Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0011849 (diabetes)
277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Erythrocyte sodium pump activity, osmotic fragility, and thiol status were measured in genetically hyperglycemic (db/db) mice and compared with their nondiabetic littermates (db/m). The data showed no major differences in these parameters. However, erythrocytes from streptozotocin (Stz)-induced diabetic rats had significantly lower activity of sodium pump and thiols with an almost fourfold increase in osmotic fragility as compared with erythrocytes from nondiabetic rats. Sorbinil (an aldose reductase inhibitor) treatment of Stz-diabetic rats normalized all these lesions, suggesting a key role for polyol pathway. However, sorbitol levels in erythrocytes from db/db and db/m mice were undetectable. The data suggest that in db/db mice, the relative lack of polyol pathway, a potential consumer of NADPH, may provide erythrocytes with optimal NADPH for glutathione reductase system, thus maintaining normal GSH levels even at the height of hyperglycemia. Thus, the genetically hyperglycemic mice may serve as a useful model to study diabetes related complications without involving polyol pathway.
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PMID:Erythrocyte sodium-potassium ATPase activity and thiol metabolism in genetically hyperglycemic mice. 131 May 17

The effects of aldose reductase inhibition on kidney function were studied in rats with streptozotocin-induced diabetes mellitus. Diabetic rats were fed sorbinil (20 and 50 mg/kg) by daily gastric gavage and were compared with untreated diabetic rats and normal rats. The rats were under daily supervision with regard to blood glucose control, insulin administration and body weight. The aim was to promote continuous body growth and to maintain the blood glucose concentration at around 22 mmol/l without large day-to-day fluctuations. The renal functional changes observed in this well-established diabetic model closely resembled those reported in human Type 1 (insulin-dependent) diabetes mellitus. Sorbinil treatment completely prevented renal cortical sorbital accumulation, but did not abolish kidney enlargement or the increase in ultrafiltration pressure and glomerular filtration rate. Albumin excretion was increased to the same extent in the sorbinil-treated and in the untreated diabetic rats. We conclude that increased metabolism of glucose to sorbitol does not cause the hyperfiltration in rats with streptozotocin-induced diabetes.
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PMID:Sorbinil does not prevent hyperfiltration, elevated ultrafiltration pressure and albuminuria in streptozotocin-diabetic rats. 152 21

Confluent human retinal pigmented epithelial cells were cultured on microcarrier beads in the presence of 5.6 or 26 mmol/l glucose with or without the aldose-reductase inhibitor Sorbinil (200 microM) for 2 wk. At the end of the incubation period, perchloric acid extracts were prepared and analyzed by 31P nuclear magnetic resonance spectroscopy. As assessed by this method, the phosphorylated metabolites of cells incubated with 5.6 or 26 mmol/l glucose differed significantly in the concentrations of a number of uridine diphosphate (UDP)-conjugated monosaccharides, which were elevated two- to threefold in cells incubated in 26 mmol/l glucose over control samples. The affected metabolites were identified (through a series of spiking experiments) to be UDP-N-acetylglucosamine, UDP-N-acetylgalactosamine, and UDP-glucuronic acid. Coincubation of the cells with Sorbinil 200 microM in the presence of 26 mmol/l glucose had no effect on this accumulation. Under normal circumstances, these molecules selectively and sequentially are incorporated into the polysaccharide chains of glycosaminoglycans (GAGs), whose presence and distribution in the basement membranes is affected adversely by diabetes mellitus. These data suggest that the availability of the monosaccharide precursor is not the rate-limiting step for GAG synthesis in the presence of pathologic glucose concentrations. Thus, the lost GAG content in the basement membranes of diabetic patients may be caused by changes elsewhere in the biosynthesis and/or catabolism of the polysaccharide-linked protein molecules.
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PMID:Human retinal pigment epithelial cells cultured in hyperglycemic media accumulate increased amounts of glycosaminoglycan precursors. 163 9

Effects of sorbinil, an aldose reductase inhibitor, were examined on renal glomerular structure, urinary albumin and IgG excretion, and vascular albumin permeation in eyes and aorta of 8-month diabetic, galactose-fed, and age-matched control rats. Sorbinil was added to the diet of one-half of the rats in each group at the time of induction of diabetes and galactosemia. Weight gain was impaired in diabetic and galactose-fed rats versus controls and was improved slightly in corresponding sorbinil-treated groups. Plasma glucose and glycosylated hemoglobin levels, food consumption, and 24-hr urine volume were increased in diabetic rats and were unaffected by sorbinil treatment. Food consumption and glycosylated hemoglobin levels were increased in galactose-fed rats, although the increases were smaller than in diabetic rats; glycosylated hemoglobin levels were decreased by sorbinil. Diabetes- and galactosemia-induced increases in albumin permeation in eyes and aorta were prevented by sorbinil. Urinary excretion of albumin and IgG was increased by diabetes and decreased by sorbinil, although differences between the two diabetic groups were not statistically significant for albumin. Galactosemia was associated with an increase in urinary albumin and IgG excretion that did not reach statistical significance. Glomerular capillary basement membrane width (GBMW) was increased in diabetic versus age-matched control rats but was unaffected by galactose feeding. GBMW was increased in controls fed sorbinil and glomerular capillary basement membrane thickening in diabetic rats was not prevented by sorbinil. The fractional volume of the glomerulus occupied by mesangium (Vvmes) was increased in diabetic and galactose fed rats versus age-matched controls, and was unaffected by sorbinil.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Discordant effects of the aldose reductase inhibitor, sorbinil, on vascular structure and function in chronically diabetic and galactosemic rats. 177 18

