决一个潜在的重要临床问题：是否 PIS，由于抑制了其他8个已知的Glut中的一个或多个 同工型，可能具有尚未检测到的医源作用。 4）确定GLUT4与PIS相互作用的结构决定因素。这 AIM将识别涉及的特定GLUT4域和氨基酸残基 它预测与PI的结合。