HIV Protease Inhibitors & Glucose Transport

描述(由申请人提供)：HIV蛋白酶抑制剂(PI)疗法的出现是HIV感染治疗的一个重大进步。逆转录酶抑制剂和PIs(高效抗逆转录病毒疗法，HAART)联合治疗HIV感染患者已被证明可以推迟显性疾病的发生，延长生存期。目前的指南建议使用HAART治疗所有新诊断的艾滋病毒感染病例。不幸的是，HAART与许多代谢异常的发展有关，包括外周性脂肪营养不良、高脂血症、胰岛素抵抗、葡萄糖耐量减低和2型糖尿病。在接受PI治疗的患者中，报告的2型糖尿病发病率至少是一般年龄和性别匹配人群中的十倍，考虑到患者群体的相对年轻和开始治疗后糖尿病的快速发病，这一点尤其令人担忧。PI已被证明能迅速和选择性地抑制GLUT4的活性，GLUT4是胰岛素反应性葡萄糖转运体，这种作用导致胰岛素抵抗和与PI治疗相关的糖尿病发病率增加。此外，PI介导的抑制葡萄糖转运到胰岛β细胞似乎减少了葡萄糖刺激的胰岛素分泌，这很可能也是导致显性糖尿病发生的原因之一。这些观察结果支持一种全球假说，即PI与葡萄糖转运体的直接结合导致一系列生化扰动，最终导致PI相关的代谢综合征。这项建议的长期目标是进一步探索这一假说，并确定PI对葡萄糖转运活性的影响机制。 为实现这些目标，将实现以下具体目标： 1)验证PI通过直接与GLUT4结合来抑制胰岛素刺激的葡萄糖转运的假设。如果这一假设被交联研究证实，GLUT4与PI相互作用的结构决定因素将通过分析嵌合和突变的葡萄糖转运蛋白来定位。 2)验证PI介导的葡萄糖转运抑制通过抑制脂肪生成和/或促进脂肪细胞凋亡直接导致脂肪营养不良的假说。

DESCRIPTION (provided by 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 (Highly Active Antiretroviral Therapy, HAART) has been shown to delay the onset of overt disease and to prolong survival. Current guidelines recommend the use of HAART for the treatment of all newly diagnosed cases of HIV infection. Unfortunately, HAART is associated with the development of numerous metabolic abnormalities, including peripheral lipodystrophy, hyperlipemia, insulin resistance, glucose intolerance, and type 2 diabetes. The reported incidence of type 2 diabetes in PI -treated patients is at least ten-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 been shown to rapidly and selectively suppress the activity of Glut4, the insulin-responsive glucose transporter, an effect that contributes to the insulin resistance and increased incidence of diabetes associated with PI therapy. Additionally, PI-mediated inhibition of glucose transport into pancreatic beta cells appears to reduce glucose-stimulated insulin secretion, which most likely also contributes to the development of overt diabetes. These observations support a global hypothesis whereby the direct binding of PIs to glucose transporters leads to a constellation of biochemical perturbations that ultimately results in the PI-associated metabolic syndrome. The long-term goal of this proposal is to further explore this hypothesis and to determine the mechanism of the effect of PIs on glucose transport activity. To accomplish these goals, the following specific aims will be pursued: 1) To test the hypothesis that PIs suppress insulin-stimulated glucose transport by direct binding to Glut4. If this hypothesis is validated by crosslinking studies, the structural determinants of Glut4 interaction with PIs will be mapped by analysis of chimeric and mutant glucose transporters. 2) To test the hypothesis that PI-mediated inhibition of glucose transport directly contributes to lipodystrophy by suppressing adipogenesis and/or by enhancing adipocyte apoptosis.