Yan Qingyun, Hruz Paul W
Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA.
J Acquir Immune Defic Syndr. 2005 Dec 1;40(4):398-403. doi: 10.1097/01.qai.0000176654.97392.c7.
The clinical use of HIV protease inhibitors (PIs) is associated with the development of peripheral insulin resistance. The incidence and degree of impaired glucose tolerance observed in treated patients vary considerably between drugs, however. To compare the ability of HIV PIs to alter peripheral glucose disposal acutely in a genetically identical model system at therapeutically relevant drug levels, healthy lean male rats previously naive to PI exposure were given ritonavir, amprenavir, lopinavir/ritonavir (4:1), or atazanavir by continuous intravenous infusion to achieve steady state drug levels of 10 or 25 muM rapidly. Under euglycemic hyperinsulinemic clamp conditions, a dose-dependent reduction in the peripheral glucose disposal rate (Rd) was observed with all the PIs except atazanavir. The rank order of sensitivity was ritonavir, lopinavir, and then amprenavir. Changes in skeletal muscle and heart 2-deoxyglucose (2-DOG) uptake correlated with reductions in Rd. All 3 of these PIs also produced significant reductions in 2-DOG uptake into primary rat adipocytes in vitro. Atazanavir had no effect on glucose uptake in vitro or in vivo. The in vivo potency of PIs to impair peripheral glucose disposal acutely correlates with the degree of insulin resistance observed in HIV-infected patients receiving these drugs. Preclinical testing of novel candidate PIs in a rodent model system may be useful in identifying the future risk of altering glucose homeostasis.
HIV蛋白酶抑制剂（PIs）的临床应用与外周胰岛素抵抗的发生有关。然而，在接受治疗的患者中观察到的糖耐量受损的发生率和程度在不同药物之间差异很大。为了在具有治疗相关性药物水平的基因相同模型系统中比较HIV PIs急性改变外周葡萄糖处置的能力，将先前未接触过PI的健康瘦雄性大鼠通过持续静脉输注给予利托那韦、安普那韦、洛匹那韦/利托那韦（4:1）或阿扎那韦，以迅速达到10或25μM的稳态药物水平。在正常血糖高胰岛素钳夹条件下，除阿扎那韦外，所有PIs均观察到外周葡萄糖处置率（Rd）呈剂量依赖性降低。敏感性排序为利托那韦、洛匹那韦，然后是安普那韦。骨骼肌和心脏2-脱氧葡萄糖（2-DOG）摄取的变化与Rd的降低相关。这3种PIs在体外也均使原代大鼠脂肪细胞对2-DOG的摄取显著降低。阿扎那韦在体外和体内对葡萄糖摄取均无影响。PIs急性损害外周葡萄糖处置的体内效力与接受这些药物的HIV感染患者中观察到的胰岛素抵抗程度相关。在啮齿动物模型系统中对新型候选PIs进行临床前测试可能有助于识别未来改变葡萄糖稳态的风险。
