Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a common human 
enzymopathy that affects cellular redox status and may lower flux into 
nonoxidative pathways of glucose metabolism. Oxidative stress may worsen 
systemic glucose tolerance and cardiometabolic syndrome. We hypothesized that 
G6PD deficiency exacerbates diet-induced systemic metabolic dysfunction by 
increasing oxidative stress but in myocardium prevents diet-induced oxidative 
stress and pathology. WT and G6PD-deficient (G6PDX) mice received a standard 
high-starch diet, a high-fat/high-sucrose diet to induce obesity (DIO), or a 
high-fructose diet. After 31 wk, DIO increased adipose and body mass compared 
with the high-starch diet but to a greater extent in G6PDX than WT mice (24 and 
20% lower, respectively). Serum free fatty acids were increased by 77% and 
triglycerides by 90% in G6PDX mice, but not in WT mice, by DIO and high-fructose 
intake. G6PD deficiency did not affect glucose tolerance or the increased 
insulin levels seen in WT mice. There was no diet-induced hypertension or 
cardiac dysfunction in either mouse strain. However, G6PD deficiency increased 
aconitase activity by 42% and blunted markers of nonoxidative glucose pathway 
activation in myocardium, including the hexosamine biosynthetic pathway 
activation and advanced glycation end product formation. These results reveal a 
complex interplay between diet-induced metabolic effects and G6PD deficiency, 
where G6PD deficiency decreases weight gain and hyperinsulinemia with DIO, but 
elevates serum free fatty acids, without affecting glucose tolerance. On the 
other hand, it modestly suppressed indexes of glucose flux into nonoxidative 
pathways in myocardium, suggesting potential protective effects.