Cancer causes metabolic perturbations associated with reduced insulin-stimulated glucose uptake in peripheral tissues and impaired muscle microvascular perfusion

Cancer is often associated with poor glycemic control but the molecular mechanisms are unknown. The aim of this study was to elucidate tissue-specific contributions and molecular mechanisms underlying impaired glycemic regulation in cancer. Basal and insulin-stimulated 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. LLC tumor-bearing mice displayed whole-body insulin resistance and glucose intolerance, which was restored by nicotinic acid or etomoxir. 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%), AKTSer473 (+65%), and AKTThr308 (+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. We show that cancer can result in marked perturbations on at least six metabolically essential functions; i) insulins blood-glucose-lowering effect, ii) glucose tolerance, iii) skeletal muscle and white adipose tissue insulin-stimulated glucose uptake, iv) intramyocellular insulin signaling, v) muscle microvascular perfusion, and vi) basal hepatic glucose production in mice. Additionally, we show that the mechanism causing cancer-induced insulin resistance may relate to fatty acid metabolism.