Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0432222 (SEM)
 47,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rats with streptozotocin-induced diabetes have a decreased rate of sciatic nerve regeneration. We studied the effects on this defect of treatment with the aldose reductase inhibitor, ponalrestat (25 mg/kg per day via an endogastric tube). The nerves of diabetic rats were crush-injured at 5 weeks of diabetes and regeneration evaluated 7 days later with the pinch-reflex test. Ponalrestat treatment was started at day 3 after streptozotocin injection and was continued for the whole experimental period, i.e. until 6 weeks of diabetes. The treatment prevented effectively the accumulation of sorbitol and fructose in the nerves of diabetic rats, but was without effect on the sciatic nerve regeneration (controls 21.8 +/- 1.2 mm/7 days (mean +/- SEM, n = 6), untreated diabetics 15.8 +/- 1.8 (n = 7), ponalrestat-treated diabetics 16.2 +/- 1.0 (n = 10]. The results indicate that there is no connection between increased sorbitol pathway flux and impaired regeneration in streptozotocin diabetic rats.
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PMID:Impaired nerve regeneration in streptozotocin-diabetic rats. Effects of treatment with an aldose reductase inhibitor. 253 88

Three clinical trials to evaluate the efficacy of the aldose reductase inhibitor sorbinil in improving or preventing diabetic neural function have either been completed or are currently in progress. In the first study from Seattle and Chicago, motor and sensory nerve conduction velocities (NCV) were evaluated in 39 insulin- and noninsulin-dependent, glycemic-stable diabetic patients in a randomized, double-blind, crossover trial. During the 9 weeks of treatment with 250 mg/d of sorbinil, there was a faster nerve conduction velocity of all 3 nerves tested when compared with the placebo period: peroneal motor NCV (+0.70 +/- 0.24 m/s; means +/- SEM; P less than 0.008), median motor NCV (+0.66 +/- 0.27 m/s; P less than 0.005), and median sensory NCV (+1.16 +/- 0.50 m/s; P less than 0.035). Conduction velocity for all 3 nerves declined significantly within 3 weeks following cessation of the drug. These effects of sorbinil were unrelated to glycemic control, which was constant during the study. Although the effects of sorbinil in improving nerve conduction velocity were small, the findings suggest that the polyol-pathway activity contributes to slowed nerve conduction velocity in diabetics. The second study is a seven-center, double-blind, randomized, 12-month trial of 210 to 280 diabetic patients with clinical signs, symptoms, and objective measurements of neuropathy. The trial has a common-core protocol with end-point evaluations of scored neural signs, symptoms, and neural measurements. Two unique neural tests were designed and validated for use in this trial: thermal and tactile perception thresholds of the fingers and toes.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Clinical trials of sorbinil on nerve function. 308 11

The etiology of diabetic osteopenia has not been established. The value of serum osteocalcin (BGP) as a marker of the bone abnormalities and the possible role of the polyol pathway in diabetic osteopenia were investigated. Three groups of rats were studied over 7 weeks: group D (n = 12), rats with streptozotocin (55 mg/kg)-induced diabetes given saline by gavage; group DS (n = 12), rats with streptozotocin-induced diabetes given the aldose reductase inhibitor sorbinil (25 mg/kg) daily by gavage; and group C (n = 6), saline-injected controls. Circulating levels of ionized calcium, BGP, amino-terminal PTH, and glucose were measured on days 0, 7, 14, 28, and 49. Tibial bone specimens were examined for the presence of aldose reductase by immunocytochemistry and by histomorphometry after tetracycline labeling. Diabetic rats with or without sorbinil treatment failed to gain weight [group D, 234 +/- 26 g; group DS, 217.0 +/- 40 g; group C, 310 +/- 33 g (mean +/- SD)]. Serum BGP levels decreased significantly in the diabetic rats within 7 days and remained lower throughout the study. BGP values on day 7 were: group D, 47.7 +/- 4.9 ng/ml; group DS, 65.9 +/- 5.5 ng/ml; and group C, 90.4 +/- 4 ng/ml (mean +/- SEM). Serum PTH levels were similar in all groups, except for day 49, when an increase in the D group was observed. Bone histomorphometry showed decreased bone remodeling in the D group, which confirmed the serum BGP findings. Aldose reductase was detectable in the small blood vessels and in bone itself. Sorbinil failed to influence the biochemical or bone histomorphometric abnormalities associated with diabetes. Serum BGP may be a valuable marker for the decreased bone remodeling in insulinopenic diabetes.
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PMID:Bone mineral metabolism in experimental diabetes mellitus: osteocalcin as a measure of bone remodeling. 313 94

