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

Abstract

20Background: Redirecting glucose from skeletal muscle and adipose tissue, likely benefits the 21 tumor's energy demand to support tumor growth, as cancer patients with type 2 diabetes have 30% 22 increased mortality rates. The aim of this study was to elucidate tissue-specific contributions and 23 molecular mechanisms underlying cancer-induced metabolic perturbations. 24Methods: Glucose uptake in skeletal muscle and white adipose tissue (WAT), as well as hepatic 25 glucose production, were determined in control and Lewis lung carcinoma (LLC) tumor-bearing 26 C57BL/6 mice using isotopic tracers. Skeletal muscle microvascular perfusion was analyzed via a 27 real-time contrast-enhanced ultrasound technique. Finally, the role of fatty acid turnover on 28 glycemic control was determined by treating tumor-bearing insulin-resistant mice with nicotinic 29 acid or etomoxir. 30Results: LLC tumor-bearing mice displayed reduced insulin-induced blood-glucose-lowering and 31 glucose intolerance, which was restored by etomoxir or nicotinic acid. Insulin-stimulated glucose 32 uptake was 30-40% reduced in skeletal muscle and WAT of mice carrying large tumors. Despite 33 compromised glucose uptake, tumor-bearing mice displayed upregulated insulin-stimulated 34 phosphorylation of TBC1D4 Thr642 (+18%), AKT Ser474 (+65%), and AKT Thr309 (+86%) in muscle. 35Insulin caused a 70% increase in muscle microvascular perfusion in control mice, which was 36 abolished in tumor-bearing mice. Additionally, tumor-bearing mice displayed increased (+45%) 37 basal (not insulin-stimulated) hepatic glucose production. 38Conclusions: Cancer can result in marked perturbations on at least six metabolically essential 39 functions; i) insulin's blood-glucose-lowering effect, ii) glucose tolerance, iii) skeletal muscle and 40 WAT insulin-stimulated glucose uptake, iv) intramyocellular insulin signaling, v) muscle 41 microvascular perfusion, and vi) basal hepatic glucose production in mice. The mechanism causing 42 cancer-induced insulin resistance may relate to fatty acid metabolism. 43 3

The many actions of insulin in skeletal muscle, the paramount tissue determining glycemia

“…Yet only a fraction of active Akt is required to fully activate GLUT4 translocation in muscle cells (Fazakerley et al, 2019;Wang et al, 1999), suggesting that the small reductions in proximal insulin signaling observed in T2D may not suffice to cause insulin resistance. Furthermore, skeletal muscle insulin resistance can occur with seemingly normal (Høeg et al, 2011;Kim et al, 1999;Ramos et al, 2020;Raun et al, 2018) or even elevated proximal insulin signaling (Han et al, 2020), clearly demonstrating that there is no uniform association between proximal insulin signaling and glucose uptake. Instead, or in addition, the distal parts of the insulin signaling cascade must be considered.…”

Wheel running improves fasting‐induced AMPK signaling in skeletal muscle from tumor‐bearing mice

“…Most preclinical models adding a physical activity or exercise treatment before either the rapid tumor growth stage or cachexia onset can attenuate or prevent wasting (Gould et al, 2013; Hardee et al, 2019). Furthermore, impaired systemic metabolism (Das et al, 2011; Han et al, 2020; Kir et al, 2014) and muscle metabolic dysfunction (Brown et al, 2017; Han et al, 2020) have been reported before cachexia onset and are potential drivers of accelerated protein turnover during cachexia's progression(VanderVeen et al, 2017). However, the effect of exercise on the feeding and fasting metabolic regulation during cachexia initiation is uncertain.…”