BACKGROUND Redirecting glucose from skeletal muscle and adipose tissue, likely benefits the tumor's energy demand to support tumor growth, as cancer patients with type 2 diabetes have 30% increased mortality rates. The aim of this study was to elucidate tissue-specific contributions and molecular mechanisms underlying cancer-induced metabolic perturbations. METHODS Glucose uptake in skeletal muscle and white adipose tissue (WAT), as well as hepatic glucose production, were determined in control and Lewis lung carcinoma (LLC) tumor-bearing C57BL/6 mice using isotopic tracers. Skeletal muscle microvascular perfusion was analyzed via a real-time contrast-enhanced ultrasound technique. Finally, the role of fatty acid turnover on glycemic control was determined by treating tumor-bearing insulin-resistant mice with nicotinic acid or etomoxir. RESULTS LLC tumor-bearing mice displayed reduced insulin-induced blood-glucose-lowering and glucose intolerance, which was restored by etomoxir or nicotinic acid. Insulin-stimulated glucose uptake was 30-40% reduced in skeletal muscle and WAT of mice carrying large tumors. Despite compromised glucose uptake, tumor-bearing mice displayed upregulated insulin-stimulated phosphorylation of TBC1D4Thr642 (+18%), AKTSer474 (+65%), and AKTThr309 (+86%) in muscle. Insulin caused a 70% increase in muscle microvascular perfusion in control mice, which was abolished in tumor-bearing mice. Additionally, tumor-bearing mice displayed increased (+45%) basal (not insulin-stimulated) hepatic glucose production. CONCLUSIONS Cancer can result in marked perturbations on at least six metabolically essential functions; i) insulin's blood-glucose-lowering effect, ii) glucose tolerance, iii) skeletal muscle and WAT insulin-stimulated glucose uptake, iv) intramyocellular insulin signaling, v) muscle microvascular perfusion, and vi) basal hepatic glucose production in mice. The mechanism causing cancer-induced insulin resistance may relate to fatty acid metabolism.

中文翻译：

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癌症引起代谢紊乱，与周围组织中胰岛素刺激的葡萄糖摄取减少和肌肉微血管灌注受损有关。

背景技术从骨骼肌和脂肪组织中重定向葡萄糖可能有益于肿瘤的能量需求以支持肿瘤生长，因为患有2型糖尿病的癌症患者死亡率增加了30％。这项研究的目的是阐明癌症诱导的代谢紊乱的组织特异性贡献和分子机制。方法使用同位素示踪剂测定了对照组和Lewis肺癌（LLC）荷瘤C57BL / 6小鼠骨骼肌和白色脂肪组织（WAT）的葡萄糖摄取以及肝葡萄糖的产生。通过实时对比增强超声技术分析骨骼​​肌微血管灌注。最后，通过用烟酸或依托莫司治疗荷瘤胰岛素抵抗小鼠来确定脂肪酸更新对血糖控制的作用。结果LLC荷瘤小鼠表现出降低的胰岛素诱导的降血糖和葡萄糖耐量下降，这可通过依托莫司或烟酸恢复。携带大肿瘤的小鼠的骨骼肌和WAT中胰岛素刺激的葡萄糖摄取降低了30-40％。尽管葡萄糖摄取受到损害，但荷瘤小鼠的肌肉中TBC1D4Thr642（+18％），AKTSer474（+ 65％）和AKTThr309（+ 86％）的胰岛素刺激的磷酸化水平却升高。胰岛素使对照小鼠的肌肉微血管灌注增加了70％，而在荷瘤小鼠中则被取消了。此外，荷瘤小鼠的基础（非胰岛素刺激）肝葡萄糖产生增加（+ 45％）。结论癌症可导致至少六个代谢必需功能的明显紊乱。i）胰岛素的降血糖作用，ii）葡萄糖耐量，iii）骨骼肌和WAT胰岛素刺激的葡萄糖摄取，iv）肌内胰岛素信号传导，v）肌肉微血管灌注，和vi）小鼠基础肝葡萄糖生成。引起癌症诱导的胰岛素抵抗的机制可能与脂肪酸代谢有关。