GS-8374, a novel HIV protease inhibitor, does not alter glucose homeostasis in cultured adipocytes or in a healthy-rodent model system.
GS-8374, a novel HIV protease inhibitor, does not alter glucose homeostasis in cultured adipocytes or in a healthy-rodent model system.
复制标题
GS-8374 是一种新型 HIV 蛋白酶抑制剂，不会改变培养脂肪细胞或健康啮齿动物模型系统中的葡萄糖稳态。
DOI：
10.1128/aac.01184-10
复制
发表时间：
2011
影响因子：
4.9
通讯作者：
Callebaut,Christian
中科院分区：
文献类型：
--
作者：
Hruz,PaulW;Yan,Qingyun;Tsai,Luong;Koster,Joseph;Xu,Lianhong;Cihlar,Tomas;Callebaut,Christian
HIV蛋白酶抑制剂（PI）引起的不良反应是限制其临床成功的重要因素。PI直接导致外周胰岛素抵抗和脂质代谢的改变。GS-8374是一种新型PI，具有强效抗逆转录病毒活性和良好的耐药性。在这里，我们报告了GS-8374对葡萄糖和脂质稳态产生不利影响的潜力。分别在体外小鼠OP 9和原代人脂肪细胞中评估GS-8374和对照PI对葡萄糖摄取和脂质蓄积的急性作用。GS-8374和阿扎那韦对胰岛素刺激的脱氧葡萄糖摄取没有影响，而利托那韦和洛匹那韦则显著降低。同样，在体外脂肪积累没有显着影响与GS-8374或阿扎那韦处理的脂肪细胞。在大鼠急性输注治疗水平PI期间进行的正常血糖-高胰岛素钳夹实验中，血清GS-8374水平持续8 μM对外周葡萄糖处置无影响（与阿扎那韦的结果相似）。洛匹那韦和利托那韦的血清水平相当，分别使活葡萄糖的处置急剧减少19%和53%。总之，与阿扎那韦相似，但与利托那韦和洛匹那韦不同，GS-8374既不影响培养中脂肪细胞中胰岛素刺激的葡萄糖摄取，也不急性改变啮齿动物模型系统中外周葡萄糖处置。这些结果将GS-8374的抗逆转录病毒活性与在一些第一代PI中观察到的对胰岛素敏感性的不良作用分离，并为在新型PI的临床前评价中使用这些实验系统提供了进一步的支持。
Adverse effects induced by HIV protease inhibitors (PIs) are a significant factor in limiting their clinical success. PIs directly contribute to peripheral insulin resistance and alterations in lipid metabolism. GS-8374 is a novel PI with potent antiretroviral activity and a favorable resistance profile. Here we report on the potential of GS-8374 to adversely affect glucose and lipid homeostasis. Acute effects of GS-8374 and control PIs on glucose uptake and lipid accumulation were assessedin vitroin mouse OP9 and primary human adipocytes, respectively. GS-8374 and atazanavir showed no effect on insulin-stimulated deoxyglucose uptake, whereas ritonavir and lopinavir caused significant reductions. Similarly,in vitrolipid accumulation was not significantly affected in adipocytes treated with either GS-8374 or atazanavir. In euglycemic-hyperinsulinemic clamp experiments performed in rats during acute infusion of therapeutic levels of PIs, sustained serum GS-8374 levels of 8 μM had no effect on peripheral glucose disposal (similar to the findings for atazanavir). Comparable serum levels of lopinavir and ritonavir produced acute 19% and 53% reductions inin vivoglucose disposal, respectively. In conclusion, similar to atazanavir, but unlike ritonavir and lopinavir, GS-8374 neither affects insulin-stimulated glucose uptake in adipocytes in culture nor acutely alters peripheral glucose disposal in a rodent model system. These results dissociate the antiretroviral activity of GS-8374 from adverse effects on insulin sensitivity observed with some of the first-generation PIs and provide further support for the use of these experimental systems in the preclinical evaluation of novel PIs.