The ability of aldose reductase inhibitors to prevent the decline in neural Na+,K(+)-ATPase activity in diabetic rats has not been confirmed by all laboratories. In this study, the efficacy of two structurally different aldose reductase inhibitors was evaluated under different experimental conditions. Na+,K(+)-ATPase activity was measured in sciatic nerves from streptozocin-induced diabetic rats fed normal rodent chow or a chow supplemented with 68% sucrose. Nerve homogenates from chow-fed rats were prepared with a Dounce tissue grinder, whereas homogenates from the sucrose-fed rats were prepared with an Ultra-Turrax disperser. In the chow-fed rats, 4 weeks of untreated diabetes resulted in an increase in neural sorbitol and fructose, a decrease in myoinositol, and a 54% decline in Na+,K(+)-ATPase activity. Sorbinil administration (20 mg/kg/day) completely prevented the rise in sorbitol and fructose and the depletion of myoinositol, but did not prevent the decline in Na+,K(+)-ATPase activity. In diabetic rats fed the sucrose diet for 4, 6, and 8 weeks, the neural sorbitol and fructose levels were elevated, the myoinositol concentration declined, and the Na+,K(+)-ATPase activity was 26 to 28% below the control. Prevention or intervention treatment with sorbinil (20 mg/kg/day) or tolrestat (50 mg/kg/day) for 4 to 6 weeks prevented the alterations in sorbitol, fructose, and myoinositol, and also prevented the decline in Na+,K(+)-ATPase activity. In conclusion, prevention and intervention therapy with aldose reductase inhibitors prevented the decline in Na+,K(+)-ATPase in sciatic nerves of sucrose-fed streptozocin-diabetic rats that were homogenized with an Ultra-Turrax disperser, but not in sciatic nerves from streptozocin-diabetic rats fed normal rodent chow that were homogenized with a Dounce tissue grinder. These findings indicate that the assessment of aldose reductase inhibitor efficacy is dramatically affected by the type of nerve preparation assayed and/or the diet.
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PMID:Adenosine triphosphatase activity in sciatic nerve tissue of streptozocin-induced diabetic rats with and without high dietary sucrose: effect of aldose reductase inhibitors. 185 65

To examine the association between renal hemodynamic abnormalities and the development of diabetic kidney disease, glomerular filtration rate (GFR) and renal plasma flow (RPF) have been determined in dogs with alloxan-induced diabetes or experimental galactosemia of 1 to 5 years duration. GFR and RPF were significantly greater than normal in insulin-deficient diabetic dogs. GFR was also significantly greater than normal in the galactosemic animals, and RPF tended to be elevated even though GFR and RPF were measured at time of day when plasma galactose is no longer elevated. GFR and effective RPF (eRPF) were found to increase in normal animals upon acute elevation of blood galactose or glucose concentration. Thus, GFR is supranormal in experimental galactosemia, as well as in diabetes, although galactosemia has been shown not to cause nephromegaly, mesangial expansion, or glomerular obliteration, which are typical of diabetes. Administration of an aldose reductase inhibitor (Sorbinil) at dosages sufficient to significantly reduce erythrocyte polyol concentration did not significantly influence GFR or RPF in diabetic or galactosemic dogs.
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PMID:Renal hemodynamics in experimentally galactosemic dogs and diabetic dogs. 190 44

To analyze the effects of sorbitol accumulation on the survival and growth of epithelial cells from rabbit renal inner medulla, cloning efficiency (an index of cell viability) was measured at normal and high glucose and NaCl concentrations and when sorbitol accumulation was prevented by Tolrestat and Sorbinil, which inhibit aldose reductase. With PAP-HT25 cells grown to near confluence, high NaCl increases aldose reductase activity, causing enough rise in cell sorbitol concentration to balance most of the increased osmolality of the high extracellular NaCl. Inhibition of aldose reductase prevents both the increased enzyme activity and sorbitol accumulation in a dose-related manner. Paralleling this, colony-forming efficiency is not affected by the inhibitors at a normal NaCl concentration but is greatly reduced when extracellular NaCl is high. On the other hand, high glucose levels, as occur in diabetes, increase sorbitol content well above the concentration required for osmotic balance and inhibit colony-forming efficiency. Under those conditions, aldose reductase inhibitors lower cell sorbitol and reverse (at 300-350 mosmol/kgH2O) or reduce (at 500-550 mosmol/kgH2O) the decrease in colony-forming efficiency caused by high glucose. Thus sorbitol accumulation is necessary for osmoregulation when induced by high osmolality but is harmful when induced by high glucose.
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PMID:Effects of NaCl, glucose, and aldose reductase inhibitors on cloning efficiency of renal medullary cells. 210 52

