Coordinate NOGP activation in response to acute hyperglycaemia results in contractile dysfunction during ischaemia-reperfusion, allowing for the development of novel cardioprotective agents.
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.
Acute hyperglycemia (AHG) e.g. high post‐prandial glycemic excursions are linked to lower glucose uptake. Chronic hyperglycemia can trigger reactive oxygen species (ROS) production and increase non‐oxidative glucose pathway (NOGP) flux, i.e. polyol pathway (PP), hexosamine biosynthetic pathway (HBP), advanced glycation end‐products (AGE), PKC, and contribute to insulin resistance. Since it is unclear whether a similar scenario exists with AHG, we hypothesized that ROS plays a pivotal role in AHG‐mediated NOGP activation and decreased myocardial glucose uptake. H9c2 cardiomyoblasts were exposed to 25 mM glucose for 24 h vs. 5 mM glucose controls ± therapeutic agents during last h of glucose exposure: a) antioxidant (250 μM 4‐OHCA), b) NOGP inhibitors − 100 μM aminoguanidine (AGE); 5 μM chelerythrine (PKC); 40 μM DON (HBP); and 10 μM zopolrestat (PP). ROS levels (mitochondrial, intracellular) and glucose uptake were evaluated by flow cytometry. AHG significantly increased mitochondrial and intracellular ROS levels, activated NOGP and blunted glucose uptake. However, transketolase (TK) activity (marker of pentose phosphate pathway) was not significantly altered. By contrast, 4‐OHCA treatment significantly reduced ROS, TK activity, NOGP activation and normalized glucose uptake. Each individual NOGP inhibitor blunted activation of the other pathways examined here. Our study reveals a convergence of downstream NOGP effects and identifies a vicious metabolic cycle, i.e. AHG stimulates NOGP that further fuel its own activation by generating more oxidative stress and further diminishing glucose uptake. Antioxidant treatment may be a useful approach to counter the potential detrimental effects of pronounced, acute hyperglycemic episodes.
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