Glucose 6-Phosphate Dehydrogenase, Macronutrient Intake, and Heart Failure

Abstract

Glucose 6-phosphate dehydrogenase (G6PD) catalyzes the conversion of G6P to 6-phosphogluconolactone and formation of NADPH. Human G6PD deficiency is very common, and may affect the development of metabolic abnormalities and heart failure through its affects on reactive oxygen species (ROS). NADPH fuels antioxidant pathways, but also fuels oxidant production by NADPH oxidase, uncoupled nitric oxide synthase, and other enzymes. Evidence suggests that high sugar intake, obesity, and heart failure increase [NADPH] and ROS formation, possibly by increasing the flux of glucose through G6PD. Therefore the goal of this project was to determine whether G6PD deficiency protects against or exacerbates oxidative stress and cardiac dysfunction in the context of obesity, high sugar intake, and heart failure. First, we found that G6PD deficiency decreased obesity but not metabolic abnormalities after long term dietary treatment. Second, G6PD deficiency moderately exacerbated redox stress and heart failure mediated by myocardial infarction, severe pressure overload, or mild pressure overload with high fructose intake. Third, although high sugar intake increased superoxide production, this did not correspond with increases in [NADPH] or mortality in a genetic model of cardiomyopathy. The results indicate that G6PD deficiency moderately exacerbates oxidative stress, diet-induced metabolic dysfunction, and heart failure.