PT  - JOURNAL ARTICLE
AU  - Xiuqing Han
AU  - Steffen H. Raun
AU  - Michala Carlsson
AU  - Kim A. Sjøberg
AU  - Carlos Henriquez-Olguín
AU  - Mona Ali
AU  - Annemarie Lundsgaard
AU  - Andreas M. Fritzen
AU  - Lisbeth L. V. Møller
AU  - Zhen Li
AU  - Jinwen Li
AU  - Thomas E. Jensen
AU  - Bente Kiens
AU  - Lykke Sylow
TI  - Cancer causes metabolic perturbations associated with reduced insulin-stimulated glucose uptake in peripheral tissues and impaired muscle microvascular perfusion
AID  - 10.1101/734764
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 734764
4099  - http://biorxiv.org/content/early/2019/12/28/734764.short
4100  - http://biorxiv.org/content/early/2019/12/28/734764.full
AB  - 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.