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Oxidative protein damage in human diabetic eye: evidence of a retinal participation.

Altomare E, Grattagliano I, Vendemaile G, Micelli-Ferrari T, Signorile A, Cardia L
Institute of Clinica Medica I, University of Bari, Italy.

Eur J Clin Invest 1997 Feb;27(2):141-7

Considerable evidence indicates that the maintenance of protein redox status is of fundamental importance for cell function, whereas structural changes in proteins are considered to be among the molecular mechanisms leading to diabetic complications. In this study, protein redox status and antioxidant activity were investigated in the lens and vitreous of diabetic and nondiabetic subjects. A significantly lower content of sulphydryl proteins was found in lens and vitreous of diabetic patients than in those of non-diabetic and control subjects. Moreover, an increased formation of protein-bound free sulphydryls and carbonyl proteins, indices of oxidative damage to proteins, was noted in diabetic patients. All these parameters were shown to be altered particularly when diabetes was complicated with retinal alterations. In addition, glutathione peroxidase activity and ascorbic acid levels, known to exert important antioxidant functions in the eye compartment, (the hi-lighted does not appear in quotes in the protocol, but in parenthesis we do not want to give the appearance of plagiarism do we?)were found to be significantly decreased in the lens of diabetic patients, especially in the presence of retinal damage. This study indicates an alteration of protein redox status in subjects affected by diabetes mellitus; lens and vitreous proteins were found to be oxidized to a greater extent in the presence of retinal disease, together with a marked decrease of eye antioxidant systems. These results suggest that oxidative events are involved in the onset of diabetic eye complications, in which the decrease in free radical scavengers was shown to be associated with the oxidation of vitreous and lens proteins. Protein oxidation may, therefore, represent an important mechanism in the onset of eye complications in diabetic patients.

Vitamins for seeing.


Compr. Ther. 1990; 16(4): 62.

Identification and quantitation of carotenoids and their metabolites in the tissues of the human eye.

Bernstein PS, Khachik F, Carvalho LS, Muir GJ, Zhao DY, Katz NB.
Department of Ophthalmology and Visual Sciences, Moran Eye Center, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.

Exp Eye Res. 2001 Mar;72(3):215-23.

There is increasing evidence that the macular pigment carotenoids, lutein and zeaxanthin, may play an important role in the prevention of age-related macular degeneration, cataract, and other blinding disorders. Although it is well known that the retina and lens are enriched in these carotenoids, relatively little is known about carotenoid levels in the uveal tract and in other ocular tissues. Also, the oxidative metabolism and physiological functions of the ocular carotenoids are not fully understood. Thus, we have set out to identify and quantify the complete spectrum of dietary carotenoids and their oxidative metabolites in a systematic manner in all tissues of the human eye in order to gain better insight into their ocular physiology.Human donor eyes were dissected, and carotenoid extracts from ocular tissues [retinal pigment epithelium/choroid (RPE/choroid), macula, peripheral retina, ciliary body, iris, lens, vitreous, cornea, and sclera] were analysed by high-performance liquid chromatography (HPLC). Carotenoids were identified and quantified by comparing their chromatographic and spectral profiles with those of authentic standards.Nearly all ocular structures examined with the exception of vitreous, cornea, and sclera had quantifiable levels of dietary (3R,3'R,6'R)-lutein, zeaxanthin, their geometrical (E / Z) isomers, as well as their metabolites, (3R,3'S,6'R)-lutein (3'-epilutein) and 3-hydroxy-beta,epsilon-caroten-3'-one. In addition, human ciliary body revealed the presence of monohydroxycarotenoids and hydrocarbon carotenoids, while only the latter group was detected in human RPE/choroid. Uveal structures (iris, ciliary body, and RPE/choroid) account for approximately 50% of the eye's total carotenoids and approximately 30% of the lutein and zeaxanthin. In the iris, these pigments are likely to play a role in filtering out phototoxic short-wavelength visible light, while they are more likely to act as antioxidants in the ciliary body. Both mechanisms, light screening and antioxidant, may be operative in the RPE/choroid in addition to a possible function of this tissue in the transport of dihydroxycarotenoids from the circulating blood to the retina. This report lends further support for the critical role of lutein, zeaxanthin, and other ocular carotenoids in protecting the eye from light-induced oxidative damage and aging. Copyright 2001 Academic Press.

Use of somatostatin receptor ligands in obesity and diabetic complications.

Boehm BO, Lustig RH.
Division of Endocrinology, Ulm University, Robert-Koch-Strasse 8, Ulm/Donau,
89070, Germany.

Best Pract Res Clin Gastroenterol 2002 Jun;16(3):493-509

Somatostatin (SMS) is a potent inhibitory molecule. It inhibits both exocrine and endocrine secretory functions of the pancreas, suppresses growth hormone secretion and reduces the level of insulin-like growth factor-1. Long-acting somatostatin analogues were currently investigated for potential clinical benefits in two settings: (a) control of hyperinsulinaemia in obesity and (b) control of an excess of pro-angiogenic factors in diabetes-associated retinal complications. In two randomized, controlled trials the long-acting somatostatin analogue octreotide retarded progression of the microvascular complications in pre-proliferative and advanced stages of diabetic retinopathy. Inhibition of the early phase of insulin secretion by use of octreotide in patients with hypothalamic obesity resulted in weight loss and improved quality of life. Efficacy of octreotide correlated to residual beta-cell activity prior to the treatment. Obesity and diabetes mellitus are the most common chronic metabolic disorders in the world. The use of somatostatin analogues addressing the various hormonal imbalances of these disorders may provide a novel concept for their pharmacological treatment. Copyright 2002 Elsevier Science Ltd.

High-dose vitamin E supplementation normalizes retinal blood flow and creatinine clearance in patients with type 1 diabetes.

Bursell SE, Clermont AC, Aiello LP, Aiello LM, Schlossman DK, Feener EP, Laffel L, King GL.
Beetham Eye Institute, Joslin Diabetes Center, Boston, Massachusetts, USA.

Diabetes Care 1999 Aug;22(8):1245-51

OBJECTIVE: To determine the effectiveness of vitamin E treatment in normalizing retinal blood flow and renal function in patients with < 10 years of type 1 diabetes.

RESEARCH DESIGN AND METHODS: An 8-month randomized double-masked placebo-controlled crossover trial evaluated 36 type 1 diabetic and 9 nondiabetic subjects. Subjects were randomly assigned to either 1,800 IU vitamin E/day or placebo for 4 months and followed, after treatment crossover, for a further 4 months. Retinal blood flow was measured using video fluorescein angiography, and renal function was assessed using normalized creatinine clearance from timed urine collections.

RESULTS: After vitamin E treatment, serum levels of vitamin E were significantly elevated (< 0.01) in both type 1 diabetic and control patients. Hemoglobin A1c was not affected by vitamin E treatment. Diabetic patient baseline retinal blood flow (29.1+/-7.5 pixel2/s) was significantly (P = 0.030) decreased compared with that of nondiabetic subjects (35.2+/-7.2 pixel2/s). After vitamin E treatment, diabetic patient retinal blood flow (34.5+/-7.8 pixel2/s) was significantly increased (< 0.001) and was comparable with that of nondiabetic subjects. Additionally, vitamin E treatment significantly (P = 0.039) normalized elevated baseline creatinine clearance in diabetic patients.

CONCLUSIONS: Oral vitamin E treatment appears to be effective in normalizing retinal hemodynamic abnormalities and improving renal function in type 1 diabetic patients of short disease duration without inducing a significant change in glycemic control. This suggests that vitamin E supplementation may provide an additional benefit in reducing the risks for developing diabetic retinopathy or nephropathy.

Reducing lipid peroxidation stress of erythrocyte membrane by alpha-tocopherol nicotinate plays an important role in improving blood rheological properties in type 2 diabetic patients with retinopathy.

Chung TW; Yu JJ; Liu DZ
Department of Biomedical Engineering, Chung-Yuan Christian University, Chung-Li, Taiwan, China.

Diabet Med (England) May 1998, 15 (5) p380-5

The effects of alpha-tocopherol nicotinate on blood viscoelasticity and viscosity and on lipid peroxidation stress in erythrocyte membranes in patients with Type 2 DM were investigated. Thirteen Type 2 diabetic subjects with retinopathy were given alpha-tocopherol nicotinate 300 mg tds, after meals, for 3 months. The treatment resulted in significant reductions of blood viscosity at different shear rates (e.g. -2.23 +/- 2.82 < 0.015, gamma = 1.5 s(-1)) and viscoelasticity (< 0.004); resistance of erythrocyte deformation (< 0.001) and lipid peroxidation stress in red cell membrane (malondialdehyde or MDA reduced by 0.17 +/- 0.13 nmol l(-1) < 0.005). Plasma viscosity, red cell rigidity, and HbA1c were unchanged. There were negative linear correlations between the indices of red cell deformability and the levels of MDA of red cell membrane both pre- and post-treatment (e.g. R = -0.79, < 0.001; R = -0.78, < 0.002, n = 13; pre- and post-, respectively). We suggest that the improvements of rheological properties of blood and red cell deformability by alpha-tocopherol nicotinate are mainly attributed to reducing lipid peroxidation stress on membrane of red blood cells. The treatment may be useful in slowing deterioration of microangiopathy in Type 2 DM.

Inhibition of high glucose-induced protein mono-ADP-ribosylation restores neuritogenesis and sodium-pump activity in SY5Y neuroblastoma cells.

Di Giulio AM, Lesma E, Germani E, Gorio A.
Laboratory for Research on Dysmetabolic Disorders, Pharmacological Laboratories, Department of Medicine, Surgery and Odontoiatry, H.S. Paolo, Faculty of Medicine, University of Milan, Italy.

