Mechanisms for Altered Glucose Homeostasis During HAART

HAART 期间改变血糖稳态的机制

• 批准号: 6654304
• 负责人: PAUL W HRUZ
• 金额: $ 26.93万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6654304
• 关键词: AIDS therapy; Xenopus oocyte; antiAIDS agent; antiviral agents; drug adverse effect; gluconeogenesis; glucose clamp technique; glucose transporter; homeostasis; laboratory rat; pancreatic islet function; protease inhibitor; radioimmunoassay

DESCRIPTION (provided by applicant): The long-term objective of this project is to understand the molecular mechanisms responsible for altered glucose homeostasis during highly active antiretroviral therapy. The studies in this proposal are intended to identify the cellular targets of HIV protease inhibitors that lead to impaired beta-cell function and alterations in hepatic glucose production and to elucidate the molecular mechanism of this inhibition. We hypothesize that the peptide structure within all currently available HIV protease inhibitors is responsible for acute and reversible inhibition of the insulin-responsive glucose transporter GLUT4 and the liver/pancreas transporter GLUT2. To test this hypothesis, the acute effects of HIV protease inhibitors on the glucose-stimulated insulin secretory pathway in freshly isolated rodent and human islets as well as cultured MIN6 cells will be determined. Euglycemic hyperinsulinemic clamp experiments will also be performed in rats to determine the acute effects of HIV protease inhibitors on hepatic glucose production. The ability of the biguanide metformin to prevent protease inhibitor mediated inhibition of GLUT4 activity will be tested in Xenopus oocytes heterologously expressing this transporter isoform. Finally, the structural determinants involved in PI-induced GLUT4 inhibition will be determined by testing a family of synthetic aromatic peptides for their ability to inhibit 2-deoxyglucose uptake in GLUT4 expressing oocytes. Taken together, these studies will provide new insights into the molecular mechanism(s) leading to insulin resistance in patients treated with HIV protease inhibitors. This may facilitate the design of newer HIV protease inhibitors that maintain their clinical efficacy while avoiding their adverse effects on glucose homeostasis and will assist efforts to develop more effective treatment strategies.

描述（由申请人提供）：该项目的长期目标是了解高度活跃抗逆转录病毒治疗期间导致葡萄糖稳态改变的分子机制。该提案中的研究旨在确定导致β细胞功能受损的HIV蛋白酶抑制剂的细胞靶标和肝葡萄糖产生的改变，并阐明这种抑制的分子机制。我们假设所有当前可用的HIV蛋白酶抑制剂中的肽结构均导致对胰岛素反应性葡萄糖转运蛋白Glut4和肝脏/胰腺转运蛋白glut2的急性和可逆抑制。为了检验这一假设，将确定HIV蛋白酶抑制剂对新鲜分离的啮齿动物和人类胰岛以及培养的MIN6细胞中葡萄糖刺激的胰岛素分泌途径的急性作用。在大鼠中还将进行葡萄糖高胰岛素夹具实验，以确定HIV蛋白酶抑制剂对肝葡萄糖产生的急性作用。 Biguanide二甲双胍预防蛋白酶抑制剂抑制GLUT4活性的能力将在异植型卵母细胞中测试，以异源表达该转运蛋白同工型。最后，将通过测试合成芳族肽的家族来确定参与PI诱导的GLUT4抑制的结构决定因素，以抑制在表达卵母细胞中抑制2-脱氧葡萄糖摄取的能力。综上所述，这些研究将提供有关分子机制的新见解，从而导致用HIV蛋白酶抑制剂治疗的患者胰岛素抵抗。这可能有助于设计新的HIV蛋白酶抑制剂，这些抑制剂保持其临床功效，同时避免对葡萄糖稳态的不利影响，并将有助于制定更有效的治疗策略。