1. Low Red Blood Cell Vitamin C Concentrations Induce Red Blood Cell Fragility: A Link to Diabetes Via Glucose, Glucose Transporters, and Dehydroascorbic Acid
- Author
-
Mark Levine, Yu Wang, Mahtab Niyyati, Hongyan Li, Jonathan A. Leshin, Yaohui Wang, and Hongbin Tu
- Subjects
Male ,Erythrocytes ,Glucose Transport Proteins, Facilitative ,DHA, dehydroascorbic acid ,Gene Expression ,lcsh:Medicine ,3-O-Methylglucose ,Ascorbic Acid ,Mice ,chemistry.chemical_compound ,Glucose Transport ,WT, wildtype mouse ,Red Blood Cells ,Biomass ,GLUT, facilitated glucose transporter ,Vitamin A ,SVCT, sodium-dependent vitamin C transporter ,Mice, Knockout ,lcsh:R5-920 ,Sewage ,Vitamin A Deficiency ,Polyhydroxyalkanoates ,Cell Cycle ,Diabetes ,β-Spectrin ,Erythrocyte fragility ,hemic and immune systems ,General Medicine ,Dehydroascorbic Acid ,3. Good health ,medicine.anatomical_structure ,Dehydroascorbic acid ,lcsh:Medicine (General) ,Research Article ,circulatory and respiratory physiology ,3-O-MG, 3-O-methylglucose ,medicine.medical_specialty ,Biology ,RIPA, Western blot cell lysis buffer ,General Biochemistry, Genetics and Molecular Biology ,Diabetes Mellitus, Experimental ,PBS, phosphate buffered saline ,Internal medicine ,Diabetes mellitus ,Diabetes Mellitus ,medicine ,Animals ,Humans ,Gulo-/-, gulonolactone oxidase knockout mouse unable to synthesize ascorbate ,Obesity ,Bacteria ,Vitamin C ,lcsh:R ,Glucose transporter ,Biological Transport ,TCEP, Tris(2-carboxyethyl)phosphine ,medicine.disease ,Ascorbic acid ,United Kingdom ,Osmotic Fragility ,Red blood cell ,Glucose ,Endocrinology ,Diabetes Mellitus, Type 2 ,chemistry ,Starvation ,Commentary ,RBCs, red blood cells ,AA, ascorbic acid - Abstract
Strategies to prevent diabetic microvascular angiopathy focus on the vascular endothelium. Because red blood cells (RBCs) are less deformable in diabetes, we explored an original concept linking decreased RBC deformability to RBC ascorbate and hyperglycemia. We characterized ascorbate concentrations from human and mouse RBCs and plasma, and showed an inverse relationship between RBC ascorbate concentrations and deformability, measured by osmotic fragility. RBCs from ascorbate deficient mice were osmotically sensitive, appeared as spherocytes, and had decreased β-spectrin. These aberrancies reversed with ascorbate repletion in vivo. Under physiologic conditions, only ascorbate's oxidation product dehydroascorbic acid (DHA), a substrate for facilitated glucose transporters, was transported into mouse and human RBCs, with immediate intracellular reduction to ascorbate. In vitro, glucose inhibited entry of physiologic concentrations of dehydroascorbic acid into mouse and human RBCs. In vivo, plasma glucose concentrations in normal and diabetic mice and humans were inversely related to respective RBC ascorbate concentrations, as was osmotic fragility. Human RBC β-spectrin declined as diabetes worsened. Taken together, hyperglycemia in diabetes produced lower RBC ascorbate with increased RBC rigidity, a candidate to drive microvascular angiopathy. Because glucose transporter expression, DHA transport, and its inhibition by glucose differed for mouse versus human RBCs, human experimentation is indicated.
- Published
- 2015