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

Metabolism. 2020 Apr;105:154169. doi: 10.1016/j.metabol.2020.154169. Epub 2020 Jan 24.


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.

Keywords: Cancer; Glycaemic regulation; Insulin resistance; Lewis lung carcinoma; Microvascular perfusion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue, White / metabolism
  • Animals
  • Blood Glucose / metabolism
  • Carcinoma, Lewis Lung / complications
  • Carcinoma, Lewis Lung / diagnostic imaging
  • Carcinoma, Lewis Lung / metabolism*
  • Female
  • Glucose / metabolism*
  • Glucose Intolerance / complications
  • Hypoglycemic Agents / pharmacology*
  • Insulin / pharmacology*
  • Insulin Resistance
  • Liver / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Microcirculation
  • Muscle, Skeletal / blood supply*
  • Muscle, Skeletal / diagnostic imaging
  • Regional Blood Flow
  • Vasodilator Agents / pharmacology


  • Blood Glucose
  • Hypoglycemic Agents
  • Insulin
  • Vasodilator Agents
  • Glucose