In two studies of patients with diabetes who did not have neurologic symptoms, nerve conduction velocity was increased either by an improvement in glucose control or by the administration of the aldose reductase inhibitor sorbinil. In a 1981 study by Graf et al, glycemic control and motor and sensory nerve conduction velocities were evaluated in 18 patients with non-insulin-dependent diabetes before and after one, three, six, and 12 months of antihyperglycemic therapy. There was an improvement in motor nerve conduction velocity (median motor, p less than 0.01; peroneal motor, p less than 0.05; and tibial motor, p less than 0.05), which was associated with the improvement in fasting plasma glucose levels after three months for some motor nerves (median motor: r = -0.62, p less than 0.01; peroneal motor: r = -0.50, p less than 0.05). A direct linear relationship between the change in fasting glucose and glycosylated hemoglobin levels and the change in median motor nerve conduction velocity after 12 months of antihyperglycemic therapy was also found. Thus, there was a tendency for those patients who had the greatest improvement in glycemic control to have the greatest improvement in motor nerve conduction velocity. The findings in the first study are consistent with the hypothesis that hyperglycemia contributes to slowed nerve conduction velocity. In a 1983 randomized, double-blind, crossover study by Judzewitsch et al, motor and sensory nerve conduction velocities were evaluated in 39 patients with insulin-dependent or non-insulin-dependent diabetes in whom glycemic control was stable. During nine weeks of treatment with 250 mg per day of sorbinil, nerve conduction velocity was faster in the three tested nerves when compared with the velocities during the placebo period (peroneal motor nerve conduction velocity: +0.70 +/- 0.24 m per second, mean +/- SEM, p less than 0.008; median motor nerve conduction velocity: +0.66 +/- 0.27 m per second, p less than 0.005; median sensory nerve conduction velocity: +1.16 +/- 0.50 m per second, p less than 0.035). Although the effect of an improvement in glycemic control and administration of sorbinil in increasing nerve conduction velocity in two groups of neurologically asymptomatic patients with diabetes was small, the findings are consistent with the hypothesis that polyol pathway activity contributes to slowed large-fiber nerve conduction velocity in these patients.
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PMID:Effects of glycemic control and aldose reductase inhibition on nerve conduction velocity. 393 64

This study examined the effect of an aldose reductase inhibitor (Sorbinil, CP 45634, Pfizer, Sandwich, Kent, United Kingdom) on the metabolite profile of the lens during the first week after induction of diabetes with alloxan. The lens content of sorbitol, fructose, glycerol 3-phosphate, and glucose 6-phosphate was, respectively, 0.33 +/- 0.03, 0.55 +/- 0.05, 0.10 +/- 0.01, and 0.074 +/- 0.006 mumol/g (means +/- SEM) in the control group rising to 12.2 +/- 0.52, 3.20 +/- 0.10, 0.76 +/- 0.10, and 0.200 +/- 0.009 in lenses from alloxan-diabetic rats. Sorbinil treatment (40 mg/kg) decreased the lens content of sorbitol to 0.60 +/- 0.06, fructose to 0.85 +/- 0.08, and glycerol 3-phosphate to 0.36 +/- 0.03 mumol/g; glucose 6-phosphate remained unchanged. Significantly, the lens content of glutathione was decreased to 60% of the normal value in the diabetic group, but was sustained at normal levels with Sorbinil treatment. The ATP content of the lens was not altered by diabetes or Sorbinil treatment at this time interval. Sorbinil has no significant effect on the above metabolites in the normal rat lens. The effect of Sorbinil in restoring normal levels of glutathione and glycerol 3-phosphate may be a potentially important facet of the action of this drug. The interlocking of metabolic pathways by the redox state of NAD+/NADH and NADP+/NADPH, their derangement in diabetes, and the wider effects of Sorbinil on the network of reactions in the lens are discussed.
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PMID:The effect of an aldose reductase inhibitor (Sorbinil) on the level of metabolites in lenses of diabetic rats. 640 81

