HIV Protease Inhibitors and Glucose Transport

描述(申请人提供)：HIV蛋白水解酶抑制剂的出现 (PI)疗法是治疗艾滋病毒感染的一大进步。组合在一起 逆转录酶抑制剂和联合用药治疗HIV感染者 PiS(强化抗逆转录病毒疗法，iart)已被证明可以延缓发病。 治疗明显的疾病并延长生存时间。目前的指南建议使用 国际抗逆转录病毒药物疗法用于治疗所有新诊断的艾滋病毒感染病例。 不幸的是，iART与许多新陈代谢的发展有关。 异常，包括外周性骨营养不良、高脂血症、胰岛素 抵抗、葡萄糖不耐受和2型糖尿病。报告的发病率 接受PI治疗的2型糖尿病患者的发病率至少是后者的10倍 在一般年龄和性别匹配的人群中，这一数字尤其令人震惊 考虑到患者群体的相对年轻年龄和 治疗开始后糖尿病发作的速度较快。PI最近一直在 显示能迅速和选择性地抑制GLUT4的活性， 胰岛素反应性葡萄糖转运体，一种可以直接解释 胰岛素抵抗与胰岛素相关性糖尿病发病率的增加 心理治疗。这项提议的长期目标是澄清这种关系 PIs对GLUT4的影响及其相关代谢异常 并确定PIs对GLUT4影响的机制 活动。为了实现这些目标，将实现以下具体目标 追查： 1)确定PIs对全身葡萄糖处置的急性影响和 葡萄糖在骨骼肌中的运输。这一目标将直接考验 假设PERS通过以下途径急性诱导全身胰岛素抵抗 抑制骨骼肌GLUT4。 2)确定PI是否通过以下方式抑制胰岛素刺激的葡萄糖转运 直接与GLUT4结合。这个目的将确定PI效应是否因此而产生 与GLUT4竞争性或非竞争性结合或与分子结合 参与质膜GLUT4活性的调节。 3)确定PI是否抑制GLUT异构体的活性 GLUT4.这一目标将解决一个潜在的重要临床问题： PIS，作为抑制其他8个已知过剩中的一个或多个的结果 异构体，可能具有尚未检测到的医源性作用。 4)确定GLUT4与PI相互作用的结构决定因素。这 AIM将确定参与其中的特定GLUT4结构域和氨基酸残基 它预测会与PI结合。

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.