Low Red Blood Cell Vitamin C Concentrations Induce Red Blood Cell Fragility: A Link to Diabetes Via Glucose, Glucose Transporters, and Dehydroascorbic Acid

EBioMedicine. 2015 Oct 3;2(11):1735-50. doi: 10.1016/j.ebiom.2015.09.049. eCollection 2015 Nov.


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.

Keywords: 3-O-MG, 3-O-methylglucose; AA, ascorbic acid; Ascorbic Acid; DHA, dehydroascorbic acid; Dehydroascorbic Acid; Diabetes; GLUT, facilitated glucose transporter; Glucose Transport; Gulo-/-, gulonolactone oxidase knockout mouse unable to synthesize ascorbate; PBS, phosphate buffered saline; RBCs, red blood cells; RIPA, Western blot cell lysis buffer; Red Blood Cells; SVCT, sodium-dependent vitamin C transporter; TCEP, Tris(2-carboxyethyl)phosphine; WT, wildtype mouse; β-Spectrin.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Ascorbic Acid / metabolism*
  • Biological Transport
  • Dehydroascorbic Acid / metabolism
  • Diabetes Mellitus, Experimental
  • Diabetes Mellitus, Type 2
  • Erythrocytes / metabolism*
  • Gene Expression
  • Glucose / metabolism
  • Glucose Transport Proteins, Facilitative / deficiency
  • Glucose Transport Proteins, Facilitative / genetics
  • Glucose Transport Proteins, Facilitative / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Osmotic Fragility*


  • Glucose Transport Proteins, Facilitative
  • Glucose
  • Ascorbic Acid
  • Dehydroascorbic Acid