Erythrocytes from diabetic patients before and after treatment with the aldose reductase inhibitor, sorbinil, were analyzed by a capillary gas chromatographic method for sorbitol and myo-inositol. The mean erythrocyte sorbitol level in the diabetic patients was significantly higher than in the control subjects (13.1 +/- 0.9 and 5.2 +/- 0.3 nmol/ml erythrocytes, respectively, mean +/- SEM, p less than 0.001). The mean erythrocyte myo-inositol level in diabetic patients was not different from that in control subjects (43.2 +/- 2.9 and 40.5 +/- 1.9 nmol/ml erythrocytes, respectively). Sorbinil treatment reduced the elevated sorbitol levels in the diabetic patients to normal or slightly below normal, but did not affect the erythrocyte myo-inositol concentration. It is concluded that the erythrocyte is not a suitable model to monitor a possible effect of sorbinil on myo-inositol concentration in less accessible tissues.
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PMID:myo-Inositol and sorbitol in erythrocytes from diabetic patients before and after sorbinil treatment. 643 88

Activities of erythrocyte aldose reductase were compared in 34 normal subjects, 45 diabetic patients, and nine young men following immersion in water at 25, 39, and 42 degrees C. Mean basal enzyme activity was 1.11 (SEM 0.12) U/g Hb and 2.07 (SEM 0.14) U/g Hb in normal controls and diabetic patients, respectively (P < 0.0001). Activities of the enzyme showed a good correlation with hemaglobin A1 (HbA1) concentrations (P < 0.01) but not with fasting plasma glucose concentrations. After immersion at 42 degrees C for 10 min, enzyme activity was increased by 37.6% (P < 0.01); however, the activity decreased by 52.2% (P < 0.005) after immersion for 10 min at 39 degrees C and by 47.0% (P < 0.05) at 25 degrees C. These changes suggest that heat stress might aggravate diabetic complications, and body exposure to hot environmental conditions is not recommended for diabetic patients.
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PMID:Thermal stress and diabetic complications. 769 55

Erythrocyte aldose reductase was isolated and its activity measured in 72 Type 1 (insulin dependent) diabetic patients and 21 age and sex matched non-diabetic subjects. The diabetic patients were categorized into two groups in terms of presence (n = 29) or absence (n = 43) of severe diabetic complications. Age, sex, duration of diabetes and HbA1c levels were matched between the diabetic groups. Erythrocyte aldose reductase (mean +/- SEM) was increased in patients with Type 1 diabetes compared to the non-diabetic subjects (7.22 +/- 0.24 vs 5.66 +/- 0.19 Ul-erythrocytes-1, < 0.0001). There was a four-fold variation in its activity among the diabetic patients (3.38-12.23 Ul-erythrocytes-1). The enzyme activity was significantly higher in patients with complications than those without (8.17 +/- 0.39 vs 6.58 +/- 0.26 Ul-erythrocytes-1, p < 0.002). When the patients were stratified by duration of the disease, the enzyme activity was highest in patients who had developed complications with a duration of less than 20 years and lowest in those without complications for 20 years or longer (8.54 +/- 0.48 vs 6.46 +/- p +/- 0.33 Ul-erythrocytes-1, p < 0.002). Patients who had an aldose reductase activity greater than the mean +/- 2SD of that seen in non-diabetic controls were four times more likely to have diabetic complications than those whose enzyme activity fell within 2SD of non-diabetic individuals (p < 0.0005).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Association of erythrocyte aldose reductase activity with diabetic complications in type 1 diabetes mellitus. 843 85