These studies were undertaken to assess the effects of increased galactose (v increased glucose) metabolism via the polyol pathway on vascular filtration function in the kidneys, eyes, nerves, and aorta. Quantitative radiolabeled tracer techniques were used to assess glomerular filtration rate (GFR) and regional tissue vascular clearance of plasma 131I-bovine serum albumin (BSA) in five groups of male Sprague-Dawley rats: nondiabetic controls, streptozotocin-diabetic rats, nondiabetic rats fed a 50% galactose diet, diabetic rats treated with sorbinil (an aldose reductase inhibitor), and galactose-fed rats treated with sorbinil. Sorbinil was added to the diet to provide a daily dose of approximately .2 mmol/kg body weight. After 2 months of diabetes or galactose ingestion, albumin clearance was increased twofold to fourfold in the eye (anterior uvea, choroid, and retina), sciatic nerve, aorta, and kidney; GFR was increased approximately twofold and urinary excretion of endogenous albumin and IgG were increased approximately 10-fold. Sorbinil treatment markedly reduced or completely prevented all of these changes in galactose-fed, as well as in diabetic rats. These observations support the hypothesis that increased metabolism of glucose via the sorbitol pathway is of central importance in mediating virtually all of the early changes in vascular filtration function associated with diabetes in the kidney, as well as in the eyes, nerves, and aorta. On the other hand, renal hypertrophy in diabetic rats and polyuria, hyperphagia, and impaired weight gain in galactose-fed and in diabetic rats were unaffected by sorbinil and therefore are unlikely to be mediated by increased polyol metabolism.
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PMID:Vascular filtration function in galactose-fed versus diabetic rats: the role of polyol pathway activity. 211 13

A 2-year randomized placebo-controlled double-blind trial of 250 mg day-1 of the aldose reductase inhibitor Sorbinil in severe symptomatic chronic peripheral neuropathy was performed in 21 diabetic patients. Due to adverse reactions 8 patients completed the trial on Sorbinil and 6 patients on placebo. Despite differences in baseline neurophysiological parameters, duration of diabetes, and presence of retinopathy between the placebo and treatment groups, there were no initial differences in in vitro platelet aggregation, albumin excretion rate (AER) or muscle capillary basement membrane thickness. After 2 years the median deterioration in AER in the placebo group was 18.4 micrograms min-1 (range 2.6-64.8 micrograms min-1). This deterioration was significant (p less than 0.03). The change in AER in the Sorbinil group was +1.25 (-10.7 to +20.4) micrograms min-1, an insignificant change. In vitro platelet responsiveness to collagen and adenosine diphosphate (ADP) increased in the placebo group (median change max% collagen + 8 (+2 to +30)%; ADP +4.5 (0 to +20)% compared with a fall in the Sorbinil treated patients (median change; collagen -17.5 (-2 to -40)%, p less than 0.05; ADP, -4 (0 to -25)%, p less than 0.05). Muscle capillary basement membrane thickness was measured in only 3 patients in each group and did not alter significantly during the trial. All 12 neurophysiological measurements showed no significant changes between the treatment and placebo groups. The data suggest that aldose reductase inhibition has effects on platelet reactivity and microalbuminuria.
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PMID:Prolonged aldose reductase inhibition in chronic peripheral diabetic neuropathy: effects on microangiopathy. 213 66

It has been suggested that sugar cataracts associated with diabetes mellitus result from the accumulation of excess sorbitol within lens fibrils. Swelling of lens fibrils occurs when water moves in to maintain osmotic balance; the excess water causes disruption of fibrils and cataract formation. Other studies have indicated that more than sorbitol-induced osmotic stress is involved. Our study used lenses collected from rats after 21 or 44 d of streptozotocin diabetes. Cataracts formed in untreated 44-d streptozotocin diabetic rats, but were not apparent in the 21-d untreated diabetic animals. Lens sorbitol increased in the diabetic animals both before and after cataract formation. Lens taurine varied inversely with the sorbitol content in a fashion that resulted in no net change in total lens osmoles. Lens water did not increase in the diabetic animals with or without cataracts. The aldose reductase inhibitor Sorbinil prevented the increase in lens sorbitol in both the 21- and 44-d streptozotocin diabetic rats; cataract formation was prevented in the 44-d diabetic animals. The lens water in untreated diabetic animals with cataracts did not differ from lens water in the Sorbinil-treated diabetic animals that did not develop cataracts. Sorbinil treatment of diabetic animals was associated with normalization of both lens sorbitol and taurine levels. Taurine has been shown to serve both as an osmoregulator and as an antioxidant. The apparent increase in lens osmolality attributed to sorbitol was counterbalanced by an equimolar reduction in taurine concentration. The reciprocal relationship between taurine and sorbitol reduces the likelihood of an osmotic mechanism for sugar cataractogenesis; the reduced lens taurine, however, may increase the risk of lens protein oxidation and subsequent cataract formation. Thus in vivo sugar cataract formation may be an oxidative process rather than an osmotic phenomenon.
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PMID:Nonosmotic diabetic cataracts. 213 28


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