The detrimental effects of acute hyperglycemia on myocardial glucose uptake

Aims: Although acute hyperglycemic (AHG) episodes are linked to lower glucose uptake, underlying mechanisms remain unclear. We hypothesized that ARC triggers reactive oxygen species (ROS) production and increases non-oxidative glucose pathway (NOGP) activation, i.e. stimulation of advanced glycation end products (AGE), polyol pathway (PP), hexosamine biosynthetic pathway (HBP), PKC; thereby decreasing cardiac glucose uptake. Main methods: H9c2 cardiomyoblasts were exposed to 25 mM glucose for 24 h vs. 5.5 mM controls +/- modulating agents during the last hour of glucose exposure: a) antioxidant #1 for mitochondrial ROS (250 mu M 4-OHCA), b) antioxidant #2 for NADPH oxidase-generated ROS (100 mu M DPI), c) NOGP inhibitors - 100 mu M aminoguanidine (AGE), 5 mu M chelerythrine (PKC); 40 mu M DON (HBP); and 10 mu M zopolrestat (PP). ROS levels (mitochondrial, intracellular) and glucose uptake were evaluated by flow cytometry. Key findings: AHG elevated ROS, activated NOGPs and blunted glucose uptake. Transketolase activity (pentose phosphate pathway [PPP] marker) did not change. Respective 4-OHCA and DPI treatment blunted ROS production, diminished NOGP activation and normalized glucose uptake. NOGP inhibitory studies identified PKC beta II as a key downstream player in lowering insulin-mediated glucose uptake. When we employed an agent (benfotiamine) known to shunt flux away from NOGPs (into PPP), it decreased ROS generation and NOGP activation, and restored glucose uptake under AHG conditions. Significance: This study demonstrates that AHG elicits maladaptive events that function in tandem to reduce glucose uptake, and that antioxidant treatment and/or attenuation of NOGP activation (PKC, polyol pathway) may limit the onset of insulin resistance. (C) 2014 Elsevier Inc. All rights reserved.