Hyperglycemia disrupts vitamin C physiology in vitro and in vivo: translational glucotoxicity

Authors

• K Patra
• H Tu
• Y Wang
• M Levine

Abstract

Vitamin C physiology is disrupted in diabetes in humans but mechanisms are unknown. Because epithelial cells are essential for normal vitamin C physiology, we hypothesized that epithelial cell function was disrupted by dysregulated vitamin C influx transport, efflux transport, or both. As a model we used human hepatocytes loaded to achieve physiologic intracellular vitamin C concentrations, with all vitamin C measures as mass measurements. We show that vitamin C efflux but not influx was reversibly inhibited by glucose concentrations at concentrations typical in diabetes (10mM), independent of insulin in vitro and in vivo. Vitamin C efflux inhibition by glucose required glucose uptake and metabolism, independent of reactive oxygen species formation, membrane potential, Ca flux, and ATP synthesis. Glucose 6-phosphate mediated efflux inhibition via increased protein synthesis that was m-TOR and transcription independent and reproduced by activating EIF2. These data indicate that hyperglycemia itself via excess glucose-6phosphate dysregulates vitamin C physiology in vitro and in vivo. The findings provide a unique explanation of why hyperglycemia produces complications of diabetes.

Scientific Focus Area: Cell Biology

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