HIV-protease inhibitors induce expression of suppressor of cytokine signaling-1 in insulin-sensitive tissues and promote insulin resistance and type 2 diabetes mellitus
HIV-protease inhibitors induce expression of suppressor of cytokine signaling-1 in insulin-sensitive tissues and promote insulin resistance and type 2 diabetes mellitus
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DOI：
10.1152/ajpendo.00167.2007
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发表时间：
2008-03-01
影响因子：
5.1
通讯作者：
Ramanadham, Sasanka
中科院分区：
文献类型：
--
作者：
Carper, Michael J.;Cade, W. Todd;Ramanadham, Sasanka
胰岛素抵抗、高血糖和2型糖尿病是60-80%接受HIV蛋白酶抑制剂（pi）治疗的人类免疫缺陷病毒（HIV）阳性患者代谢综合征的后遗症。然而，阐明导致这些变化的分子机制的研究主要集中在pi的急性体外作用上。在这里，我们研究了PI indinavir （IDV）对雄性Zucker糖尿病脂肪（fa/ fa） （ZDF）大鼠的慢性（7周）体内效应。与药物治疗的ZDF大鼠相比，IDV暴露加速了ZDF大鼠的糖尿病状态，并显著加重了高血糖和口服葡萄糖耐受不良。寡核苷酸基因阵列分析显示IDV大鼠胰岛素敏感组织中细胞因子信号传导抑制因子-1 （SOCS-1）表达上调。已知SOCS-1是胰岛素抵抗和糖尿病的诱导剂，免疫印迹分析显示，idv给药的ZDF大鼠脂肪、骨骼肌和肝脏组织中SOCS-1蛋白表达增加。这与上游调节因子tnf - α和下游效应因子甾醇调节元件结合蛋白-1的增加以及IRS-2的减少有关。IDV和目前临床使用的其他pi在正常培养条件下急性暴露于pi的L6肌管和3T3-L1脂肪细胞中，以及在给予pi 3周的Zucker野生型瘦对照大鼠的组织中，也诱导了SOCS-1信号级联，这表明这些药物即使在没有背景高血糖/高脂血症的情况下也有作用。因此，我们的研究结果表明，pi诱导的SOCS-1信号级联可能是与长期暴露于hiv - pi相关的代谢失调发展的重要因素。
Insulin resistance, hyperglycemia, and type 2 diabetes are among the sequelae of metabolic syndromes that occur in 60-80% of human immunodeficiency virus (HIV)-positive patients treated with HIV-protease inhibitors (PIs). Studies to elucidate the molecular mechanism(s) contributing to these changes, however, have mainly focused on acute, in vitro actions of PIs. Here, we examined the chronic (7 wk) in vivo effects of the PI indinavir (IDV) in male Zucker diabetic fatty (fa/ fa) (ZDF) rats. IDV exposure accelerated the diabetic state and dramatically exacerbated hyperglycemia and oral glucose intolerance in the ZDF rats, compared with vehicle-treated ZDF rats. Oligonucleotide gene array analyses revealed upregulation of suppressor of cytokine signaling-1 (SOCS-1) expression in insulin-sensitive tissues of IDV rats. SOCS-1 is a known inducer of insulin resistance and diabetes, and immunoblotting analyses revealed increases in SOCS-1 protein expression in adipose, skeletal muscle, and liver tissues of IDV-administered ZDF rats. This was associated with increases in the upstream regulator TNF-alpha and downstream effector sterol regulatory element-binding protein-1 and a decrease in IRS-2. IDV and other PIs currently in clinical use induced the SOCS-1 signaling cascade also in L6 myotubes and 3T3-L1 adipocytes exposed acutely to PIs under normal culturing conditions and in tissues from Zucker wild-type lean control rats administered PIs for 3 wk, suggesting an effect of these drugs even in the absence of background hyperglycemia/ hyperlipidemia. Our findings therefore indicate that induction of the SOCS-1 signaling cascade by PIs could be an important contributing factor in the development of metabolic dysregulation associated with long-term exposures to HIV-PIs.