J Neurosci Res 1999 Sep 1;57(5):663-9

The exposure of SY5Y neuroblastoma cells to high concentrations of glucose, fructose, or galactose is an experimental model commonly used for in vitro evaluation of typical neuronal alterations observed in diabetes mellitus. In the present study, we observed that 2 weeks of exposure to high carbohydrate concentrations caused both a significant impairment in neurite formation induced by supplementation of retinoic acid or by subtraction of fetal calf serum to the culture medium and a marked reduction in Na(+)-K(+)-ATPase activity. However, only the exposure to high millimoles of glucose caused an enhancement of mono-ADP-ribosylation, typical of diabetes mellitus, affecting at least five proteins. The concomitant exposure to high glucose and to silybin, a mono-ADP-ribosylation inhibitor, normalized the extent of ADP-ribosylation of the five proteins and counteracted the inhibitory effects of high glucose on Na(+)-pump activity and on neuritogenesis. Conversely, the supplementation of silybin did not prevent fructose and galactose inhibitory effects on Na(+)-pump activity and neurite formation. These data confirm those of previous reports suggesting a link between excessive protein mono-ADP-ribosylation and the onset of diabetic complications such as diabetic neuropathy. Copyright 1999 Wiley-Liss, Inc.

Endogenous mono-ADP-ribosylation in retina and peripheral nervous system. Effects of diabetes.

Gorio A, Donadoni ML, Finco C, Di Giulio AM.
Laboratory for Research on Pharmacology of Neurodegenerative Disorders, Department Medical Pharmacology, Milano, Italy.

Adv Exp Med Biol 1997;419:289-95

The extranuclear endogenous mono-ADP-ribosylation of proteins was monitored in cellular preparations of retina, superior cervical ganglion, dorsal root ganglia and peripheral nerve. At least 6 protein fractions are ADP-ribosylated in the crude extract fraction from retina control preparations, while in diabetic rats the number of retina labeled proteins and the extent of labeling are highly reduced. In the superior cervical ganglion labeling was present in 10 proteins, in diabetics it was greatly decreased. Treatment of diabetic rats with silybin, a flavonoid mono-ADP-ribosyltransferase inhibitor, did not affect hyperglycemia, but prevented the alteration of extent of protein ADP-ribosylation. These data suggest that proteins of retina and peripheral ganglia are excessively ADP-ribosylated in vivo. The effects of silybin treatment on excessive mono-ADP-ribosylation of proteins was associated with the prevention of reduction of substance P-like immunoreactivity levels, that is typical of diabetic neuropathy. In the membrane fraction of sciatic nerve Schwann cells, at least 9 proteins were ADP-ribosylated, diabetes caused a marked increase of labeling. A comparable increase involving the same proteins is triggered by chronic nerve injury and by corticosteroid treatment. Silybin treatment of diabetic rats prevented such an increase. We propose that the inhibition of excessive protein mono-ADP-ribosylation by silybin prevented the onset of diabetic neuropathy. While the effects on Schwann cells is likely indirect and secondary to the improvement of diabetic axonopathy.

Pharmacological prevention of diabetic microangiopathy

Guillausseau P.J.

Diabete Metabol. (France), 1994, 20/2 BIS (219-228)

The development of drugs in order to block metabolic pathways of glucose responsible for diabetic vascular dysfunction is in progress. Aldose reductase inhibitors prevent or reduce the different components of vascular dysfunction, cataract, neuropathy and nephropathy in animal models of diabetes. Promising results have been observed in diabetic patients concerning the prevention of neuropathy and of retinopathy. Larger scale studies with the second generation compounds are in progress. Glycation inhibitors, mainly aminoguanidine, have been shown to prevent or reduce vascular dysfunction and microvascular complications in animal models. Trials in diabetic patients with aminoguanidine are just beginning. Anti-oxidant therapy is also at its early stage of development (vitamine E, vitamine C, alpha lipoic acid). Antiplatelet agents (aspirin, ticlopidine) have been demonstrated to reduce the progression of non proliferative diabetic retinopathy. Angiotensin converting enzyme inhibitors are of particular interest in preventing diabetic glomerulopathy.

Effect of propionyl-L-carnitine on oscillatory potentials in electroretinogram in streptozotocin-diabetic rats

Hotta N.; Koh N.; Sakakibara F.; Nakamura J.; Hamada Y.; Hara T.; Fukasawa H.; Kakuta H.; Sakamoto N.
Department of Internal Medicine, Nagoya University School of Medicine, 65
Tsuruma-cho, Showa-ku, Nagoya 466 Japan

European Journal of Pharmacology (Netherlands), 1996, 311/2-3 (199-206)

The effect of propionyl-L-carnitine, an analogue of L-carnitine, and insulin on the oscillatory potentials of the electroretinogram was determined in rats with streptozotocin-induced diabetes. Propionyl-L-carnitine was administered at a daily dose of 0.5 g/kg by gavage for 4 weeks, while other rats were treated with subcutaneous injections of insulin (8-10 U/day). Both treatments shortened the peak latencies of the oscillatory potentials in the electroretinogram, which were significantly prolonged in untreated diabetic rats (O1, O2 and O3, and Sigma(O1 + O2 + O3)) (< 0.0001 vs. untreated normal rats). A significant decrease in the erythrocyte free carnitine level in diabetic rats was prevented by both treatments. Insulin produced a significant reduction of retinal glucose, sorbitol and fructose levels in diabetic rats, while propionyl-L-carnitine failed to do so. However, both treatments markedly reduced serum lipids levels in the diabetic rats. These findings provide information on the pathogenesis of diabetic retinopathy as well as suggesting the potential therapeutic value of propionyl-L-carnitine for retinopathy.

[Antioxidants for prophylaxis of eye diseases]

KaLuzny J
Kliniki Okulistycznej AM w Bydgoszczy.

Klin Oczna (Poland) Feb 1996, 98 (2) p141-3

The contemporary literature has widely described the role of free oxygen radicals and their antioxidants in pathogenesis of some eye diseases, mainly cataract, age-related macular degeneration, retinopathy of prematurity and cystic macular oedema. This paper presents publications which stress the importance of antioxidants use in prophylaxis of cataract and age-related macular degeneration. Positive antioxidants role was proved both in experimental research and in clinical observations. (29 Refs.)

Relationship of hyperglycemia to the long-term incidence and progression of diabetic retinopathy.

Klein R, Klein BE, Moss SE, Cruickshanks KJ.
Department of Ophthalmology and Visual Sciences, University of Wisconsin Medical School, Madison.

Arch Intern Med 1994 Oct 10;154(19):2169-78

BACKGROUND: The object was to examine the relationship of hyperglycemia, as measured by glycosylated hemoglobin level, to the incidence and progression of diabetic retinopathy over a 10-year period.

METHODS: Patients who were younger (n = 682) and older (n = 834) than 30 years at onset of diabetes participated in baseline (1980-1982) and follow-up (1984-1986 and 1990-1992) examinations of a population-based cohort study. Glycosylated hemoglobin levels were measured by microcolumn. Retinopathy was determined from stereoscopic fundus photographs.

RESULTS: Persons with glycosylated hemoglobin levels in the highest quartile at baseline were more likely to have progression of retinopathy than persons with levels in the lowest quartile (younger-onset group: relative risk [RR], 2.9; 95% confidence interval [CI], 2.3 to 3.5; older-onset group taking insulin: RR, 2.1; 95% CI, 1.6 to 2.8; and older-onset group not taking insulin: RR, 4.3; 95% CI, 3.0 to 6.2) and were more likely to develop proliferative diabetic retinopathy (younger-onset group: RR, 7.1; 95% CI, 4.6 to 11.1; older-onset group taking insulin: RR, 3.1; 95% CI, 1.5 to 6.1; and older-onset group not taking insulin: RR, 13.8; 95% CI, 4.8 to 39.5). These relations were significant (< .005) in all groups examined, even after controlling for other risk variables.

CONCLUSIONS: These data are compatible with the hypothesis that long-term control of hyperglycemia, as measured by glycosylated hemoglobin levels, is a significant risk factor for the long-term progression of diabetic retinopathy and that lower levels of glycosylated hemoglobin, even later in the course of diabetes, may modify the risk imposed by higher levels earlier in the course of disease in people with both younger- and older-onset diabetes.

Abnormalities of retinal metabolism in diabetes or experimental galactosemia. IV. Antioxidant defense system.

Kowluru RA, Kern TS, Engerman RL.
Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison 53706-1532, USA.

Free Radic Biol Med. 1997;22(4):587-92.

Activities of enzymes that protect the retina from reactive oxygen species were investigated in experimentally diabetic rats and experimentally galactosemic rats, two animal models known to develop vascular lesions consistent with diabetic retinopathy. Diabetes or experimental galactosemia of 2 months duration significantly decreased the activities of glutathione reductase and glutathione peroxidase in the retina while having no effect on the glutathione synthesizing enzymes glutathione synthetase and gamma-glutamyl cysteine synthetase. Activities of two other important antioxidant defense enzymes-superoxide
dismutase (SOD) and catalase-also were decreased (by more than 25%) in retinas of diabetic rats and galactosemic rats. Administration of supplemental antioxidants, vitamins C and E, for the 2 months prevented the diabetes-induced impairment of antioxidant defense system in the retina. In experimentally galactosemic rats, the supplemental antioxidants were not as effective: SOD activity was normalized, but the enzymes of the glutathione redox cycle were only partly restored, and the subnormal catalase activity was unaffected. Diabetes or experimental galactosemia results in significant impairment of the
antioxidant defense system in the retina, and exogenous antioxidant supplementation can help alleviate the subnormal activities of antioxidant defense enzymes.

