Are Diabetic Neuropathy, Retinopathy and Nephropathy Caused by Hyperglycemic Exclusion of Dehydroascorbate Uptake by Glucose Transporters?

Root‐Bernstein, Robert; Busik, Julia V.; Henry, Douglas N.

doi:10.1006/jtbi.2002.2535

Cited by 36 publications

(33 citation statements)

References 96 publications

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“…Oxidative stress is implicated in the pathogenesis of DN (7). As a powerful antioxidant, ascorbate plays a crucial role in the antioxidant defense system and helps to relieve the oxidative stress associated with diabetic complications (25). A higher level of ascorbate was detected in urine samples from diabetic 8-wk rats, but not diabetic 2-wk rats.…”

Section: F953mentioning

confidence: 98%

¹H-NMR-based metabonomic analysis of metabolic profiling in diabetic nephropathy rats induced by streptozotocin

Zhao

Gao

Lian

et al. 2011

American Journal of Physiology-Renal Physiology

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Elucidation of the metabolic profiling in diabetic nephropathy (DN) rats is of great assistance for understanding the pathogenesis of DN. In this study, 1H-nuclear magnetic resonance (NMR)-based metabonomics combined with HPLC measurements was used to quantitatively analyze the metabolic changes in urine and kidney extracts from diabetic 2-wk and 8-wk rats induced by streptozotocin (STZ). Pattern recognition analysis of either urine or kidney extracts indicated that the two diabetic groups were separated obviously from the control group, suggesting that the metabolic profiles of the diabetic groups were markedly different from the control. The diabetic 8-wk rats showed lower levels of creatine, dimethylamine, and higher levels of ascorbate, succinate, lactate, citrate, allantoin, 2-ketoglutarate, and 3-hydrobutyrate (3-HB) in the urine samples. Moreover, the diabetic 8-wk rats displayed lower levels of succinate, creatine, myo-inositol, alanine, lactate, and ATP, and higher levels of 3-HB and glucose in the kidney extracts. The observed metabolic changes imply the enhanced pathways of either lipid or ketone body synthesis and decreased pathways of either tricarboxylic acid cycle or glycolysis in DN rats compared with the control. Our results suggest that the energy metabolic changes are associated with the pathogenic process of DN.

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Section: F953mentioning

confidence: 98%

¹H-NMR-based metabonomic analysis of metabolic profiling in diabetic nephropathy rats induced by streptozotocin

Zhao

Gao

Lian

et al. 2011

American Journal of Physiology-Renal Physiology

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“…Continuous reduction of DHA increases cellular ascorbate stores to levels 10-100 times higher than plasma concentration depending on the cell type. Insulin was observed to increase DHA uptake [63], high levels of blood glucose as in poorly controlled diabetes theoretically decrease DHA uptake by 30-80% [64]. Slowing of DHA uptake may render cells that primarily rely on DHA uptake such as some cells of the kidney and intestine [65] with an impaired antioxidant capacity.…”

Section: Dehydroascorbic Acidmentioning

confidence: 99%

“…Slowing of DHA uptake may render cells that primarily rely on DHA uptake such as some cells of the kidney and intestine [65] with an impaired antioxidant capacity. Consequently, the development of diabetic nephropathy has in part been attributed to the exclusion of DHA from cellular uptake resulting in a disturbed intracellular redox homeostasis [64]. Deficient regeneration of ascorbate from DHA may contribute to the development of osteopenia since ascorbate is a cofactor for collagen synthesis by osteoblasts [63].…”

Section: Dehydroascorbic Acidmentioning

confidence: 99%

Vitamin C in Chronic Kidney Disease and Hemodialysis Patients

Deicher

Hörl

2003

Kidney Blood Press Res

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Increments of oxidative stress have been addressed as one potential cause for the accelerated atherosclerosis of chronic kidney disease patients. Ascorbate represents one of the most prominent antioxidants both in plasma as well as intracellulary, exerting beneficial effects by an inhibition of lipid peroxidation and by reducing endothelial dysfunction. However, in the presence of transition metals like iron, ascorbate may give rise to an increased generation of oxidants, and ascorbylation may impose additional carbonyl stress to uremic patients. Unsupplemented dialysis patients have reportedly lower plasma levels of ascorbate in comparison to healthy controls, mostly due to a loss into the dialysate or, in case of not dialyzed patients, increased urinary losses. Currently, 60 mg of ascorbate are recommended for chronic kidney disease patients, and 1–1.5 g of oral ascorbate/week in case of suspected subclinical ascorbate deficiency or 300 mg parenteral ascorbate/dialysis session, respectively. Ascorbate’s role in modifying arterial blood pressure remains unclear, but anemic patients with functional iron deficiency might benefit from short-term, moderately dosed ascorbate supplements.

