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/en.130.1.43
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发表时间：
1992-01-01
期刊：
影响因子：
4.8
通讯作者：
BAGBY, GJ
中科院分区：
文献类型：
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作者：
LANG, CH;DOBRESCU, C;BAGBY, GJ
本研究考察了长期输注肿瘤坏死因子（TNF）是否能维持短期暴露所观察到的全身葡萄糖代谢率的增加，以及TNF是否会产生肝脏或外周胰岛素抵抗。在开始持续输注重组人TNF (1 μ g/kg.h) 18 h后，用[3-H-3]葡萄糖测定基础糖代谢。此后，进行两步正糖高胰岛素钳夹，以确定TNF是否损害胰岛素的作用。通宵输注TNF对血浆葡萄糖浓度的影响最小（17%），但对全身葡萄糖生成和利用率的影响较大（133%）。在高胰岛素血症条件下，tnf治疗大鼠维持血糖正常所需的葡萄糖输注率降低30%，表明胰岛素抵抗状态。这是由于在输注tnf的动物中，胰岛素抑制肝脏葡萄糖产生和刺激外周葡萄糖利用的能力受损。使用体内示踪剂[U-C-14]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的增加。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）对葡萄糖的摄取。由于其相对较大的质量和/或较高的葡萄糖摄取率，皮肤（25%）、肠道（24%）、肌肉（23%）和肝脏（15%）的摄取增加是tnf诱导的全身葡萄糖处置增加的主要原因。在正常血糖高胰岛素状态下，肌肉和皮肤葡萄糖摄取的增加（85%）占对照大鼠葡萄糖消耗的大部分。然而，在输注tnf的动物中，高胰岛素血症未能增加皮肤对葡萄糖的摄取，并使胰岛素介导的肌肉增加减少了73%。这些结果表明，慢性治疗期间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的持续产生可能是这些疾病中葡萄糖通量增强以及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-H-3]glucose 18 h after initiating a constant infusion of recombinant human TNF (1-mu-g/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-C-14]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.