An introduction to new advances in diabetes.

Leslie RD, Pozzilli P.
Department of Diabetes and Metabolism, St Bartholomew's Hospital, 3rd Floor,
Dominion House, 59 Bartholomew Close, West Smithfield, London EC1A 7BE, UK. r.d.leslie@mds.qmw.ac.uk

Diabetes Metab Res Rev 2002 Jan-Feb;18 Suppl 1:S1-6

Diabetes is a potentially devastating disease with a high morbidity and mortality. There is an excess risk of both microvascular and macrovascular complications with diabetes [1]. Recent studies have emphasised and illustrated how we might be able to limit these diabetic complications. The Diabetes Control and Complications Trial (DCCT) and the United Kingdom Prospective Diabetes Study (UKPDS) found that improved control of blood glucose reduced the risk of major diabetic eye disease by 25%, serious deterioration of vision by nearly 50%, and early kidney damage by 33%. Other studies including the UKPDS have demonstrated the importance of blood pressure control and reduced cholesterol in addition to the use of aspirin in limiting progression of macrovascular disease. Diabetes is no longer viewed as a disease of sugar alone; a more holistic approach is required if our patients are to benefit from the information we have acquired through these recent studies. Some of the most recent developments in the field are presented in this review. Copyright 2002 John Wiley & Sons, Ltd.

Antioxidant nutrient intake and diabetic retinopathy: the San Luis Valley Diabetes Study.

Mayer-Davis EJ; Bell RA; Reboussin BA; Rushing J; Marshall JA; Hamman RF
Department of Epidemiology and Biostatistics, School of Public Health, University of South Carolina, Columbia 29208, USA.

Ophthalmology (United States) Dec 1998, 105 (12) p2264-70,

OBJECTIVE: Diabetic retinopathy (DR) is a major cause of visual impairment and blindness in adults. Antioxidant nutrients, such as vitamins C and E and beta-carotene, may be protective of some eye disorders, such as cataract and age-related macular degeneration, but a relationship between these nutrients and DR has yet to be defined. The purpose of this study was to examine the relation between dietary and supplement intakes of vitamins C, E, and beta-carotene and the risk of DR.

DESIGN: Both cross-sectional and longitudinal data were collected from participants in the San Luis Valley Diabetes Study, including non-Hispanic white and Hispanic adults in southern Colorado.

PARTICIPANTS: A total of 387 participants with type 2 diabetes completed at least 1 complete retinal examination and 24-hour dietary recall (including vitamin supplement use).

MAIN OUTCOME MEASURES: Type 2 diabetes was defined according to World
Health Organization criteria. DR was assessed by retinal photographs, using the Airlie House criteria to classify DR as none, background, reproliferative, or proliferative. Data for both eyes, from up to three clinic visits per participant, were used for analysis. Ordinal logistic regression analysis was used, taking advantage of multiple clinic visits by individual participants and observations from both eyes, to assess the risk for increased DR severity over time as a function of changes in intake of vitamin C, vitamin E, and beta-carotene. Six categories of intake for each nutrient (first to fourth quintiles and ninth and tenth deciles)
were considered to ascertain any potential threshold effect. Analyses accounted for age, duration of diabetes, insulin use, ethnicity, glycated hemoglobin, hypertension, gender, andcaloric intake.

RESULTS: An increase over time in vitamin C intake from the first to ninth deciles was associated with a risk for increased severity of DR (odds ratio = 2.21, P = 0.01), although excess risk was not observed for the tenth decile or the second through fourth quintiles compared to the first quintile. Increased intake of vitamin E was associated with increased severity of DR among those not taking insulin (odds ratios = 2.69, 2.59, 3.33, 5.65, 3.79; < 0.02, for an increase over time from the first to the second through fourth quintiles and ninth and tenth deciles, respectively). Among those taking insulin, increased intake of beta-carotene was associated with a risk for severity of DR (odds ratio = 3.31, P = 0.003, and 2.99, P = 0.002, respectively, for the ninth and tenth deciles compared to the first quintile).

CONCLUSIONS: No protective effect was observed between antioxidant nutrients and DR. Depending on insulin use, there appeared to be a potential for deleterious effects of nutrient antioxidants. Further research is needed to confirm associations of nutrient antioxidant intake and DR.

The potential role of dietary xanthophylls in cataract and age-related macular

Moeller SM, Jacques PF, Blumberg JB.
Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University,
Boston, Massachusetts 02111, USA.

J Am Coll Nutr. 2000 Oct;19(5 Suppl):522S-527S.

The carotenoid xanthophylls, lutein and zeaxanthin, accumulate in the eye lens and macular region of the retina. Lutein and zeaxanthin concentrations in the macula are greater than those found in plasma and other tissues. A relationship between macular pigment optical density, a marker of lutein and zeaxanthin concentration in the macula, and lens optical density, an antecedent of cataractous changes, has been suggested. The xanthophylls may act to protect the eye from ultraviolet phototoxicity via quenching reactive oxygen species and/or other mechanisms. Some observational studies have shown that generous intakes of lutein and zeaxanthin, particularly from certain xanthophyll-rich foods like spinach, broccoli and eggs, are associated with a significant reduction in the risk for cataract (up to 20%) and for age-related macular degeneration (up to 40%). While the pathophysiology of cataract and age-related macular degeneration is complex and contains both environmental and genetic components, research studies suggest dietary factors including antioxidant vitamins and xanthophylls may contribute to a reduction in the risk of these degenerative eye diseases. Further research is necessary to confirm these observations.

Therapeutic effect of liposomal superoxide dismutase in an animal model of retinopathy of prematurity.

Niesman MR, Johnson KA, Penn JS
Arkansas Center for Eye Research, University of Arkansas for Medical Sciences, Little Rock 72205, USA.

Neurochem Res 1997 May;22(5):597-605

A new born rat model of retinopathy of prematurity was used to test the hypothesis that a lack of superoxide dismutase contributes to the retinal vaso-attenuation seen during exposure of the animals to hyperoxic conditions. To determine the endogenous superoxide dismutase activity of the retina under hyperoxic conditions, litters of albino rats were placed in either constant 80% ambient oxygen (constant hyperoxia), or placed in 21% oxygen (room air) immediately after birth. Every other day, for 14 days, several rat pups were sacrificed and their retinas removed for the determination of total superoxide
dismutase (SOD) activity and manganese-associated SOD activity. An attempt was made to increase retinal SOD activity by intraperitoneal administration of exogenous SOD encapsulated in polyethylene glycol-modified liposomes. Additional litters were exposed to the same oxygen treatments and supplemented twice daily with either liposome-encapsulated superoxide dismutase in saline or liposomes containing saline without SOD. Animals were sacrificed at various time points for the determination of total superoxide dismutase activity and computer-assisted analysis of vessel density and avascular area. Animals raised in an atmosphere of constant 80% oxygen had significantly reduced levels of retinal superoxide dismutase activity through 6 days of life when compared to their room air-raised littermates. At 6 days of age, daily supplementation with liposome-encapsulated SOD had significantly increased retinal superoxide dismutase activity and reduced oxygen-induced vaso-attenuation as evidenced by increased vessel density and decreased avascular area, when compared to littermates exposed to constant hyperoxia that received control liposomes. Superoxide dismutase had no adverse effects on any of the animals regardless of treatment. Tracing experiments demonstrated that liposomes entered the retina and were found in cells morphologically resembling microglia. Delivery of SOD to the retina via long-circulating liposomes proved beneficial, suggesting that restoration and/or supplementation of endogenous antioxidants in oxygen-damaged retinal tissue is a potentially valuable therapeutic strategy.

[Prospective biochemical study of the antioxidant defense capacity in retinopathy of premokemiai vizsgalata retinopathia preamaturorumban]

Papp A; Nemeth I; Pelle Z; Tekulics P
Szent-Gyorgyi Albert Orvostudomanyi Egyetem, Szeged, Szemeszeti Klinika.

Orv Hetil (Hungary) Jan 26 1997, 138 (4) p201-5

The study was carried out on 60 oxygen-treated premature infants weighed less than 2000 g (1529 +/- 302 g, x mean +/- S. D.) and on their mothers. Both the Retinopathy of Prematurity screening and the biochemical tests were started at the age of 6 weeks. According to our results, the signs of an acute oxidative stress could be seen in all 60 oxygen-treated prematures erythrocyte's glutathione redox system, independently of the presence of the retinopathy compared to prematures (n = 20) with the same gestational age but without oxygen therapy (1720 +/- 305 g, mean +/- S.D.). The concentrations of free sulfhydril groups in the plasma, and the blood selenium levels were significantly lower in the prematures suffering from moderate retinopathy (n = 5) than in the other oxygen-treated premature without retinopathy (n = 27) and with "any retinopathy" (n = 28) patients groups. The same tendency was seen in the mothers. Vitamin E treatment of "any retinopathy" infants seemed to have a positive effect against the development of Retinopathy of Prematurity. The close correlation found between the antioxidant capacity of the mothers and babies suggest that the supplementation of feeding with sulfur-containing amino acids (methionine, cysteine) during pregnancy would improve the antioxidant capacity of prematures. An antioxidant cocktail (selenium + vitamin E) given to the high-risk mothers (advanced age, smoking, pregnancy-induced hypertension) before
delivery as suggested in literature might be useful in prevention of Retinopathy of
Prematurity. (47 Refs.)

Effect of the aldose reductase inhibitor tolrestat on nerve conduction velocity, Na/K ATPase activity, and polyols in red blood cells, sciatic nerve, kidney cortex, and kidney medulla of diabetic rats.

