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.

Highlights

  • Diabetes type 2 is an epidemic public health problem

  • The original clue linking ascorbate, diabetes and red blood cells (RBCs) came from unexpected observations of whole blood obtained from mice (Gulo−/−) unable to synthesize vitamin C

  • Ascorbate in RBCs from these subjects was inversely correlated with fasting glucose (Fig. 7A, supplementary Fig. 7); and osmotic fragility and severity of diabetes (Fig. 7B)

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Summary

Introduction

Diabetes type 2 is an epidemic public health problem. Controlled diabetes results in accelerated microvascular disease and chronic debilitating morbidities and mortality (Beckman et al, 2002). Diabetic microvascular angiopathy is the leading cause of blindness, end stage renal disease and amputations worldwide, as well as myocardial infarction, stroke and peripheral arterial disease. Preventing or delaying microvascular disease could improve the lives of millions, prevent catastrophic illness, and save billions of dollars. The pathogenesis of microangiopathy in diabetes is unknown. Clinical efforts are based on glycemic control. The research focus of some prevention efforts is the endothelium and its role in protecting blood vessels (Fioretto et al, 2010; Wong et al, 2010). Platelet dysfunction, abnormal coagulation and impaired vascular repair

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