Levels of aldose reductase, glyoxalase I, and glyoxalase II in mononuclear and polymorphonuclear cells from insulin-dependent diabetes mellitus (IDDM) patients with long term diabetic complications were compared to levels in IDDM patients without complications and to those in nondiabetic controls. Cells were isolated from 22 asymptomatic long term IDDM patients, 22 symptomatic IDDM patients, and 16 controls, using a double gradient centrifugation procedure. Aldose reductase was determined by Western blots using polyclonal antiserum to human aldose reductase purified from skeletal muscle. Glyoxalase I and glyoxalase II were determined spectrophotometrically. Aldose reductase in mononuclear cells from symptomatic IDDM patients is significantly elevated compared to that in asymptomatic IDDM patients (mean +/- SEM, 0.96 +/- 0.20 vs. 0.46 +/- 0.08 microgram/mg protein; P < 0.02). Aldose reductase was not detected in polymorphonuclear cells. Glyoxalase I in mononuclear and polymorphonuclear cells from symptomatic IDDM patients is significantly elevated compared to that in controls [mean for mononuclear cells, 0.46 +/- 0.03 vs. 0.37 +/- 0.03 mumol/min.mg (P < 0.05); mean for polymorphonuclear cells, 0.16 +/- 0.01 vs. 0.10 +/- 0.01 mumol/min.mg (P < 0.002)]. Glyoxalase II is significantly elevated only in polymorphonuclear cells from symptomatic IDDM patients compared to controls (mean, 0.13 +/- 0.01 vs. 0.063 +/- 0.016 mumol/min.mg; P < 0.005). Glutathione peroxidase and glutathione S-transferase were not significantly different in these populations. Aldose reductase, glyoxalase I, and glyoxalase II are involved in the metabolism of methylglyoxal, suggesting that methylglyoxal may play a role in the etiology of diabetic complications.
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PMID:Increased levels of methylglyoxal-metabolizing enzymes in mononuclear and polymorphonuclear cells from insulin-dependent diabetic patients with diabetic complications: aldose reductase, glyoxalase I, and glyoxalase II--a clinical research center study. 863 55

This study was aimed at evaluating the potent and specific aldose reductase inhibitor fidarestat, on diabetes-associated cataract formation, and retinal oxidative-nitrosative stress, glial activation, and apoptosis. Control and streptozotocin-diabetic rats were treated with or without fidarestat (16 mg kg(-1)d(-1)) for 10 weeks after an initial 2-week period without treatment. Lens changes were evaluated by indirect ophthalmoscopy and portable slit lamp. Nitrotyrosine, poly(ADP-ribose), and glial fibrillary acidic protein expression were assessed by immunohistochemistry. The rate of apoptosis was quantified in flat-mounted retinas by TUNEL assay with immunoperoxidase staining. To dissect the effects of high glucose exposure in retinal microvascular cells, primary bovine retinal pericytes and endothelial cells were cultured in 5 or 30 mM glucose, with or without fidarestat (10 microM) for 3-14 days. Apoptosis was assessed by TUNEL assay, nitrotyrosine and poly(ADP-ribose) by immunocytochemistry, and Bax and Bcl-2 expression by Western blot analyses. Fidarestat treatment prevented diabetic cataract formation and counteracted retinal nitrosative stress, and poly(ADP-ribose) polymerase activation, as well as glial activation. The number of TUNEL-positive nuclei (mean +/- SEM) was increased approximately 4-fold in diabetic rats vs. controls (207+/-33 vs. 49+/-4, p<0.01), and this increase was partially prevented by fidarestat (106+/-34, p<0.05 vs. untreated diabetic group). The apoptotic cell number increased with the prolongation of exposure of both pericytes and endothelial cells to high glucose levels. Fidarestat counteracted nitrotyrosine and poly(ADP-ribose) accumulation and apoptosis in both cell types. Antiapoptotic effect of fidarestat in high glucose-exposed retinal pericytes was not associated with the inhibition of Bax or increase in Bcl-2 expression. In conclusion, the findings, i) support an important role for aldose reductase in diabetes-associated cataract formation, and retinal oxidative-nitrosative stress, glial activation, and apoptosis, and ii) provide a rationale for the development of aldose reductase inhibitors, and, in particular, fidarestat, for the prevention and treatment of diabetic ocular complications.
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PMID:Aldose reductase inhibitor fidarestat counteracts diabetes-associated cataract formation, retinal oxidative-nitrosative stress, glial activation, and apoptosis. 1850 58


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