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Exploring mechanisms that attenuate myocardial glucose uptake in response to acute hyperglycemia: identification of a vicious metabolic cycle
Author(s) -
Joseph Danzil,
Kimar Charlene Patricia,
Essop M. Faadiel
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.1192.8
Subject(s) - pentose phosphate pathway , glucose uptake , reactive oxygen species , oxidative stress , polyol pathway , mitochondrial ros , medicine , chemistry , carbohydrate metabolism , glycation , endocrinology , glucose transporter , oxidative phosphorylation , intracellular , glycolysis , insulin , diabetes mellitus , biochemistry , metabolism , biology , aldose reductase
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.