Mechanisms for the deterioration in glucose tolerance associated with HIV protease inhibitor regimens
Mechanisms for the deterioration in glucose tolerance associated with HIV protease inhibitor regimens
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DOI：
10.2337/diabetes.52.4.918
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发表时间：
2003-04-01
期刊：
影响因子：
7.7
通讯作者：
Gerich, JE
中科院分区：
文献类型：
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作者：
Woerle, IJ;Mariuz, PR;Gerich, JE
在HIV感染中，与含有蛋白酶抑制剂的疗法相关的糖耐量恶化的机制尚不清楚。胰岛素抵抗已被认为是一个主要因素，但受影响的组织尚未确定。此外，β细胞的功能还没有得到详细的评估。因此，本研究旨在评估含有蛋白水解酶抑制剂的方案对肝脏、肌肉和脂肪组织胰岛素敏感性以及胰岛β细胞功能的影响。我们使用高血糖钳夹技术结合同位素测量，评估了13名HIV感染患者和14名正常健康志愿者在治疗12周前后的β细胞功能，以及葡萄糖产生、葡萄糖处置和游离脂肪酸(FFA)转化。用稳态模型评估(HOMA)评估胰岛β细胞功能和胰岛素敏感性。治疗提高了所有受试者的空腹和血糖浓度(P<；0.001)。根据HOMA和CLAMP评估的胰岛素敏感性，实验降低了类似于50%(P<；0.003)。对于普遍存在的高胰岛素血症，吸收后葡萄糖的产生被适当地抑制，而葡萄糖清除减少(P<；0.001)。根据HOMA评估，β细胞功能下降了近50%(P=0.002)，而通过钳位数据评估，第一时相胰岛素释放下降了类似于25%(P=0.002)。血浆游离脂肪酸周转率和清除量均显著增加(P<；0.001)。在开始使用核苷逆转录酶抑制剂(NRTI)加蛋白酶抑制剂的药物NAVE患者和长期接受NRTI治疗并添加了蛋白酶抑制剂的患者之间，在基线或治疗后的反应方面没有观察到差异。本研究表明，含有蛋白酶抑制剂的方案通过两种机制损害HIV感染患者的糖耐量：1)诱导骨骼肌和脂肪组织的外周胰岛素抵抗；2)β细胞补偿能力的损害。
dThe mechanisms responsible for the deterioration in glucose tolerance associated with protease inhibitor-containing regimens in HIV infection tire unclear. Insulin resistance has been implicated as a major factor, but the affected tissues have not been identified. Furthermore, beta-cell function has not been evaluated in detail. The present study was therefore undertaken to assess the effects of protease inhibitor-containing regimens on hepatic, muscle, and adipose tissue insulin sensitivity as well as pancreatic beta-cell function. We evaluated beta-cell function in addition to glucose production, glucose disposal, and free fatty acid (FFA) turnover using the hyperglycemic clamp technique in combination with isotopic measurements in 13 HIV-infected patients before and after 12 Weeks of,treatment and in 14 normal healthy volunteers. beta-Cell function and insulin sensitivity were also assessed by homeostasis model assessment (HOMA). Treatment increased fasting,plasma glucose concentrations in all subjects (P < 0.001). Insulin sensitivity as assessed by HOMA and clamp, experiments decreased by similar to50% (P < 0.003). Postabsorptive glucose production was appropriately suppressed for the prevailing hyperinsulinemia, Whereas glucose clearance was, reduced (P < 0.001). beta-Cell function decreased by similar to50% (P = 0.002), as assessed by HOMA, and first-phase insulin release decreased by similar to25%, as assessed by clamp data (P = 0.002). Plasma FFA turnover and clearance both increased significantly (P < 0.001). No differences at baseline or in responses after treatment were observed between drug nave patients who were started on a nucleoside reverse transcriptase inhibitor (NRTI) plus a protease inhibitor and patients who had been on long-term NRTI treatment and had a protease inhibitor added. The present study indicates that protease inhibitor containing regimens impair glucose tolerance in HIV-infected patients by two mechanisms: 1) inducement of peripheral insulin resistance in skeletal muscle and adipose tissue and 2) impairment of the ability of the beta-cell to compensate.