HIV protease inhibitors acutely impair glucose-stimulated insulin release
HIV protease inhibitors acutely impair glucose-stimulated insulin release
复制标题
DOI：
10.2337/diabetes.52.7.1695
复制
发表时间：
2003-07-01
期刊：
影响因子：
7.7
通讯作者：
Hruz, PW
中科院分区：
文献类型：
--
作者：
Koster, JC;Remedi, MS;Hruz, PW
HIV蛋白酶抑制剂（PI）急性可逆地抑制胰岛素应答性葡萄糖转运蛋白Glut 4，导致外周胰岛素抵抗和葡萄糖耐量受损。PI治疗患者葡萄糖耐量试验的最小建模分析显示胰岛素分泌反应受损，提示额外的胰腺β细胞功能障碍。为了确定β细胞功能是否受到PI的急性影响，我们测定了啮齿动物胰岛和胰岛素瘤细胞系MIN6中葡萄糖刺激的胰岛素分泌。PI茚地那韦显著抑制MIN6细胞和啮齿类动物胰岛的胰岛素释放，IC 50值分别为1.1和2.1 mumol/l。MIN6细胞中2-脱氧葡萄糖的摄取也受到类似的抑制（IC50为2.0 μ mol/l），而葡萄糖激酶活性在药物水平高达1 mmol/l时不受影响。在相当的药物水平下，葡萄糖利用也受损。作用于葡萄糖转运下游的胰岛素促分泌素主要逆转MIN6细胞中茚地那韦介导的胰岛素释放抑制。在大鼠高血糖钳夹期间静脉输注茚地那韦显著抑制第一时相胰岛素反应。这些数据表明PI的治疗水平足以损害β细胞的葡萄糖感知。因此，与外周胰岛素抵抗一起，β细胞功能障碍可能有助于改变与高效抗逆转录病毒治疗相关的葡萄糖稳态。
HIV protease inhibitors (PIs) acutely and reversibly inhibit the insulin-responsive glucose transporter Glut 4, leading to peripheral insulin resistance and impaired glucose tolerance. Minimal modeling analysis of glucose tolerance tests on PI-treated patients has revealed an impaired insulin secretory response, suggesting additional pancreatic beta-cell dysfunction. To determine whether beta-cell function is acutely affected by PIs, we assayed glucose-stimulated insulin secretion in rodent islets and the insulinoma cell line MIN6. Insulin release from MIN6 cells and rodent islets was significantly inhibited by the PI indinavir with IC50 values of 1.1 and 2.1 mumol/l, respectively. The uptake of 2-deoxyglucose in MIN6 cells was similarly inhibited (IC50 of 2.0 mumol/l), whereas glucokinase activity was unaffected at drug levels as high as 1 mmol/l. Glucose utilization was also impaired at comparable drug levels. Insulin secretogogues acting downstream of glucose transport mostly reversed the indinavir-mediated inhibition of insulin release in MIN6 cells. Intravenous infusion of indinavir during hyperglycemic clamps on rats significantly suppressed the first-phase insulin response. These data suggest that therapeutic levels of PIs are sufficient to impair glucose sensing by beta-cells. Thus, together with peripheral insulin resistance, beta-cell dysfunction likely contributes to altered glucose homeostasis associated with highly active antiretroviral therapy.