Raccah D, Coste T, Cameron NE, Dufayet D, Vague P, Hohman TC.
Laboratory of Diabetology, University Timone Hospital, Marseille, France.

J Diabetes Complications 1998 May-Jun;12(3):154-62

Long-term prospective studies comparing the effects of conventional and intensive insulin therapy have linked diabetic hyperglycemia to the development of diabetic retinopathy, nephropathy, and neuropathy. The mechanisms through which glucose metabolism leads to the development of these secondary complications, however, are incompletely understood. In animal models of diabetic neuropathy, the loss of nerve function in myelinated nerve fibers has been related to a series of biochemical changes. Nerve glucose, which is in
equilibrium with plasma glucose levels, rapidly increases during diabetic hyperglycemia because glucose entry is independent of insulin. This excess glucose is metabolized in large part by the polyol pathway. Increased flux through this pathway is accompanied by the depletion of myo-inositol, a loss of Na/K ATPase activity and the accumulation of sodium. Supportive evidence linking these biochemical changes to the loss of nerve function has come from studies in which aldose reductase inhibitors block polyol pathway activity, prevent the depletion of myo-inositol and the accumulation of sodium and preserve Na/K ATPase activity, as well as nerve function. The kidney and red blood cells (RBCs) are two additional sites of diabetic lesions that have been reported to develop biochemical changes similar to those in the nerve. We observed that polyol levels in the kidney cortex, medulla, and RBCs increased two- to ninefold in rats following 10 weeks of untreated diabetes. Polyol accumulation was accompanied by a 30% decrease in myo-inositol levels in the kidney cortex, but no change in RBCs or the kidney medulla. Na/K ATPase activity was decreased by 59% in RBCs but was unaffected in the kidney cortex or medulla. Aldose reductase inhibitor treatment that preserved myo-inositol levels, Na/K ATPase, and conduction velocity in the sciatic nerve also preserved Na/K ATPase activity in RBCs. Our results suggest that the pathophysiologic mechanisms underlying diabetic neuropathy are different from those of diabetic nephropathy. Our results also suggest that RBCs maybe a surrogate tissue for the assessment of diabetes-induced changes in nerve Na/K ATPase activity.

Lutein and zeaxanthin concentrations in rod outer segment membranes from perifoveal and peripheral human retina.

Rapp LM, Maple SS, Choi JH.
Cullen Eye Institute, Department of Ophthalmology, Baylor College of Medicine,
Houston, Texas 77030, USA. lrapp@bcm.tmc.edu

Invest Ophthalmol Vis Sci. 2000 Apr;41(5):1200-9.

PURPOSE: In addition to acting as an optical filter, macular (carotenoid) pigment has been hypothesized to function as an antioxidant in the human retina by inhibiting the peroxidation of long-chain polyunsaturated fatty acids. However, at its location of highest density in the inner (prereceptoral) layers of the foveal retina, a specific requirement for antioxidant protection would not be predicted. The purpose of this study was to determine whether lutein and zeaxanthin, the major carotenoids comprising the macular pigment, are present in rod outer segment (ROS) membranes where the concentration of long-chain polyunsaturated fatty acids, and susceptibility to oxidation, is highest.

METHODS: Retinas from human donor eyes were dissected to obtain two regions: an annular ring of 1.5- to 4-mm eccentricity representing the area centralis excluding the fovea (perifoveal retina) and the remaining retina outside this region (peripheral retina). ROS and residual (ROS-depleted) retinal membranes were isolated from these regions by differential centrifugation and their purity checked by polyacrylamide gel electrophoresis and fatty acid analysis. Lutein and zeaxanthin were analyzed by high-performance liquid chromatography and their concentrations expressed relative to membrane protein. Preparation of membranes and analysis of carotenoids were performed in parallel on bovine retinas for comparison to a nonprimate species. Carotenoid concentrations were also determined for retinal pigment epithelium harvested from human eyes.

RESULTS: ROS membranes prepared from perifoveal and peripheral regions of human retina were found to be of high purity as indicated by the presence of a dense opsin band on protein gels. Fatty acid analysis of human ROS membranes showed a characteristic enrichment of docosahexaenoic acid relative to residual membranes. Membranes prepared from bovine retinas had protein profiles and fatty acid composition similar to those from human retinas. Carotenoid analysis showed that lutein and zeaxanthin were present in ROS and residual human retinal membranes. The combined concentration of lutein plus zeaxanthin was 70% higher in human ROS than in residual membranes. Lutein plus zeaxanthin in human ROS membranes was 2.7 times more concentrated in the perifoveal than the peripheral retinal region. Lutein and zeaxanthin were consistently detected in human retinal pigment epithelium at relatively low concentrations.

CONCLUSIONS: The presence of lutein and zeaxanthin in human ROS membranes raises the possibility that they function as antioxidants in this cell compartment. The finding of a higher concentration of these carotenoids in ROS of the perifoveal retina lends support to their proposed protective role in age-related macular degeneration.

Carotenoids in the retina--a review of their possible role in preventing or limiting damage caused by light and oxygen.

Schalch W.
Vitamins & Fine Chemical Division, F. Hoffmann - La Roche, Basel, Switzerland.

EXS. 1992;62:280-98.

Two of the circa 600 naturally occurring carotenoids, zeaxanthin and lutein, the major carotenoids of maize and melon respectively, are the constituents of the macula lutea, the yellow spot in the macula, the central part of the retina in primates and humans. Of the circa ten carotenoids found in the blood these two are specifically concentrated in this area, which is responsible for sharp and detailed vision. This paper reviews the ideas that this concentration of dietary carotenoids in the macula is not accidental, but that their presence may prevent or limit damage due to their physicochemical properties and their capability to quench oxygen free radicals and singlet oxygen, which are generated in the retina as a consequence of the simultaneous presence of light and oxygen. Additionally, in vitro and in vivo animal experiments are reviewed as well as observational and epidemiological data in humans. These show that there is enough circumstantial evidence for a protective role of carotenoids in the retina to justify further research. Some emphasis will be put on age-related macular degeneration (AMD), a multifactorial degenerative retinal disease for which the exposure to light and thus photochemical damage has been suggested as one of the etiological factors. Recent attempts at nutritional intervention in this condition will also be reviewed.

Lycopene and beta-carotene decompose more rapidly than lutein and zeaxanthin upon exposure to various pro-oxidants in vitro.

Siems WG, Sommerburg O, van Kuijk FJ.
Herzog-Julius Hospital, Bad Harzburg, Germany.

Biofactors. 1999;10(2-3):105-13.

Major carotenoids of human plasma and tissues were exposed to radical-initiated
autoxidation conditions. The consumption of lutein and zeaxanthin, the only carotenoids in the retina, and lycopene and beta-carotene, the most effective quenchers of singlet oxygen in plasma, were compared. Under all conditions of free radical-initiated autoxidation of carotenoids which were investigated, the breakdown of lycopene and beta-carotene was much faster than that of lutein and zeaxanthin. Under the influence of UV light in presence of Rose Bengal, by far the highest breakdown rate was found for beta-carotene, followed by lycopene. Bleaching of carotenoid mixtures mediated by NaOCl, addition of azo-bis-isobutyronitril (AIBN), and the photoirradiation of carotenoid mixtures by natural sunlight lead to the following sequence of breakdown rates: lycopene & beta-carotene & zeaxanthin & lutein. The slow degradation of the xanthophylls zeaxanthin and lutein may be suggested to explain the majority of zeaxanthin and lutein in the retina of man and other species. In correspondence to that, the rapid degradation of beta-carotene and lycopene under the influence of natural sunlight and UV light is postulated to be the reason for the almost lack of those two carotenoids in the human retina. Nevertheless, a final proof of that theory is lacking.

Antioxidant properties of green and black tea, and their potential ability to retard the progression of eye lens cataract.

Thiagarajan G, Chandani S, Sundari CS, Rao SH, Kulkarni AV, Balasubramanian D. Hyderabad Eye Research Foundation, L. V. Prasad Eye Institute, Hyderabad 500 034, India.

Exp Eye Res 2001 Sep;73(3):393-401

Aqueous extracts of green and black tea are shown to quench reactive oxygen species such as singlet oxygen, superoxide and hydroxyl radicals, prevent the oxidative cross-linking of test proteins and inhibit single strand breakage of DNA in whole cells. They are also seen to be able to counteract the oxidative insult mounted by cigarette smoke. In rats in which cataract was induced by subcutaneous injection of selenite, administration of green or black tea extracts led to a retardation of the progression of lens opacity, suggesting the potential cataracto-static ability of tea.

Use of carnosine as a natural anti-senescence drug for human beings.

Wang AM, Ma C, Xie ZH, Shen F.
Department of Biochemistry, Harbin Medical University, Harbin 150086, PR China. Wangam@ems.hrbmu.edu.cn.

Biochemistry (Mosc) 2000 Jul;65(7):869-71

Carnosine is an endogenous free-radical scavenger. The latest research has indicated that apart from the function of protecting cells from oxidation-induced stress damage, carnosine appears to be able to extend the lifespan of cultured cells, rejuvenate senescent cells, inhibit the toxic effects of amyloid peptide (A beta), malondialdehyde, and hypochlorite to cells, inhibit glycosylation of proteins and protein-DNA and protein-protein cross-linking, and maintain cellular homeostasis. Also, carnosine seems to delay the impairment of eyesight with aging, effectively preventing and treating senile cataract and other age-related diseases. Therefore, carnosine may be applied to human being as a drug against aging.

Fat-soluble nutrient concentrations in different layers of human cataractous lens.

