Tumor-bearing mice display reduced insulin-stimulated glucose uptake and microvascular perfusion and exhibit increased hepatic glucose production

Abstract Cancer is often associated with poor glycemic control. However, the underlying 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. 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 reduced in muscle and WAT of mice carrying large tumors. Despite compromised muscle glucose uptake, tumor-bearing mice displayed upregulated insulin-stimulated phosphorylation of TBC1D4Thr642 (+18%), AKTSer473 (+65%), and AKTThr308 (+86%). Insulin caused a 20% increase in muscle microvascular perfusion in control mice, which was completely abolished in tumor-bearing mice. Additionally, tumor-bearing mice displayed increased (+ 45%) basal (but not insulin-stimulated) hepatic glucose production. In conclusion, cancer causes significant whole-body insulin resistance, which was restored by inhibition of adipose tissue lipolysis or whole-body fatty acid oxidation. Insulin resistance in tumor-bearing mice was associated with to i) impaired muscle glucose uptake despite augmented insulin signaling and impaired glucose uptake in adipose tissue ii) abrogated muscle microvascular perfusion in response to insulin, and iii) increased basal hepatic glucose production.

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