The Elusive Link between 18FDG uptake and Glycolytic Flux explains the Preserved Diagnostic Accuracy of PET-CT in Diabetic Cancer Patients

Aim/Introduction: The present study aims to verify whether the link between [18F]-2-deoxy-glucose (FDG) uptake and activity of the reticular enzyme hexose-6P-dehydrogenase (H6PD) contributes to preserve PET/CT diagnostic power in experimental models of streptozotocin-induced diabetes mellitus (STZ-DM). Materials and Methods: The study included 72 Balb/c mice subcutaneously implanted with colon (CT26, n=36) or breast (4T1, n=36) cancer cells. Each cohort was subdivided into two clusters ("control" and "STZ-DM") that were further subdivided into three groups treated with saline or metformin (MTF) at low or high doses (10 or 750 mg/Kg daily, respectively). Two weeks after cancer cells inoculation, all mice were submitted to micro-PET imaging. After sacrifice, enzymatic pathways and response to oxidative stress were evaluated in harvested tumors. Finally, competition by 2-deoxy-glucose (2DG) on cell uptake of FDG and the fluorescent analogue 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxyglucose (2NBDG) was studied in cultured cells. Results: At microPET imaging, 4T1 and CT26 cancer volumes and average metabolic rate of glucose (MRGlu) were superimposable in "control" mice and showed a similar reduction under MTF treatments. In STZDM group, both cancer volumes and MRGlu were slightly, yet significantly, lower than control ones, while MTF capability to decelerate lesion growth and MRGlu was virtually abolished. This metabolic reprogramming was not explained by any change in expression or activity of hexokinases, phosphofructokinase or glucose-6-phosphate-dehydrogenase while it closely agreed with the response of H6PD catalytic function. Differently from glucose, coincubation with 2DG virtually abolished FDG uptake in cultured cells and their capability to concentrate 2NBDG within the endoplasmic reticulum. Conclusion: These data challenge the current dogma linking 2DG/FDG uptake to the glycolytic rate and introduce a new model to explain the relation between glucose analogues uptake and hexoses reticular metabolism. This selective fate of FDG contributes to the high sensitivity of PET imaging despite moderate hyperglycemia. References: None.