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

Han, X.; Raun, S.; Carlsson, M.; Sjoberg, K. A.; Henriquez-Olguin, C.; Ali, M.; Lundsgaard, A.; Fritzen, A. M.; Moller, L. L. V.; Li, Z.; Li, J.; Jensen, T. E.; Kiens, B.; Sylow, L.

doi:10.1101/734764

bioRxiv · 10.1101/734764

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

Han, X.·Raun, S.·Carlsson, M.·Sjoberg, K. A.·Henriquez-Olguin, C.·Ali, M.·Lundsgaard, A.·Fritzen, A. M.·Moller, L. L. V.·Li, Z.·Li, J.·Jensen, T. E.·Kiens, B.·Sylow, L.

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Abstract

BackgroundRedirecting glucose from skeletal muscle and adipose tissue, likely benefits the tumors 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. MethodsGlucose 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. ResultsLLC 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. ConclusionsCancer 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 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.

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Han, X., Raun, S., Carlsson, M., Sjoberg, K. A., Henriquez-Olguin, C., Ali, M., Lundsgaard, A., Fritzen, A. M., Moller, L. L. V., Li, Z., Li, J., Jensen, T. E., Kiens, B., Sylow, L.. 2019-08-13. Tumor-bearing mice display reduced insulin-stimulated glucose uptake and microvascular perfusion and exhibit increased hepatic glucose production. https://doi.org/10.1101/734764

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