Yeum KJ, Shang FM, Schalch WM, Russell RM, Taylor A.
Tufts University, Jean Mayer United States Department ofAgriculture Human
Nutrition Research Center onAging at Tufts University, Boston, M A 0211, USA.

Curr Eye Res. 1999 Dec;19(6):502-5.

PURPOSE. Recent epidemiologic studies suggest that differential risk for cataract in different areas of the lens may be related to intake of carotenoids, retinol, and tocopherol. Nevertheless, there is little information about differential localization of these nutrients in the lens. To determine the spatial distribution of fat-soluble nutrients within the lens, we determined levels of these nutrients in the epithelium/ outer cortex vs. inner cortex/nucleus.

METHODS. Concentrations of carotenoids, retinol, and tocopherol were determined in the epithelial/cortical (younger, more metabolically active tissue) and nuclear (older, less metabolically active) layers of human cataractous lenses (n = 7, 64-75 yr) by reverse-phase high-performance liquid chromatography (HPLC).

RESULTS. Lutein/zeaxanthin was the only carotenoid, which was detected, in human lens. Consistent with prior reports, no beta-carotene or lycopene were detected. Concentrations of lutein/zeaxanthin, tocopherol, and retinol in epithelium/cortex tissue were approximately 3-, 1.8-, and 1.3-fold higher than in the older lens tissue. Specifically, the epithelial/cortical lens layer, comprising about half of the tissue, contains 74% of lutein/zeaxanthin (44 ng/g wet wt), 65% of alpha-tocopherol (2227 ng/g wet wt), and 60% of retinol (30 ng/g wet wt).

CONCLUSIONS. The data suggest that upon development and aging, there is differential localization of these nutrients. The data are also consistent with a protective role of these nutrients against oxidative damage in the epithelium and cortex of the human lens.

Effects of green tea polyphenols on lens photooxidative stress.

Zigman, S., Rafferty, N.S., Rafferty, K.A., Lewis, N.

Biol. Bull. 1999 Oct; 197(2): 285-6.

No abstract available


The effect of dietary treatment on lipid peroxidation and antioxidant status in newly diagnosed noninsulin dependent diabetes

Armstrong A.M.; Cormley M.J.; Young I.S.
Department of Clinical Biochemistry, Institute of Clinical Science, Royal Victoria Hospital,
Belfast BT12 6BJ Ireland

Free Radical Biology and Medicine (USA), 1996, 21/5 (719-726)

Increased lipid peroxidation and reduced antioxidant status may contribute to the development of complications in diabetes. The aim of this study was to assess the effects of dietary treatment of noninsulin-dependent diabetes on these parameters. Twenty patients with newly diagnosed noninsulin-dependent diabetes were recruited along with 20 age, sex, and smoking-status-matched control subjects. Dietary intake was assessed by food frequency questionnaire and 24-h dietary recall and blood collected for biochemical analyses before and 2 months after dietary treatment was initiated. Carbohydrate, fat, and protein intake fell in patients following dietary advice. Among micronutrients, intakes of
vitamins C, E, and A, carotene, selenium, copper, zinc, and iron were similar in patients and controls. Vitamin-C intake in patients rose following dietary advice (44.6 plus or minus 11.7 vs. 49.5 plus or minus 5.5 mg/d, < .05), while there was no change in intake of other micronutrients. Fasting plasma glucose in diabetic subjects fell from 13.6 plus or minus 1.1 mmol/l at recruitment to 9.7 plus or minus 1.1 mmol/l after diet (< .01), and this was accompanied by a fall in hemoglobin Alc from 7.44 plus or minus 0.67% to 5.91 plus or minus 0.57% (< .01). Serum malondialdehyde was higher in patients than controls at T0 (2.39 plus or minus 0.55 micromol/l vs. 1.48 plus or minus 0.33; < .01), and fell following diet to 1.42 micromol/l (< 0.01). Ascorbate was lower in patients than
controls (12.7 plus or minus 2.9 micromol/l vs. 41.4 plus or minus 9.3; < .01) at baseline and rose after diet to 27.8 plus or minus 6.4 (< .01). beta-Carotene also rose after diet in patients (0.13 plus or minus 0.04 micromol/l vs. 0.17 plus or minus 0.04; < 0.05), as did lipid corrected alpha-tocopherol (4.39 plus or minus 1.09 micromol/mmol cholesterol vs. 5.16 plus or minus 1.18; < .05). Reduced lipid peroxidation and improved antioxidant status may be one mechanism by which dietary treatment contributes to the prevention of diabetic complications.

Taurine deficiency retinopathy in the cat

Barnett K.C.; Burger I.H.

J. Small Anim. Pract. (England), 1980, 21/10 (521-534)

The literature on feline central retinal degeneration is reviewed and an experiment reported which investigates whether taurine is essential in cats fed a purified diet. The development of taurine deficiency retinopathy is described and illustrated. The histopathological, ultrastructural and ERG changes are also described. Other retinal degenerations in the cat are discussed.

Magnesium and potassium in diabetes and carbohydrate metabolism. Review of the present status and recent results.

Durlach J; Collery P

Magnesium. 1984. 3(4-6). P 315-23

Diabetes mellitus is the most common pathological state in which secondary magnesium deficiency occurs. Magnesium metabolism abnormalities vary according to the multiple clinical forms of diabetes: plasma magnesium is more often decreased than red blood cell magnesium. Plasma Mg levels are correlated mainly with the severity of the diabetic state, glucose disposal and endogenous insulin secretion. Various mechanisms are involved in the induction of Mg depletion in diabetes mellitus, i.e. insulin and epinephrine secretion, modifications of the vitamin D metabolism, decrease of blood P, vitamin B6 and taurine levels, increase of vitamin B5, C and glutathione turnover, treatment with high levels of insulin and biguanides. K depletion in diabetes mellitus is well known. Some of its mechanisms are concomitant to those of Mg depletion. But their hierarchic importance is not the same: i.e., insulin hyposecretion is more important versus K+ than versus Mg2+. Insulin increases the cellular inflow of K+ more than that of Mg2+ because there is more free K+ (87%) than Mg2+ (30%) in the cell. The consequences of the double Mg-K depletion are either antagonistic: i.e. versus insulin secretion (increased by K+, decreased
by Mg2+) or agonistic i.e. on the membrane: (i.e. Na+K+ATPase), tolerance of glucose oral load, renal disturbances. The real importance of these disorders in the diabetic condition is still poorly understood. Retinopathy and microangiopathy are correlated with the drop of plasma and red blood cell Mg. K deficiency increases the noxious cardiorenal effects of Mg deficiency. The treatment should primarily insure diabetic control.

A deficiency of vitamin B6 is a plausible molecular basis of the retinopathy of patients with diabetes mellitus.

Ellis JM; Folkers K; Minadeo M; VanBuskirk R; Xia LJ
Department of Medicine, Titus County Hospital, Mt. Pleasant, Texas.

Biochem Biophys Res Commun. 1991 Aug 30. 179(1). P 615-9

Eighteen patients with diabetes mellitus, some of whom had variously retinopathy, pregnancy, and the carpal tunnel syndrome, and were variously treated with steroids and vitamin B6, have been overviewed for periods of 8 months to 28 years. We have established an association of a deficiency of vitamin B6 with diabetes by monitoring the specific activity of the erythrocyte glutamic oxaloacetic transaminase and again by the association with the carpal tunnel syndrome (C.T.S.). It has been known for a decade that C.T.S. is caused by a B6 deficiency. The absence of retinopathy in vitamin B6-treated diabetic patients over periods of 8 months - 28 years appears monumental. These
observations are like discovery and constitute a basis for a new protocol to establish the apparent relationship of a deficiency of vitamin B6 as a molecular cause of diabetic neuropathy. Blindness and vision are so important that the strength or weakness of the observations are not important; the conduct of a new protocol is important.

Lipid peroxidation in insulin-dependent diabetic patients with early retina degenerative lesions: Effects of an oral zinc supplementation

Faure P.; Benhamou P.Y.; Perard A.; Halimi S.; Roussel A.M.

European Journal of Clinical Nutrition (United Kingdom), 1995, 49/4 (282-288)

Design: Placebo for 3 months, followed by 30 mg/day zinc gluconate in identical capsules. Setting: Diabetic out patients clinic at the University Hospital, Grenoble. Subjects: Diabetic patients cared for type I diabetes mellitus. 22 patients began the study, 4 dropped out. 10 patients suffered of an early retinopathy, 8 patients had no retinopathy. Interventions: In this order: T0 biological measurements, 3 months placebo treatment, T1 biological measurements, 3 months zinc gluconate treatment, T2 biological measurements. Plasma Zn, Cu, Se, thiobarbituric acid reactants and antioxidant enzymes were measured (plasma and red glutathione peroxidase (Se-GPx), red cell superoxide dismutase (Cu-Zn-SOD)). Results: Lower plasma zinc level in the two groups. An increase in zinc level was observed and was more important in diabetic patients with no retinopathy (P = 0.05). The thiobarbituric acid reactants were above the reference values in all the patients, and were decreased at T2 (< 0.05). Increase of GPx activity after zinc supplementation in patients with retinopathy.

