Diabetes-Induced Changes in Retinal NAD-Redox Status
Abstract
Diabetes-induced changes in retinal metabolism and function have been linked to increased aldose reductase activity, hypoxia or ‘pseudohypoxia’ (increase in NADH/NAD+ attributed to increased sorbitol dehydrogenase activity). To address this controversy, we evaluated the effects of two vasoactive compounds, α 1-adrenoceptor antagonist prazosin and antioxidant DL-α-lipoic acid, as well as sorbitol dehydrogenase inhibitor (SDI-157) and aldose reductase inhibitor (sorbinil) on retinal free mitochondrial and cytosolic NAD+/NADH ratios in streptozotocin-diabetic rats. Diabetes-induced decrease in mitochondrial and cytosolic NAD+/NADH ratios was completely or partially corrected by prazosin and DL-α-lipoic acid (despite the fact that prazosin did not affect and DL-α-lipoic acid even further increased sorbitol pathway activity) as well as by sorbinil, whereas SDI-157 was totally ineffective. Hypoxia-like metabolic changes in the diabetic retina originate from aldose reductase, but not sorbitol dehydrogenase activity.
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In STZ-diabetic rats, α-lipoic acid mitigated the diabetes-induced decrease in retinal mitochondrial and cytosolic NAD+/NADH ratio.
“In STZ-diabetic rats, α-lipoic acid mitigated the diabetes-induced decrease in retinal mitochondrial and cytosolic NAD+/NADH ratio (243).”
From Mitochondrial Dysfunction in Diabetes: From Molecular Mechanisms to Functional Significance and Therapeutic Opportunities (2010) · cites this paper as [243]
Cites
A Flexible System of Enzymatic Analysis
Lowry, O. H., & Passonneau, J. V. (1972) · Elsevier eBooks · doi:10.1016/b978-0-12-457950-7.x5001-3 · Cited by 4,050 · see citing works
Williamson, D., Lund, P., & Krebs, H. (1967) · Biochemical Journal · doi:10.1042/bj1030514 · Cited by 1,871 · see citing works
Hyperglycemic Pseudohypoxia and Diabetic Complications
Williamson, J. R., Chang, K. C., Frangos, M., Hasan, K. S., Ido, Y., Kawamura, T., Nyengaard, J. R., den Enden, M. V., Kilo, C., & Tilton, R. G. (1993) · Diabetes · doi:10.2337/diab.42.6.801 · Cited by 1,092 · see citing works
The formation of methylglyoxal from triose phosphates
Phillips, S. A., & Thornalley, P. J. (1993) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1993.tb17638.x · Cited by 565 · see citing works
Tuck, R. R., Schmelzer, J. D., & Low, P. A. (1984) · Brain · doi:10.1093/brain/107.3.935 · Cited by 424 · see citing works
Nagamatsu, M., Nickander, K. K., Schmelzer, J. D., Raya, Á., Wittrock, D. A., Tritschler, H., & Low, P. A. (1995) · Diabetes Care · doi:10.2337/diacare.18.8.1160 · Cited by 378 · see citing works
The role of aldose reductase in the development of diabetic complications
Kador, P. F. (1988) · Medicinal Research Reviews · doi:10.1002/med.2610080302 · Cited by 298 · see citing works
Cameron, N. E., Cotter, M. A., Archibald, V., Dines, K. C., & Maxfield, E. K. (1994) · Diabetologia · doi:10.1007/s001250050131 · Cited by 240 · see citing works
Retinal hypoxia in long-term diabetic cats.
