Tumor necrosis factor impairs insulin action on peripheral glucose disposal and hepatic glucose output.
Tumor necrosis factor impairs insulin action on peripheral glucose disposal and hepatic glucose output.
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DOI：
10.1210/endo.130.1.1727716
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发表时间：
1992
期刊：
影响因子：
4.8
通讯作者：
C. Lang;C. Dobrescu;G. Bagby
中科院分区：
文献类型：
--
作者：
C. Lang;C. Dobrescu;G. Bagby
本研究探讨是否长期输注肿瘤坏死因子（TNF）到大鼠可以维持全身葡萄糖代谢率的增加，观察短期暴露，以及TNF是否产生肝脏或外周胰岛素抵抗。在开始恒定输注重组人TNF（1 μ g/kg.h）后18 h，使用[3- 3 H]葡萄糖测定基础葡萄糖代谢。此后，进行两步正常血糖高胰岛素钳夹以确定TNF是否损害胰岛素作用。TNF的过夜输注使血浆葡萄糖浓度轻微升高（17%），但使全身葡萄糖产生和利用率大幅增加（133%）。在高胰岛素血症条件下，TNF处理的大鼠维持正常血糖所需的葡萄糖输注速率降低30%，表明存在胰岛素抵抗。这是由于胰岛素抑制肝脏葡萄糖产生和刺激TNF输注动物外周葡萄糖利用的能力受损所致。使用体内示踪剂[U-14 C]2-脱氧葡萄糖技术进行了第二系列实验，以阐明哪些组织负责TNF诱导的基础（无外源性胰岛素）葡萄糖处置和外周胰岛素抵抗增加。在基础条件下，TNF增加了各种肌肉（腓肠肌、心脏和膈肌）以及非肌肉组织（肝、肺、脾、肠、皮肤和脂肪）的葡萄糖摄取。由于其相对较大的质量和/或高葡萄糖摄取率，皮肤（25%），肠（24%），肌肉（23%）和肝脏（15%）的摄取增加占TNF诱导的全身葡萄糖处置增量的大部分。在血糖正常的高胰岛素血症条件下，肌肉和皮肤的葡萄糖摄取增加（85%）占对照大鼠葡萄糖处置的大部分。然而，在TNF输注的动物中，高胰岛素血症未能增加皮肤对葡萄糖的摄取，并使肌肉中胰岛素介导的增加减弱了73%。这些结果表明，在慢性治疗过程中TNF的持续升高以及恶性肿瘤或感染性疾病患者和实验动物TNF的长期产生可能是葡萄糖通量增强以及在这些条件下观察到的胰岛素抵抗的重要机制。
The present study examined whether a prolonged infusion of tumor necrosis factor (TNF) into rats could sustain the increased rate of whole body glucose metabolism observed with short term exposure, and whether TNF produced hepatic or peripheral insulin resistance. Basal glucose metabolism was determined with the use of [3-3H]glucose 18 h after initiating a constant infusion of recombinant human TNF (1 microgram/kg.h). Thereafter, a two-step euglycemic hyperinsulinemic clamp was performed to determine whether TNF impaired insulin action. The overnight infusion of TNF minimally elevated plasma glucose concentrations (17%), but produced large increases in the whole body rate of glucose production and utilization (133%). Under hyperinsulinemic conditions, the glucose infusion rate necessary to maintain euglycemia was 30% lower in TNF-treated rats, indicating an insulin-resistant condition. This resulted from an impaired ability of insulin to both suppress hepatic glucose production and stimulate peripheral glucose utilization in TNF-infused animals. A second series of experiments was performed, using the in vivo tracer [U-14C]2-deoxyglucose technique, to elucidate which tissues were responsible for the TNF-induced increase in basal (no exogenous insulin) glucose disposal and peripheral insulin resistance. Under basal conditions, TNF increased glucose uptake by various muscles (gastrocnemius, heart, and diaphragm) as well as nonmuscle tissues (liver, lung, spleen, gut, skin and fat). Because of their relatively large mass and/or high rate of glucose uptake, the increased uptake by skin (25%), intestine (24%), muscle (23%), and liver (15%) accounted for the majority of the TNF-induced increment in whole body glucose disposal. Under euglycemic hyperinsulinemic conditions, the increment in glucose uptake by muscle and skin (85%) accounted for the majority of the glucose disposal in control rats. However, in TNF-infused animals, hyperinsulinemia failed to increase glucose uptake by skin and blunted the insulin-mediated increase in muscle by 73%. These results suggest that sustained elevations of TNF during chronic therapy and prolonged production of TNF by patients and experimental animals with malignancies or infectious diseases may be an important mechanism for the enhanced glucose flux as well as the insulin resistance seen in these conditions.