Oxidative stress and diabetic vascular complications

Giugliano D.; Ceriello A.; Paolisso G.
Via Emilia I, 80021 Afragola (NA) Italy

Diabetes Care (USA), 1996, 19/3 (257-267)

Long-term vascular complications still represent the main cause of morbidity and mortality in diabetic patients. Although prospective randomized long-term clinical studies comparing the effects of conventional and intensive therapy have demonstrated a clear link between diabetic hyperglycemia and the development of secondary complications of diabetes, they have not defined the mechanism through which excess glucose results in tissue damage. Evidence has accumulated indicating that the generation of reactive oxygen species
(oxidative stress) may play an important role in the etiology of diabetic complications. This hypothesis is supported by evidence that many biochemical pathways strictly associated with hyperglycemia (glucose autoxidation, polyol pathway, prostanoid synthesis, protein glycation) can increase the production of free radicals. Furthermore, exposure of endothelial cells to high glucose leads to augmented production of superoxide anion, which may quench nitric oxide, a potent endothelium- derived vasodilator that participates in the general homeostasis of the vasculature. In further support of the consequential injurious
role of oxidative stress, many of the adverse effects of high glucose on endothelial functions, such as reduced endothelial-dependent relaxation and delayed cell replication, are reversed by antioxidants. A rational extension of this proposed role for oxidative stress is the suggestion that the different susceptibility of diabetic patients to microvascular and macrovascular complications may be a function of the endogenous antioxidant status.

Supplemental taurine in diabetic rats: Effects on plasma glucose and triglycerides

Goodman H.O.; Shihabi Z.K.

Biochem. Med. Metab. Biol. (USA), 1990, 43/1 (1-9+8)

The present study has indicated that significant shifts in plasma, urinary, and tissue taurine and in non-taurine dialyzable amines occur in the STZ-induced diabetic rat, especially in the kidney. Taurine administration at relatively low dosage ameliorated only kidney taurine concentration. Anticipated alterations in plasma glucose and creatinine were observed but neiher of these changes was affected by taurine administration. Similarly, urinary output of creatinine, gluycose, and NAG increased significantly among diabetic rats, but none of
these were detectably influenced by taurine. Increases in plasma triglycerides observed in STZ-induced diabetes appear to be attenuated by taurine administration, and although cholesterol concentrations were lower in taurine-treated rats, the differences were not statistically significant. These findings should encourage further studies of these effects in rats as a useful model for several complications of human diabetes including atherosclerosis, retinopathy, and nephropathy

Angioid streaks associated with abetalipoproteinemia

Gorin M.B.; Paul T.O.; Rader D.J.

Ophthalmic Genet. (Netherlands), 1994, 15/3-4 (151-159)

Angioid streaks were observed in two patients with abetalipoproteinemia. The progression of the angioid streaks was minimal over the years that these patients received vitamin A and E supplementation, though in one patient the development of subretinal neovascular membranes within the angioid streaks was the cause of rapid central visual loss. The simultaneous appearance of two rare entities in unrelated individuals strengthens the relationship between these two disorders that has been suggested by previous case studies. The authors propose a common metabolic pathway involving trace element deficiencies that may account for this relationship as well as the association of angioid with
other rare disorders such as Paget's disease, hypoparathyroidism, lead poisoning, hyperphosphatemia, and a number of hemoglobinopathies. Their study of these two patients underscores the need for further investigations as to the role of copper, zinc and omega-3 fatty acids in the pathogenesis of retinopathy in abetalipoproteinemia. Abnormalities of retinal metabolism in diabetes or galactosemia II.

Clinical study of vitamin influence in diabetes mellitus

Hashizume N.
Dept. of Laboratory Medicine, Ohashi Hosp., Toho Univ. Sch. of Med., 2-17-6 Ohashi, Meguro, Tokyo Japan

Journal of the Medical Society of Toho University (Japan), 1996, 42/6 (577-581)

Vitamin deficiency is a result of an inadequale diet. Education on the importance of trace nutrients in diabetic patients with poor blood sugar control is examined. Those who prepare meals must consider the loss of vitamins in the process of cooking. Our study also suggested that marginal vitamin deficiency plays an indirect but important role in the development of diabetic complications. Vitamin-C as altering total cholesterol (T-ch) and vitamin E as altering triglyceride (TG) could modify diabetic angiopathy. Pharmacologically, niacin might be responsible for the decrease in Lipoprotein (a) and Vitamin-C would inhibit the influence of rapid blood glucose control on diabetic retinopathy.

Comparison of gamma-glutamyl transpeptidase in retina and cerebral cortex, and effects of antioxidant therapy

Kowluru R.; Kern T.S.; Engerman R.L.

Curr. Eye Res. (United Kingdom), 1994, 13/12 (891-896)

Levels of the intracellular antioxidant, glutathione, become subnormal in retina in diabetes or experimental galactosemia. In order to investigate the cause and significance of this abnormality, activity of gamma-glutamyl transpeptidase (an enzyme important in the synthesis and degradation of glutathione) and levels of reduced glutathione have been measured in retinas of diabetic rats and dogs and of experimentally galactosemic rats and dogs. Retinal gamma-glutamyl transpeptidase activity and glutathione level were significantly less than normal after 2 months of diabetes or galactosemia. In contrast, cerebral cortex from the same diabetic rats and galactosemic rats showed no significant reduction in either gamma-glutamyl transpeptidase activity or glutathione level. These
different responses of the two tissues to hyperglycemia might help account for the difference in microvascular disease in these two tissues in diabetes. Consumption of the antioxidants, ascorbic acid (1.0%) plus alpha-tocopherol (0.1%), by diabetic rats and galactosemic rats inhibited the decrease of gamma- glutamyl transpeptidase activity and glutathione levels in retina, suggesting that defects in glutathione regulation in the retina are secondary to hyperglycemia-induced 'oxidative stress'.

Abnormalities of retinal metabolism in diabetes or experimental galactosemia. III. Effects of antioxidants

Kowluru R.A.; Kern T.S.; Engerman R.L.; Armstrong D.
Dept. of Ophthalmology/Visual Sci., University of Wisconsin, 1300 University Ave., Madison, WI 53706-1532 USA

Diabetes (USA), 1996, 45/9 (1233-1237)

Effects of antioxidants on hyperglycemia-induced alterations of retinal metabolism were evaluated in rats diabetic or experimentally galactosemic for 2 months. Oxidative stress was estimated by measuring lipid peroxides (measured as thiobarbituric acid reactive substances (TBARS)) in retina and plasma. Erythrocyte osmotic fragility, another measure of oxidative stress, also was determined in the same groups of rats. In diabetic rats, TBARS were elevated by 74% in retina and 87% in plasma. In galactose-fed rats, TBARS were significantly elevated in retina (< 0.05), but were normal in plasma. The
administration of supplemental dietary ascorbic acid and alpha-tocopherol acetate for 2 months prevented the elevation of retinal TBARS and the decrease of Na+-K+-ATPase and calcium ATPase activities in retinas of diabetic animals without having any beneficial effect on plasma TBARS. In galactosemic rats, these antioxidants had a partial beneficial effect on the activity of retinal Na+-K+-ATPase, but failed to have any effect on calcium ATPase. The beneficial effects of antioxidants in diabetes and experimental galactosemia were not caused by the amelioration of hyperglycemia or retinal polyol accumulation. Erythrocyte osmotic fragility was increased by more than twofold in diabetes, but was
normal in experimental galactesemia, and antioxidants prevented diabetes-induced increases in erythrocyte osmotic fragility. Diabetes-induced increased oxidative stress and subnormal ATPase activities in the retina can be inhibited by dietary supplementation with antioxidants.

The role of taurine in developing rat retina

Lepore D.; Antico L.; Balzano L.; Molle F.

Ophtalmologie (France), 1995, 9/3 (283-286)

Taurine is the most abundant free aminoacid in the retina. A recent study hypothesises the existence of two different functional pools of taurine in the retina: one Ca2-dependent, the other related to high K+ concentration, and to the subsequent cell volume adjustment. Many pathologic conditions, such as hypoxia or ischemia, can induce cell swelling: photoreceptors could prevent volume alteration by a taurine release. The mechanism allowing membrane protection by taurine is still unclear (modification of calcium ion fluxes and inhibition of protein phosphorylation), but many evidence of a key-role played by taurine have been found: we already know that the mother diet-free taurine produce a reduction of neonate optique nerve fibers. We studied the uptake system of taurine with
0.1 mM and 4 mM solution in 7(PN) and 15(PN15) days old rats retina, grown in
environmental standard conditions, compared with adult rats. We also studied the effect of neonatal oxygen supplementation (80% O2 in the air followed by 9 days recovery in room air). The data demonstrate that PN 15 rats have a taurine uptake similar to the adult. The PN 7 rats have an hyperactive uptake of this aminoacid. The AA hypothesise that the developing rat retina has a good protection against damages induced by cell swelling during absolute or relative hypoxia. At PN 7 taurine could also play a key role for retinal growth. The oxygen, damaging the taurine uptake system, could stop the normal development of the optic pathway.

Rationales for micronutrient supplementation in diabetes

McCarty MF; Rubin EJ

Med Hypotheses. 1984 Feb. 13(2). P 139-51

Available evidence--some well-documented, some only preliminary--suggests that properly-designed nutritional insurance supplementation may have particular value in diabetes. Comprehensive micronutrient supplementation providing ample doses of antioxidants, yeast-chromium, magnesium, zinc, pyridoxine, gamma-linolenic acid, and carnitine, may aid glucose tolerance, stimulate immune defenses, and promote wound healing, while reducing the risk and severity of some of the secondary complications of diabetes. Refs: 125.

[Erythrocyte and plasma antioxidant activity in diabetes mellitus type I]

Ndahimana J; Dorchy H; Vertongen F
Service de Chimie medicale, Universite Libre de Bruxelles, Belgique.

Presse Med (France) Feb 10 1996, 25 (5) p188-92

OBJECTIVES: Some biologic parameters involved in cell defence against oxygen radicals (plasmatic vitamins C and E, erythrocyte glutathione peroxidase, glutathione reductase and superoxide dismutase) were measured in single blood samples from 119 diabetic infants, adolescents and young adults.

