Delayed response of insulin-stimulated fluorine-18 deoxyglucose uptake in glucose transporter-4-null mice hearts

Objectives We sought to evaluate the time course of insulin-stimulated myocardial glucose uptake (MGU) in mice that had undergone ablation of glucose transporter-4 (GLUT4). Background The relative importance of GLUT4, the most abundant insulin-responsive glucose transporter, to modulate myocardial glucose metabolism is not well defined. Methods Myocardial glucose uptake was assessed at various time points after glucose (1 mg/g) and insulin (8 mU/g) injection in GLUT4-null (G4N) (n = 48) and wild-type (WT) (n = 48) mice with ¹⁸F-2-deoxy-2-fluoro-D-glucose (FDG) using in vivo positron emission tomography (PET), in vitro gamma-counter biodistribution, and isolated, perfused hearts. Results Baseline assessment with PET imaging showed comparable MGU in G4N (0.66 ± 0.12) and WT (0.67 ± 0.11, p = 0.70) mice. Early after insulin injection, WT mice demonstrated a 3.5-fold increase in MGU (2.45 ± 0.45, p = 0.03), whereas G4N mice presented no increase (1.11 ± 0.24, p = 0.28). At 60 min, MGU was comparable in G4N (3.19 ± 0.60) and WT (2.66 ± 0.47, p = 0.28) mice. In vitro gamma-counter biodistribution evaluation confirmed in G4N mice a lack of MGU increase early after insulin, but a slow response over 120 min. The isolated, perfused hearts of G4N mice during short-term (15 min) insulin stimulation displayed no increase in MGU (0.08 ± 0.01 ml/g/min), whereas WT mice presented a threefold increase (0.22 ± 0.01 ml/g/min, p < 0.01). With long-term (60 min) insulin stimulation, similar MGU was found in G4N (0.31 ± 0.02 ml/g/min) and WT (0.33 ± 0.04 ml/g per min, p = 0.04) mice. Conclusions The G4N mice displayed an increase of MGU in response to insulin similar to that of controls, but with a markedly delayed time response. Our findings underscore the important role of GLUT4 in the rapid adaptive response of myocardial glucose metabolism.