Are diabetic neuropathy, retinopathy and nephropathy caused by hyperglycemic exclusion of dehydroascorbate uptake by glucose transporters?
Vitamin C exists in two major forms. The charged form, ascorbic acid (AA), is taken up into cells via sodium-dependent facilitated transport. The uncharged form, dehydroascorbate (DHA), enters cells via glucose transporters (GLUT) and is then converted back to AA within these cells. Cell types such as certain endothelial and epithelial cells as well as neurons that are particularly prone to damage during diabetes tend to be those that appear to be dependent on GLUT transport of DHA rather than sodium-dependent AA uptake. We hypothesize that diabetic neuropathies, nephropathies and retinopathies develop in part by exclusion of DHA uptake by GLUT transporters when blood glucose levels rise above normal. AA plays a central role in the antioxidant defense system. Exclusion of DHA from cells by hyperglycemia would deprive the cells of the central antioxidant, worsening the hyperglycemia-induced oxidative stress level. Moreover, AA participates in many cellular oxidation-reduction reactions including hydroxylation of polypeptide lysine and proline residues and dopamine that are required for collagen production and metabolism and storage of catecholamines in neurons. Increase in the oxidative stress level and metabolic perturbations can be expected in any tissue or cell type that relies exclusively or mainly on GLUT for co-transport of glucose and DHA including neurons, epithelial cells, and vascular tissues. On the other hand, since DHA represents a significant proportion of total serum ascorbate, by increasing total plasma ascorbate concentrations during hyperglycemia, it should be possible to correct the increase in the oxidative stress level and metabolic perturbations, thereby sparing diabetic patients many of their complications.
Department of Physiology, Michigan State University, East Lansing, MI 48824, USA.
Robert
R
Root-Bernstein
Julia V
JV
Busik
Douglas N
DN
Henry
D001205:Ascorbic Acid / Q000378:metabolism; D001692:Biological Transport; D001786:Blood Glucose / Q000378:metabolism*; D003683:Dehydroascorbic Acid / Q000378:metabolism*; D003920:Diabetes Mellitus / Q000209:etiology*; D003928:Diabetic Nephropathies / Q000209:etiology / Q000378:metabolism; D003929:Diabetic Neuropathies / Q000209:etiology / Q000378:metabolism; D003930:Diabetic Retinopathy / Q000209:etiology / Q000378:metabolism; D004727:Endothelium / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008954:Models, Biological; D009004:Monosaccharide Transport Proteins / Q000378:metabolism*; D009420:Nervous System / Q000378:metabolism; D018384:Oxidative Stress; D012160:Retina / Q000378:metabolism
D001786:Blood Glucose; D009004:Monosaccharide Transport Proteins; D001205:Ascorbic Acid; D003683:Dehydroascorbic Acid