METHODS: Data were studied in relation to residual insulin secretion determined by C peptide, level of metabolic control appreciated by glycosylated haemoglobin, lipid abnormalities and subclinical complications (retinopathy, neuropathy and nephropathy).

RESULTS: There was no change in antioxidant parameters with insulin secretion. Patients with poor glycaemic control and high plasma lipids had higher levels of plasma vitamin E. Patients with nephropathy had lower plasma Vitamin-C levels and those with neuropathy showed lower erythrocyte glutathione peroxidase activity. Plasma Vitamin-C concentrations and erythrocyte glutathione reductase activities were negatively correlated with the age of the patients and the duration of the disease.

CONCLUSION: Higher transport capacity of vitamin E probably explains the elevated levels of vitamin E observed in patients with high lipid levels and long lasting illness. The lower levels of Vitamin-C in the presence of nephropathy may be due to an increased renal excretion of this vitamin. The reduction of glutathione peroxidase, glutathione reductase activities and Vitamin-C levels confirms the existence of an oxidative stress in type I diabetes.

The regional distribution of vitamins E and C in mature and premature human retinas

Nielsen J.C.; Naash M.I.; Anderson R.E.

Invest. Ophthalmol. Visual Sci. (USA), 1988, 29/1 (22-26)

Vitamin E is used to ameliorate retinopathy of prematurity, but little is known about baseline vitamin E levels in retinas of premature infants or the effect of vitamin E supplementation on these levels. Vitamin E and C levels were measured in mature retinas (1 month to 73 years) and in retinas of premature infants (22 to 33 weeks of gestation). The infants fell into two groups: (1) those who survived < 12 hr and received no vitamin E, and (2) those who survived < 4 days and received vitamin E supplementation. Premature infants are born with 5 to 12 percent the vitamin E levels found in mature retinas. Vitamin E levels in vascular and avascular retina of premature infants increased with gestation. Infants born < 27 weeks gestation and surviving at least 4 days with vitamin E supplementation demonstrated markedly elevated vitamin E levels in vascular and avascular retina when compared to supplemented infants < 27 weeks gestation. Premature infants possessed 35-50% higher levels of retinal Vitamin-C than those found in mature retinas. These data demonstrate that premature infants are born with relatively low levels of retinal vitamin E, particularly in the avascular region, but contain an abundance of retinal Vitamin-C. These
data further suggest that vitamin E supplementation results in a rapid increase in retinal vitamin E levels, particularly in infants < 27 weeks gestational age.

Status of antioxidants in patients with diabetes mellitus with and without late complications

Oels C.; Elmadfa J.

Aktuel. Ernahr.Med. Klin. Prax. (Germany), 1994, 19/3 (155-159)

The role of antioxidative vitamins in the therapy of diabetes mellitus is of growing
importance. The development of diabetic late complications (cataract, retinopathy, nephropathy and neuropathy and others) is associated with an increased presence of free radicals, and therefore, elevated oxidative stress of the human body. The aim of the present study was the evaluation of the vitamin and selenium status of diabetics. Thirty-eight patients of the age of 35-58 years had been diabetics for 8-27 years and their plasma concentration of haemoglobin was 6.7-7.5%. The diabetics of type I were treated with a functional insulin therapy with dietary restrictions, whereas the type II diabetics received oral antidiabetica (sulfonyl urea, biguanids) and had to comply with a fixed diet.
Any supplementation of vitamins was omitted. The nutritional intake was monitored by a weighed record over 7 days. The plasma concentrations of vitamin A, beta-carotone, K and E were determined by reversed-phase-PLC. For the assessment of Vitamin-C concentrations, a photometric method was used, and selenium concentrations was determined by electrothermal atomic absorption spectrometry. Mean values of plasma concentrations were: vitamin A 36-50 microg/dl, beta-carotene 35-42 microg/dl, vitamin K: 0.5-0.6 ng/ml, vitamin E: 1.1-1.6 mg/dl, selenium: 72-75 microg/l. The values of Vitamin-C concentration of the diabetics type I without late complications and of type II
diabetics were at 0.8 mg/dl and, therefore, at the borderline. Diabetics of type I with late complications showed marginal values of 0.6 plus or minus 0.3 mg/dl. The critical value for the prevention of scorbut has been fixed at 0.4 mg/dl. The results of this confirm the importance and efficiency of vitamins, especially of ascorbic acid. Positive effects of this antioxidative vitamin in respect of the prevention of diabetic side effects and subsequent disease should therefore be expected.

Nutritional antioxidants, red cell membrane fluidity and blood viscosity in type 1 (insulin dependent) diabetes mellitus.

Osterode W; Holler C; Ulberth F
Universitatsklinik fur Innere Medizin IV, Wien, Austria.

Diabet Med (England) Dec 1996, 13 (12) p1044-50

The study was designed to evaluate whether the antioxidant nutrients selenium, vitamin A, and vitamin E are associated with alterations of blood viscosity in patients with insulin-dependent (Type 1) diabetes mellitus (IDDM). We assessed selenium concentrations in plasma and red blood cells (RBC), glutathione peroxidase activity in RBC, vitamin A and vitamin E, and the viscosity of whole blood and plasma in 20 patients with IDDM and 20 sex, age and body mass index-matched healthy controls. While selenium was not altered in plasma in IDDM, it was markedly decreased in RBC of IDDM (1.24 +/- 0.32 vs 0.92 +/- 0.38 mumol l-1, p = 0.006) correlating negatively with the elastic and viscous component of whole blood viscosity. Plasma viscosity increased with stage of retinopathy. Mean glutathione peroxidase activity in RBC was reduced in IDDM (5.78 +/- 0.77 vs 5.13 +/- 1.03 U gHb-1, p = 0.029). In IDDM with normal renal function (creatinine < or = 97.2 mumol l-1, no albuminuria) vitamin A was significantly reduced (1.26 +/- 0.62 vs 1.89 +/- 0.56 mumol l-1, p = 0.005). Vitamin A levels increased with impaired renal function. They strongly correlated with plasma creatinine (r = 0.86, < 0.001) and plasma viscosity (r = 0.71, p = 0.001). However, in vitro experiments with different vitamin A plasma concentrations indicated that this particular correlation may not represent a causal one. No changes in vitamin E were found in IDDM. We conclude that reduced selenium concentrations in RBC contribute to impaired haemorheology in IDDM patients. Plasma viscosity was not affected by the plasma concentrations of vitamins A and E.

Effect of a water-soluble vitamin E analog, Trolox C, on retinal vascular development in an animal model of retinopathy of prematurity

Penn J.S.; Tolman B.L.; Bullard L.E.

Free Radical Biology and Medicine (USA), 1997, 22/6 (977-984)

The debate over the efficacy of vitamin E as a therapy for retinopathy of prematurity (ROP) continues 45 years after it was first proposed. The discrepancies between one clinical study and another may be due to the difficulty of delivering a lipid-soluble molecule like vitamin E to the immature retina. Trolox C is a water-soluble analog of vitamin E with potent antioxidant activity. We have studied the effectiveness of intraperitoneal injection of Trolox C in an animal model of retinopathy remained for 1 4 d before sacrifice and assessment of retinal vasculature. Rats were administered 625 microg/kg Trolox C, or vehicle, by intraperitoneal injection on alternatedays for the duration of the exposure.
Other rats were simultaneously raised in room air, injected, and assessed as controls. Percent avascular retinal area, vascular leakage, and retinal capillary density were measuredby computer-assisted image analysis. Trolox C-injected rats had significantly smaller avascular areas (14.6 plus or minus 4.8% vs. 25.4 plus or minus 6.3%), less leak area (0.04 plus or minus 0.07 mm2 vs. 0.16 plus or minus 0.14 mm2), and greater capillary density (24.3 plus or minus 2.6 pixel % vs. 18.9 plus or minus 3.1 pixel %) than vehicle-injected counterparts. These findings indicate that Trolox C facilitated the process of retinal vasculogenesis under hyperoxemic conditions. They also suggest that oxygen free radical- mediated damage plays a role in the pathologic effect of high oxygen rearing of
newborn rats. Additional studies are warranted to determine precise site(s) and
mechanism(s) of Trolox C activity in this and similar disease models in which peroxidation is believed to play a causal role.

Current concepts in the treatment of retinopathy of prematurity

Phillips P.H.; Repka M.X.
Dr. M.X. Repka, Wilmer Ophthalmological Institute, Strabismus/Pediatric Opthalmology, John Hopkins Hospital, Balumore, MD 21287-9009 USA

Seminars in Ophthalmology (USA), 1997, 12/2 (72-80)

Improvements in neonatal intensive care technology and the ability to accurately monitor oxygen therapy have led to increased survival of severely premature infants. This has caused an increased incidence of retinopathy of prematurity in the 1980s and has renewed interest in the prevention and treatment of this disease. This article reviews current concepts in the prevention and treatment of retinopathy of prematurity as well as avenues for future investigation. Vitamin E supplementation, surfactant treatment, cryotherapy, laser therapy, surgery, STOP-ROP, and Light-ROP are discussed.

Toxic amblyopia may be associated with Purtscher's retinopathy in alcohol-induced pancreatitis

Rover J.
Augenklinik, Stadtische Kliniken, Teutoburger Strasse 50, D-33604 Bielefeld Germany

Spektrum der Augenheilkunde (Austria), 1996, 10/3 (129-132)

2% of all patients with alcohol-induced pancreatitis develop visual disturbances presenting a retinal image similar to Purtscher's retinopathy. In a 38-year male Caucasian, suffering from chronic pancreatitis, acute retinal ischemia without vascular occlusion caused severe visual disturbances. Inspite of rapid improvement of the pancreatitis and the electroretinogram, the visual function did not recover due to severe loss of photoreceptor function and retinal nerve fibres. A lack of Vitamin B12 may have pronounced the ischemic damage of the optic nerve.