Linsenmeier, R. A., Braun, R. D., McRipley, M. A., et al. (1998) · PubMed · Cited by 232 · see citing works
Cameron, N. E., Cotter, M. A., Basso, M., & Hohman, T. C. (1997) · Diabetologia · doi:10.1007/s001250050674 · Cited by 154 · see citing works
Kador, P. F. (1990) · Archives of Ophthalmology · doi:10.1001/archopht.1990.01070110117035 · Cited by 154 · see citing works
Rudich, A., Tirosh, A., Potashnik, R., Khamaisi, M., & Bashan, N. (1999) · Diabetologia · doi:10.1007/s001250051253 · Cited by 150 · see citing works
Tilton, R. G., Chang, K. C., Nyengaard, J. R., den Enden, M. V., Ido, Y., & Williamson, J. R. (1995) · Diabetes · doi:10.2337/diab.44.2.234 · Cited by 150 · see citing works
Aldose Reductase Inhibition Protects Diabetic and Nondiabetic Rat Hearts from Ischemic Injury
Ramasamy, R., Oates, P. J., & Schaefer, S. (1997) · Diabetes · doi:10.2337/diab.46.2.292 · Cited by 137 · see citing works
Cameron, N. E., Cotter, M. A., Jack, A. M., Basso, M., & Hohman, T. C. (1999) · Diabetologia · doi:10.1007/s001250051280 · Cited by 132 · see citing works
Effect of Carbon Dioxide on Cerebral Metabolism during Hypoxia-Ischemia in the Immature Rat
Vannucci, R. C., Brucklacher, R. M., & Vannucci, S. J. (1997) · Pediatric Research · doi:10.1203/00006450-199707000-00005 · Cited by 131 · see citing works
Diabetes-induced vascular dysfunction in the retina: role of endothelins
Deng, D. X., Evans, T., Mukherjee, K., Downey, D. B., & Chakrabarti, S. (1999) · Diabetologia · doi:10.1007/s001250051296 · Cited by 127 · see citing works
Permeability of ocular vessels and transport across the blood-retinal-barrier
Törnquist, P., Alm, A., & Bill, A. (1990) · Eye · doi:10.1038/eye.1990.41 · Cited by 116 · see citing works
Increased NADH Oxidase Activity in the Retina of the BBZ/WOR Diabetic Rat
Ellis, E. A., Grant, M. B., Murray, F. T., et al. (1998) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(97)00202-5 · Cited by 113 · see citing works
Sasaki, H., Schmelzer, J. D., Zollman, P. J., et al. (1997) · Acta Neuropathologica · doi:10.1007/s004010050592 · Cited by 103 · see citing works
Kishi, Y., Schmelzer, J. D., Yao, J. K., Zollman, P. J., Nickander, K. K., Tritschler, H., & Low, P. A. (1999) · Diabetes · doi:10.2337/diabetes.48.10.2045 · Cited by 99 · see citing works
Cameron, N. E., Cotter, M. A., & Hohman, T. C. (1996) · Diabetologia · doi:10.1007/bf00403960 · Cited by 97 · see citing works
The Gibbs-Donnan near-equilibrium system of heart
Masuda, T., Dobson, G. P., & Veech, R. L. (1990) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)30507-0 · Cited by 96 · see citing works
González, A.-M., Sochor, M., & McLean, P. (1983) · Diabetes · doi:10.2337/diab.32.5.482 · Cited by 95 · see citing works
Bursell, S. E., Takagi, C., Clermont, A., et al. (1997) · PubMed · Cited by 92 · see citing works
Modulation of cellular reducing equivalent homeostasis by α-lipoic acid
Roy, S., Sen, C. K., Tritschler, H., & Packer, L. (1997) · Biochemical Pharmacology · doi:10.1016/s0006-2952(96)00764-2 · Cited by 85 · see citing works
Endothelial cell dysfunction and the pathogenesis of diabetic macroangiopathy
Laight, D. W., CARRIER, M. J., & Änggård, E. (1999) · Diabetes/Metabolism Research and Reviews · doi:10.1002/(sici)1520-7560(199907/08)15:4 · Cited by 82 · see citing works
Subnormal retinal oxygenation response precedes diabetic-like retinopathy.
