Long-Term Effects of Increased Glucose Entry on Mouse Hearts During Normal Aging and Ischemic Stress

Abstract

Background— A shift of substrate preference toward glucose in the heart is considered a reversion to fetal metabolic profile, but its role in the pathogenesis of cardiac diseases is incompletely understood. Methods and Results— We performed a 2-year follow-up study in transgenic mice with sustained high glucose uptake and utilization in the heart by cardiac-specific overexpression of the insulin-independent glucose transporter GLUT1 (GLUT1-TG). Compared with wild-type litter mates, the GLUT1-TG mice showed a normal survival rate and unaltered contractile function of the heart monitored by serial echocardiography and by pressure–volume studies in isolated perfused hearts in the 2-year period. Furthermore, when hearts were subjected to ischemia-reperfusion, cardiac function of young and old GLUT1-TG recovered to the same level (86% and 83%, respectively) and exceeded that of both young and old wild-type hearts (52% and 35%, respectively; P <0.05). Nuclear magnetic resonance spectroscopic measurements with 31 P showed delayed ATP depletion, reduced acidosis during ischemia, and improved recovery of high-energy phosphate content in old GLUT1-TG hearts ( P <0.05 versus old wild-type). During reperfusion, glucose oxidation was 3-fold higher and fatty acid oxidation was 45% lower in old GLUT1-TG hearts compared with old wild-type ( P <0.05), which suggests that the deleterious effects of excessive fatty acid oxidation during reperfusion was prevented in old GLUT1-TG hearts. Conclusions— We have demonstrated that a normal heart is able to adapt to long-term increases in basal glucose entry into cardiomyocytes without development of glucotoxicity. Furthermore, life-long increases in glucose uptake result in a favorable metabolic phenotype that affords protections against aging-associated increase of susceptibility to ischemic injury.