Exogenous detection of 13C-glucose metabolism in tumor and diet-induced obesity models

Abstract

Metabolic rewiring is a hallmark feature prevalent in cancer cells as well as insulin resistance (IR) associated with diet-induced obesity (DIO). For instance, tumor metabolism shifts towards an enhanced glycolytic state even under aerobic conditions. In contrast, DIO triggers lipid-induced IR by impairing insulin signaling and reducing insulin-stimulated glucose uptake. Based on physiological differences in systemic metabolism, we used a breath analysis approach to discriminate between different pathological states using glucose oxidation as a readout. We assessed glucose utilization in lung cancer-induced cachexia and DIO mouse models using a U-¹³C glucose tracer and stable isotope sensors integrated into an indirect calorimetry system. Our data showed increased ¹³CO₂ expired by tumor-bearing (TB) mice and a reduction in exhaled ¹³CO₂ in the DIO model. Taken together, our findings illustrate high glucose uptake and consumption in TB animals and decreased glucose uptake and oxidation in obese mice with an IR phenotype. Our work has important translational implications for the utility of stable isotopes in breath-based detection of glucose homeostasis in models of lung cancer progression and DIO.

Keywords: circadian clock; diet-induced obesity (DIO); glucose oxidation and detection; insulin resistance; tumor metabolism.