Berkowitz, B. A., Kowluru, R. A., Frank, R. N., et al. (1999) · PubMed · Cited by 78 · see citing works
Obrosova, I. G., Cao, X., Greene, D. A., et al. (1998) · Diabetologia · doi:10.1007/s001250051090 · Cited by 78 · see citing works
Self-citationGlucose metabolism of the inner retina in pigs in darkness and light
Wang, L., Törnquist, P., & Bill, A. (1997) · Acta Physiologica Scandinavica · doi:10.1046/j.1365-201x.1997.00030.x · Cited by 76 · see citing works
Frank, R. N. (1997) · Archives of Ophthalmology · doi:10.1001/archopht.1997.01100160206011 · Cited by 75 · see citing works
Obrosova, I. G., Fathallah, L., Lang, H., et al. (1999) · Diabetologia · doi:10.1007/s001250051290 · Cited by 71 · see citing works
Self-citationGlucose transporters in rat peripheral nerve: Paranodal expression of GLUT1 and GLUT3
Magnani, P., Cherian, P., Gould, G. W., Greene, D. A., Sima, A. A. F., & Brosius, F. C. (1996) · Metabolism · doi:10.1016/s0026-0495(96)90174-2 · Cited by 71 · see citing works
Winkler, B. S., Arnold, M. J., Brassell, M. A., et al. (1997) · PubMed · Cited by 70 · see citing works
Gonzalez, A. M., Sochor, M., Hothersall, J. S., et al. (1986) · Diabetes · doi:10.2337/diab.35.11.1200 · Cited by 67 · see citing works
McCaleb, M. L., McKean, M., Hohman, T. C., et al. (1991) · Diabetologia · doi:10.1007/bf00401513 · Cited by 56 · see citing works
Interaction between osmotic and oxidative stress in diabetic precataractous lens
Obrosova, I. G., Fathallah, L., & Lang, H. (1999) · Biochemical Pharmacology · doi:10.1016/s0006-2952(99)00315-9 · Cited by 54 · see citing works
Self-citationThe use of electrophysiology for the assessment of diabetic neuropathy
Arezzo, J. C. (1997) · Neuroscience Research Communications · doi:10.1002/(sici)1520-6769(199707)21:1 · Cited by 53 · see citing works
Hotta, N., Koh, N., Sakakibara, F., Nakamura, J., Hamada, Y., Hara, T., Mori, K., Nakashima, E., Naruse, K., Fukasawa, H., et al. (1996) · Diabetes · doi:10.2337/diab.45.3.361 · Cited by 52 · see citing works
Obrosova, I. G., Huysen, C. V., Fathallah, L., Cao, X., Stevens, M. J., & Greene, D. A. (2000) · The FASEB Journal · doi:10.1096/fj.99-0803com · Cited by 51 · see citing works
Self-citationObrosova, I. G., Faller, A. M., Burgan, J., Ostrow, E., & Williamson, J. R. (1997) · Current Eye Research · doi:10.1076/ceyr.16.1.34.5113 · Cited by 49 · see citing works
Self-citationNeuenschwander, H., Takahashi, Y., & Kador, P. F. (1997) · Journal of Ocular Pharmacology and Therapeutics · doi:10.1089/jop.1997.13.517 · Cited by 44 · see citing works
Diabetic-like retinopathy ameliorated with the aldose reductase inhibitor WAY-121,509.
Robinson, W. G., Laver, N., JACOT, J. L., et al. (1996) · PubMed · Cited by 42 · see citing works
Adrenergic alpha 1 and alpha 2 binding sites are present in bovine retinal blood vessels.
Forster, B. A., Ferrari-Dileo, G., & Anderson, D. R. (1987) · PubMed · Cited by 42 · see citing works
Changes in the Redox State in the Retina and Brain During the Onset of Diabetes in Rats
Salceda, R., Vilchis, C., Coffe, V., et al. (1998) · Neurochemical Research · doi:10.1023/a:1022467230259 · Cited by 42 · see citing works
Heath, H., Kang, S. S., & Philippou, D. (1975) · Diabetologia · doi:10.1007/bf00422819 · Cited by 41 · see citing works
Kador, P. F., Inoue, J., SECCHI, E. F., et al. (1998) · Experimental Eye Research · doi:10.1006/exer.1998.0502 · Cited by 40 · see citing works
Sorbitol-accumulating pyrimidine derivatives.