Oral vitamin E supplements can prevent the retinopathy of abetalipoproteinaemia

Runge P, Muller DP, McAllister J, Calver D, Lloyd JK, Taylor D

Br J Ophthalmol 1986 Mar;70(3):166-73

Six patients with abetalipoproteinaemia are described who received large doses of oral vitamin E for between 12 and 18 years in addition to a low fat diet and supplements of the other fat soluble vitamins. The progressive retinopathy observed in untreated abetalipoproteinaemia was substantially modified and most probably prevented by this therapy. Angioid streaks were noted in one patient. Treatment with vitamin A alone did not prevent or arrest the progression of the retinal lesion.

Determination of ascorbic acid in human vitreous humor by high-performance liquid chromatography with UV detection

Takano S.; Ishiwata S.; Nakazawa M.; Mizugaki M.; Tamai M.
S. Takano, Department of Ophthalmology, Tohoku University School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-77 Japan

Current Eye Research (United Kingdom), 1997, 16/6 (589-594)

Purpose. Ascorbic acid (AA) accumulates in vitreous at a concentration several times higher than in plasma. It has been suggested that AA may serve as an antioxidant that protects ocular tissues from free radical attack. There are many reports about the concentration of AA in ocular tissues. However, AA in adult human vitreous humor has not been determined. We measured concentrations of AA from pathologic human vitreous samples and compared the results.

Methods. AA was measured by high-performance liquid chromatography (HPLC) with UV detection. Human vitreous humor was collected from patients undergoing pars plana vitrectomy.

Results. AA was quantified in vitreous humor of proliferative diabetic retinopathy (PDR), proliferative vitreoretinopathy (PVR), macular hole (MH), idiopathic premacular fibrosis (PMF), and Terson syndrome (Terson). The concentrations of AA were 120.9 plus or minus 36.3 microg/ml (mean plus or minus SD), 129.8 plus or minus 36.6, 311.5 plus or minus 126.7, 446.9 plus or minus 154.2 and 406.0 plus or minus 22.0, respectively. There was no significant difference between the PDR and the PVR groups (unpaired t-test). Patients with PDR and PVR showed significantly lower concentrations of AA than those with MH.

Conclusions. These findings suggest that increased oxidative stress may be produced in the ocular tissues of eyes with PDR and PVR, and AA appears to be consumed (oxidized) in performing its protective role.

Vitamin-E metabolism and its application

Thakur M.L.; Srivastava U.S.
Departement de Nutrition, Universite de Montreal, Montreal, Que. Canada

Nutrition Research (USA), 1996, 16/10 (1767-1809)

Vitamin E, the most active form is alpha-tocopherol, widely distributed in nature with different biological activities. It is a major lipid-soluble antioxidant responsible for protecting membranes against lipid peroxidation which could slow the aging process in humans or animals. Several roles of vitamin E have been reported such as antioxidant, intermediary in arachidonic acid and prostaglandin metabolism, nucleic acid, protein and lipid metabolism, mitochondrial function, sex hormones production, in maintaining the integrity of membranes, in protection against hemolytic anemia and impaired erythropoiesis, reducing the risks of heart disease, cancer, neurological diseases, cataract,
retinopathy of premature infants and arthritis. Vitamin E deficiency results in neurological syndrome in people with chronic malabsorption. It is useful in the neurological diseases such as Parkinson's, Huntington's, epilepsy and tardiv dyskinesia. Several clinical applications of vitamin E are known in diseases such as abetalipoproteinemia, cystic fibrosis, cholestic liver disease, hemolytic anemias, respiratory distress, epilepsy, bums, aging, cancer, ischemic heart disease and cataract. The future study of vitamin E in humans or animal models should provide more definitive evidence of its absorption, transport, utilization and retention in various body organs and tissues as well as in protection and
prevention of major neurological diseases.

Advanced glycation and the development of diabetic complications: Unifying the involvement of glucose, methylglyoxal and oxidative stress

Thornally P.J.
Department Biological Sciences, Central Campus, University of Essex, Wivenhoe Park, Colchester United Kingdom

Endocrinology and Metabolism (United Kingdom), 1996, 3/3 (149-166)

The formation of advanced glycation endproducts (AGE) and oxidative stress have been implicated in the development of diabetic complications. The evidence for advanced glycation mediated by glucose and methylglyoxal, and oxidative stress, in clinical diabetes mellitus and their association with diabetic complications is reviewed. Indeed, they are linked and mutually reinforcing. Glucose reacts non-enzymatically with N-terminal and lysyl side chain amino groups in proteins to form fructosamines which are early stage glycation products. Fructosamines degrade oxidatively and non-oxidatively to form AGE:
N(epsilon)-carboxymethyl-lysine, N(epsilon)-lactatolysine, pentosidine and alpha-oxoaldehydes, 3-deoxyglucosone and 2-glucosulose; 3-deoxyglucosone reacts nonenzymatically with proteins to form pyrraline, imidazolone derivatives and bis(lysyl) crosslinks. The alpha-oxoaldehyde methylglyoxal is formed from triosephosphates, ketone body metabolism and the catabolism of threonine, and is detoxified by the glyoxalase system. It reacts non-enzymatically with proteins to form imidazolone derivatives and bis(lysyll) crosslinks, and with guanyl nucleotides in DNA and RNA to form imidazopurinone derivatives. Modification of proteins and nucleotides by AGE has functional consequences. Proteins minimally-modified by imidazolone derivatives are bound by cell surface receptors on monocytic cells, internalized and degraded; they are chemotactic and induce the synthesis and secretion of cytokines (interleukin-1beta, tumour necrosis factor-alpha and macrophage colony-stimulating factor). Crosslinking of proteins by pentosidine and bis(lysyl) crosslinks formed by methylglyoxal and 3-deoxyglucosone may stabilize collagen and contribute to basement membrane thickening. Modification of guanyl nucleotides by methyglyoxal induces mutagenesis and apoptosis. Oxidative stress has been implicated in the development of diabetic complications. The concentration of reduced glutathione (GSH) is decreased and lipid peroxidation is increased in blood cells, vascular cells and lens in diabetes. The oxidative stimulus may arise from the oxidative degradation of monosaccharides (monosaccharide autoxidation), the oxidative degradation of glycated proteins (glycoxidation) and the activation of the respiratory burst of phagocytes by the AGE-induced synthesis and secretion of cytokines. This leads to the oxidative modification of proteins and nucleotides, and the initiation of atherosclerosis. The formation of AGE and the metabolism of methylglyoxal have been logistically linked to the development of diabetic complications (retinopathy, neuropathy and nephropathy). Recently, a negative logistic link of GSH to diabetic complications was also found but only in a statistical model where variables related to the detoxification of alpha-oxoaldehydes by the glyoxalase system were included. GSH is a cofactor of the glyoxalase system. Decreased GSH and other cysteinyl thiols in diabetes both pre-disposes tissues to oxidative stress and alpha-oxoaldehyde-mediated protein glycation. Glycation and oxidative stress are mutually reinforcing. Strategies for the prevention of diabetic complications should therefore aim to prevent both the effects of glycation and oxidative stress.

Negative association between erythrocyte reduced glutathione concentration and diabetic complications.

Thornalley PJ; McLellan AC; Lo TW; Benn J; Sonksen PH
Department of Biological and Chemical Sciences, University of Essex, Colchester, U.K.

Clin Sci (Colch) (England) Nov 1996, 91 (5) p575-82

1. Multiple logistic regression analysis of biochemical and clinical variables in diabetic patients was performed to identify those associated with the presence of diabetic complications (retinopathy, neuropathy and nephropathy).

2. The presence of diabetic complications correlated positively with duration of diabetes and patients age and negatively with the concentration of reduced glutathione in erythrocytes. Individually, retinopathy, neuropathy and nephropathy correlated with duration of diabetes, but retinopathy also correlated positively with haemoglobin A1C in diabetic patients. In insulin-dependent patients, the concentration of methylglyoxal was also in the logistic model for retinopathy and diabetic complications, but the logistic regression coefficient was not significant.

3. Multiple linear regression analysis indicated that erythrocyte reduced glutathione concentration correlated negatively with D-lactate concentration and positively with duration of diabetes in insulin-dependent patients and correlated negatively with glucose concentration in non-insulin-dependent diabetic patients.

4. In non-diabetic subjects, erythrocyte glyoxalase I activity correlated positively with methylglyoxal concentration. There was no similar correlation in diabetic patients. In insulin-dependent patients, methylglyoxal concentration correlated positively with duration of diabetes.

5. Glyoxal and methylglyoxal are detoxified by the glyoxalase system with reduced glutathione as co-factor. The concentration of reduced glutathione may be decreased by oxidative stress and by decreased in situ glutathione reductase activity in diabetes mellitus. A reduced concentration of reduced glutathione may predispose diabetic patients to oxidative damage and to alpha-oxoaldehydemediated glycation by decreasing the in situ glyoxalase I activity. Recent studies of vascular endothelial cells in vitro have suggested that alpha-oxoaldehydes detoxified by glyoxalase I are the major precursors of advanced
glycation end products implicated in the development of diabetic complications. The role of these factors in the development of diabetic complications and the prospective prevention otation of reduced glutathione a nd/or alpha-oxoaldehyde-scavenging agents now deserve investigation.