FDG uptake tracks the oxidative damage in diabetic skeletal muscle: an experimental study

Abstract Objectives The present study aims to verify the relationship between glucose consumption and uptake of [18F]-2-deoxy-glucose (FDG) in the skeletal muscle (SM) of experimental models of streptozotocin-induced diabetes mellitus (STZ-DM). Methods The study included 36 Balb/c mice. Two weeks after intraperitoneal administration of saline (n=18 “control”) or 150 mg streptozotocin (n=18 “STZ-DM”), the two cohorts were submitted to oral glucose tolerance test and were further subdivided into three groups (n=6 each) untreated and treated metformin (MTF) at low or high doses (10 or 750 mg/Kg daily, respectively). Two weeks thereafter, all mice were submitted to dynamic micro-PET imaging after prolonged fasting. After sacrifice, enzymatic pathways and response to oxidative stress were evaluated in harvested SM. Results At PET imaging, FDG uptake rate in hindlimb SM was significantly lower in non-diabetic with respect to STZ-DM untreated mice. MTF had no significant effect on SM FDG uptake in untreated mice, however its high dose induced a significant decrease in STZ-DM animals. At conventional analysis, SM standard uptake value (SUV) was higher in STZ-DM while MTF was virtually ineffective in either control or STZ-DM models. This metabolic reprogramming was not explained by any change in cytosolic glucose metabolism. By contrast, it closely agreed with the catalytic function of hexose-6P-dehydrogenase (H6PD), i.e. the trigger of a specific pentose phosphate pathway selectively located within the endoplasmic reticulum. In agreement with this role, H6PD enzymatic response to both STZ-DM and MTF matched the activation of the NADPH-dependent antioxidant responses to the increased ROS generation caused by chronic hyperglycemia. Ex vivo analysis of tracer kinetics confirmed that the enhanced SM avidity for FDG occurred despite a significant reduction in glucose consumption while it was associated with an increased radioactivity transfer to the endoplasmic reticulum. Conclusions These data challenge the current dogma linking FDG uptake to the glycolytic rate. They instead introduce a new model considering a strict link between the uptake of this glucose analog, H6PD reticular activity and oxidative damage in diabetes, at least under fasting condition.