Abstract
ObjectivesThe 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). MethodsThe study included 36 Balb/c mice. Two weeks after intraperitoneal administration of saline (control group, n = 18) or 150 mg streptozotocin (STZ-DM group, n = 18), the two cohorts were submitted to an oral glucose tolerance test and were further subdivided into three groups (n = 6 each): untreated and treated with metformin (MTF) at low or high doses (10 or 750 mg/kg daily, respectively). Two weeks thereafter, all mice were submitted to dynamic micro–positron emission tomography (PET) imaging after prolonged fasting. After sacrifice, enzymatic pathways and response to oxidative stress were evaluated in harvested SM. ResultsOn PET imaging, the FDG uptake rate in hindlimb SM was significantly lower in nondiabetic mice as compared with 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. Upon conventional analysis, the SM standard uptake value was higher in STZ-DM mice, 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, the H6PD enzymatic response to both STZ-DM and MTF matched the activation of the NADPH-dependent antioxidant responses to the increased generation of reactive oxygen species 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 increased radioactivity transfer to the endoplasmic reticulum. ConclusionsThese 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.
Highlights
Skeletal muscle (SM) is a key player in the pathogenesis of type 2 diabetes mellitus, accounting for up to 85% of insulin’s effect on blood clearance of glucose under physiologic conditions [1,2]
Effect of diabetes and MTF treatment on serum glucose level The studies were completed in all mice, and no visible side effects occurred after STZ or MTF administration
Both MTF regimens decreased serum glucose levels in streptozotocin-induced diabetes mellitus (STZ-DM) mice to values not significantly different from those of control mice, in which the biguanide was virtually ineffective (Figure 1C). This difference matched the response of blood FDG clearance: tracer removal from the bloodstream was reduced in all STZ-DM groups but not by MTF (Figure 1D)
Summary
Skeletal muscle (SM) is a key player in the pathogenesis of type 2 diabetes mellitus, accounting for up to 85% of insulin’s effect on blood clearance of glucose under physiologic conditions [1,2]. In the past decades, this complex methodology has been replaced by imaging techniques and, in particular, by the analysis of 18F-fluoro-deoxyglucose (FDG) kinetics with positron emission tomography (PET), which so far represents a reference method for studying muscular glucose metabolism (MRGlu). The theoretical basis for this approach has been described by Phelps et al [5], who extended FDG to the kinetic model previously described by Sokoloff and coworkers for brain uptake of 14C-2-deoxyglucose [6]. According to this model, FDG competes with glucose for transmembrane
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