Geisen, K., Utz, R., Grötsch, H., et al. (1994) · PubMed · Cited by 39 · see citing works
Effects of Antioxidants on Ischemic Retinal Dysfunction
Block, F., & Schwarz, M. (1997) · Experimental Eye Research · doi:10.1006/exer.1996.0244 · Cited by 35 · see citing works
Effects of carbon dioxide-induced anesthesia on cholinergic parameters in rat brain.
Berger-Sweeney, J. E., Berger, U. V., Sharma, M., & Paul, C. A. (1994) · PubMed · Cited by 33 · see citing works
Kuruvilla, R., & Eichberg, J. (1998) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1998.71020775.x · Cited by 32 · see citing works
Increases in retinovascular prostaglandin receptor functions by cyclooxygenase-1 and -2 inhibition.
Hardy, P., Bhattacharya, M., Abran, D., et al. (1998) · PubMed · Cited by 31 · see citing works
Effects of aldose reductase inhibitor on retinal microangiopathy in streptozotocin-diabetic rats.
Kojima, K., Matsubara, H., Harada, T., et al. (1985) · PubMed · Cited by 28 · see citing works
Effect of Sorbitol Dehydrogenase Inhibition on Experimental Diabetic Autonomic Neuropathy
Schmidt, R. E., DORSEY, D. A., Beaudet, L. N., et al. (1998) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/00005072-199812000-00010 · Cited by 27 · see citing works
González, A.-M., Sochor, M., & McLean, P. (1980) · Biochemical and Biophysical Research Communications · doi:10.1016/0006-291x(80)91596-x · Cited by 27 · see citing works
Diabetic-like retinopathy: early and late intervention therapies in galactose-fed rats.
Robison, W. G., JACOT, J. L., Glover, J. P., et al. (1998) · PubMed · Cited by 26 · see citing works
Cameron, N. E., Cotter, M. A., Dines, K. C., et al. (1996) · Journal of Diabetes and its Complications · doi:10.1016/1056-8727(94)00076-x · Cited by 25 · see citing works
Amelioration of Diabetes-like Retinal Changes in Galactose-Fed Dogs
Kador, P. F., Takahashi, Y., Sato, S., et al. (1994) · Preventive Medicine · doi:10.1006/pmed.1994.1122 · Cited by 25 · see citing works
Okuda, Y., Kawashima, K., Suzuki, S., Asakura, Y., Asano, M., Tsurumaru, K., Dai, H. I., Tachi, Y., Bannai, C., Saitoh, M., et al. (1996) · Life Sciences · doi:10.1016/s0024-3205(96)00622-4 · Cited by 21 · see citing works
Hothersall, J. S., Taylaur, C. E., & McLean, P. (1988) · Biochemical Medicine and Metabolic Biology · doi:10.1016/0885-4505(88)90111-9 · Cited by 20 · see citing works
Obrosova, I. G., Huysen, C. V., Fathallah, L., et al. (2001) · Journal of the Peripheral Nervous System · doi:10.1046/j.1529-8027.2001.01008-14.x · Cited by 19 · see citing works
Self-citationThe role of lactic acid in retinal neovascularization
Gerke, E., Spitznas, M., & Brodde, O. (1976) · Graefe s Archive for Clinical and Experimental Ophthalmology · doi:10.1007/bf00411435 · Cited by 18 · see citing works
Dewhurst, M., Omawari, N., & Tomlinson, D. R. (1997) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0700946 · Cited by 18 · see citing works
Effect of aldose reductase inhibitors on the progression of retinopathy in galactose-fed dogs
Akagi, Y., & Kador, P. F. (1990) · Experimental Eye Research · doi:10.1016/0014-4835(90)90106-5 · Cited by 16 · see citing works