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“…4,5) Reduction of the supply of AA to the retina and brain through competition of D-glucose and DHA for a common transporter would reduce the antioxidant and could lead to accumulation of reactive oxygen species followed by acti- vation of the protein kinase C and aldose reductase pathway and advanced glycation end-products in the retina and brain. 20) Moreover, AA is a required cofactor for several intracellular hydroxylases, including proline hydroxylase and dopamine-b-hydroxylase. 1) Therefore, chronic hyperglycemia appears to cause disregulation of catecholamine metabolism in the retina and brain.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Dehydroascorbic Acid Transport across the Rat Blood-Retinal and -Brain Barriers in Experimental Diabetes

Minamizono

Tomi

Hosoya

2006

Biological & Pharmaceutical Bulletin

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Vitamin C plays an essential role as a cofactor involved in the enzymatic biosynthesis of collagen, catecholamine, and peptide neurohormones and antioxidant and free radical scavengers to detoxify free radicals in the retina and brain. 1)Vitamin C is present in retinal and brain tissues at high concentrations compared with other organs and there is a greater than 10-fold gradient between the concentration of ascorbic acid (AA) in the retina and brain tissues and blood.2,3) Recent reports indicate that vitamin C is mainly transported across the blood-retinal barrier (BRB) and -brain barrier (BBB) as dehydroascorbic acid (DHA) via a facilitative glucose transporter, GLUT1, and accumulates as AA in the retina and brain.4-6) DHA, which is an oxidized form of AA, is present at a concentration of 10 mM in rat and human plasma. 7,8) To maintain a high concentration of AA in the retina and brain, GLUT1 at the BRB and BBB supplies DHA to the retina and brain as well as D-glucose under normal conditions. Thus, one hypothesis to explain its action in diabetes mellitus is that hyperglycemia inhibits the supply of DHA to the retina and brain because of competitive inhibition of D-glucose for DHA transport via GLUT1.The purpose of this study was to evaluate how the DHA transport to the retina and brain changes under hyperglycemic conditions by using integration plot analysis in streptozotocin-induced diabetic and normal rats. MATERIALS AND METHODS AnimalsMale Wistar rats at 3 weeks of age (body weights: 50-55 g) were purchased from SLC (Shizuoka, Japan). The investigations using rats described in this report conformed to the provisions of the Animal Care Committee, Toyama Medical and Pharmaceutical University (currently University of Toyama) (#2004-48) and the ARVO Statement on the Use of Animals in Ophthalmic and Vision Research. 5) All other chemicals were of reagent grade and available commercially.Animal Model of Diabetes Melitus Rats at 3 weeks of age were randomly assigned to become diabetic (nϭ5) or to remain non-diabetic controls (nϭ5). Diabetes was induced by the injection of a freshly prepared solution of streptozotocin in citrate buffer (pH 4.5) at a dose of 45 mg/kg into the tail vein, whereas non-diabetic control rats were treated with citrate buffer alone. A sample of blood was obtained from this vein over a period from 1 to 3 weeks after streptozotocin injection for measurement of the blood D-glucose concentrations to confirm the presence of hyperglycemia. Blood glucose concentrations were determined by the glucoseoxidase method (Nipro Freestyle, Osaka, Japan).Determination of Influx Permeability Clearance The rats were anesthetized with an intramuscular injection of ketamine-xylazine (1.22 mg xylazine and 125 mg ketamine/kg) and then [ 14 C]DHA (5 mCi/rat, approximately 200 mmol DHA in 200 ml/head) was injected via the femoral vein. At the times designated (0.5, 1, 3 or 5 min) after administration, rats were sacrificed and the plasma and tissues were removed. Tissue sampling and determination of radioactivity ...

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Are Diabetic Neuropathy, Retinopathy and Nephropathy Caused by Hyperglycemic Exclusion of Dehydroascorbate Uptake by Glucose Transporters?

Cited by 36 publications

References 96 publications

¹H-NMR-based metabonomic analysis of metabolic profiling in diabetic nephropathy rats induced by streptozotocin

¹H-NMR-based metabonomic analysis of metabolic profiling in diabetic nephropathy rats induced by streptozotocin

Vitamin C in Chronic Kidney Disease and Hemodialysis Patients

Inhibition of Dehydroascorbic Acid Transport across the Rat Blood-Retinal and -Brain Barriers in Experimental Diabetes

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Are Diabetic Neuropathy, Retinopathy and Nephropathy Caused by Hyperglycemic Exclusion of Dehydroascorbate Uptake by Glucose Transporters?

Cited by 36 publications

References 96 publications

1H-NMR-based metabonomic analysis of metabolic profiling in diabetic nephropathy rats induced by streptozotocin

1H-NMR-based metabonomic analysis of metabolic profiling in diabetic nephropathy rats induced by streptozotocin

Vitamin C in Chronic Kidney Disease and Hemodialysis Patients

Inhibition of Dehydroascorbic Acid Transport across the Rat Blood-Retinal and -Brain Barriers in Experimental Diabetes

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¹H-NMR-based metabonomic analysis of metabolic profiling in diabetic nephropathy rats induced by streptozotocin

¹H-NMR-based metabonomic analysis of metabolic profiling in diabetic nephropathy rats induced by streptozotocin