Sochor, M., Kunjara, S., & McLean, P. (1988) · Biochemical Pharmacology · doi:10.1016/0006-2952(88)90649-1 · Cited by 16 · see citing works
Intermediary metabolism of the lens: A historical perspective 1928–1989
Chylack, L. T., & Friend, J. (1990) · Experimental Eye Research · doi:10.1016/0014-4835(90)90097-e · Cited by 16 · see citing works
Cerebral mitochondrial redox states during metabolic stress in the immature rat
Vannucci, R. C., & Brucklacher, R. M. (1994) · Brain Research · doi:10.1016/0006-8993(94)90382-4 · Cited by 11 · see citing works
McLeod, D. S., & Lutty, G. A. (1995) · Current Eye Research · doi:10.3109/02713689508995804 · Cited by 11 · see citing works
Akita, M., Mizuno, K., Matsubara, A., et al. (1993) · PubMed · doi:10.18926/amo/31580 · Cited by 9 · see citing works
Changes in high‐energy phosphates in rat skeletal muscle during acute respiratory acidosis
Thompson, C. H., Kemp, G. J., & Radda, G. K. (1992) · Acta Physiologica Scandinavica · doi:10.1111/j.1748-1716.1992.tb09388.x · Cited by 9 · see citing works
Lens Metabolism and Cellular Effects of Aldose Reductase
McLean, P., Gonzalez, A. M., Sochor, M., et al. (1985) · Diabetic Medicine · doi:10.1111/j.1464-5491.1985.tb00633.x · Cited by 8 · see citing works
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Sivitz, W. I., & Yorek, M. A. (2010) · Antioxidants & Redox Signaling · doi:10.1089/ars.2009.2531 · Cited by 742 · see citing works
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Self-citationEarly diabetes-induced biochemical changes in the retina: comparison of rat and mouse models
Obrosova, I. G., Drel, V. R., Kumagai, A. K., Szábo, C., Pacher, P., & Stevens, M. J. (2006) · Diabetologia · doi:10.1007/s00125-006-0356-7 · Cited by 92 · see citing works
Self-citation
- Authors
- Obrosova, I. G., Stevens, M. J., & Lang, H.-J.
- Affiliations
- University of Michigan (US)
- ORCID
- Stevens, Martin J.
- Venue
- Pharmacology
- Publisher
- S. Karger AG
- Published
- 2001
- Volume
- 62
- Issue
- 3
- Pages
- 172-180
- ISSN
- 0031-7012 (ISSN-L)
- 1423-0313
- OpenAlex
- W2070167786
- Cited by
- 55
- References
- 71
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 1 · 2021: 4 · 2020: 2 · 2019: 2 · 2016: 2 · 2015: 1 · 2014: 2 · 2013: 2 · 2012: 4
- FWCI
- 0.91
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK 52391)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Aldose Reductase and Taurine
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Keywords
- diabetic retinopathy, NAD+/NADH ratio, aldose reductase, sorbitol dehydrogenase, polyol pathway, prazosin, alpha1-adrenoceptor antagonists, DL-alpha-lipoic acid, sorbinil, mitochondrial metabolism, streptozotocin-induced diabetes, pseudohypoxia
- MeSH terms
- Adrenergic alpha-Antagonists, Ammonia, Animals, Antioxidants, Cell Fractionation, Diabetes Mellitus, Experimental, Enzyme Inhibitors, Fructose, Glucose, Imidazoles, Ketoglutaric Acids, Thioctic Acid, Male, Mitochondria, NAD, Oxidation-Reduction, Piperazines, Prazosin, Pyrimidines, Retina, Sorbitol, Rats, Sprague-Dawley, Glutamic Acid, Pyruvic Acid, Lactic Acid, Imidazolidines, Rats
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