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)

Aldose reductase is the first enzyme in the polyol pathway and catalyses the NADPH-dependent reduction of D-glucose to D-sorbitol. Under normal physiological conditions aldose reductase participates in osmoregulation, but under hyperglycaemic conditions it contributes to the onset and development of severe complications in diabetes. Here we present the crystal structure of pig lens aldose reductase refined to an R-factor of 0.232 at 2.5-A resolution. It exhibits a single domain folded in an eight-stranded parallel alpha/beta barrel, similar to that in triose phosphate isomerase and a score of other enzymes. Hence, aldose reductase does not possess the expected canonical dinucleotide-binding domain. Crystallographic analysis of the binding of 2'-monophospho-adenosine-5'-diphosphoribose, which competitively inhibits NADPH binding reveals that it binds into a cleft located at the C-terminal end of the strands of the alpha/beta barrel. This represents a new type of binding for nicotinamide adenine dinucleotide coenzymes.
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PMID:Novel NADPH-binding domain revealed by the crystal structure of aldose reductase. 173 86

The effects of a high-glucose medium, insulin, and an aldose reductase inhibitor (ONO-2235) on sorbitol accumulation were compared in the human erythrocyte and the rabbit retina, while the effects of epinephrine on in vitro sorbitol accumulation were investigated in the human and rabbit retina. In both erythrocytes and the retina, linear increments of sorbitol accumulation were observed in a dose-dependent manner with 5 to 50 mM glucose. These increments were markedly inhibited by 100 microM ONO-2235 but not by insulin (400 microU/ml). In the presence of 5 mM glucose, a dose-dependent increase of the sorbitol content of the rabbit retina was seen following epinephrine stimulation (0.4-4.0 microM and this was markedly reduced by 100 microM ONO-2235. Moreover, both 50 mM glucose and 4.0 microM epinephrine increased the sorbitol content of the retina from a diabetic patient, and the glucose-induced increment in sorbitol was significantly reduced by 100 microM ONO-2235. Our data suggested that aldose reductase inhibitors might be useful for the treatment of diabetic retinopathy, since the polyol pathway appears to be an important factor in its pathogenesis, and that catecholamines might have some role in the activation of the retinal polyol pathway.
Diabetes Res Clin Pract 1991 Oct
PMID:In vitro retinal and erythrocyte polyol pathway regulation by hormones and an aldose reductase inhibitor. 174 61

A double blind placebo controlled trial was performed to evaluate the effects of the aldose reductase inhibitor, ponalrestat, on symptomatic diabetic neuropathy. After a 4-week placebo run-in phase, 60 patients were 2:1 randomized to receive either 600 mg ponalrestat or placebo once daily over 12 months. Forty-six patients, 30 of whom were treated with ponalrestat and 16 with placebo, completed the study. Motor and sensory nerve conduction, thermal and vibration sensation thresholds, heart rate variation at rest, E/I ratio, pupillary dilation velocity and pupillary reflex latency were determined at baseline and after 6 and 12 months. Neuropathic symptom scores were assessed every 3 months. Among the fifteen nerve function parameters studied, only trends in favour of ponalrestat were noted for heart rate variation and E/I ratio after 6 months (P = 0.06), but no significant differences between the groups could be demonstrated during the study. No adverse reactions were observed. It is concluded that one-year treatment with ponalrestat has no beneficial effects on symptoms or electrophysiological parameters in diabetic neuropathy.
Diabetes Res Clin Pract 1991 Oct
PMID:One-year treatment with the aldose reductase inhibitor, ponalrestat, in diabetic neuropathy. 174 64

Flux via the polyol pathway, which comprises the enzymes aldose reductase (AR) and sorbitol dehydrogenase (SDH), has been implicated in the debilitating complications of diabetes. Previous studies in this laboratory have indicated that erythrocyte AR activities are increased (by 72%) in insulin-dependent diabetic patients. To investigate the mechanism underlying this activation, the response of AR activity to oral glucose challenge was investigated in eight overnight-fasted human volunteers. Glucose consumption led to a transient activation (by 76%: P less than 0.01) of erythrocyte AR, which paralleled the rise and subsequent fall in blood glucose concentrations. It is concluded that erythrocyte AR activity is acutely modulated in response to hyperglycaemia by an as yet unknown mechanism.
Diabetes Res Clin Pract 1991 Oct
PMID:Activation of erythrocyte aldose reductase in man in response to glycaemic challenge. 174 66

Although the enzyme aldose reductase (AR) is implicated in the development of tissue pathology in diabetes, the exact mechanism of this involvement remains unclear. To better understand the role that expression of the aldose reductase-encoding gene (ALR) may play in diabetic complications, we have begun to analyze the gene and its regulatory regions, and we present here the sequence of four ALR genes in the rat. The putative functional gene is 14.1 kb long, has ten exons which show perfect sequence identity to the rat lens AR RNA sequence, and nine introns with classical splice-site consensus sequences. Potential regulatory elements in the 5'-flanking region of this gene include a TATA box and two CCAAT boxes. Probing rat genomic Southern blots with a fragment from the first intron indicates that there is probably only one copy of this gene in the rat genome. The other three genes are processed pseudogenes which show approx. 90% identity to the rat lens AR RNA sequence, contain no introns, and have poly(A) regions at their 3' ends. Chromosomal localization studies show the presence of ALR genes on chromosomes 3, 4 and 6 in the rat with the putative functional gene mapped on chromosome 4.
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PMID:Characterization of the aldose reductase-encoding gene family in rat. 174 96

Diabetes was induced with streptozotocin in rats weighing about 160 g. These were maintained with age-matched controls for up to 14 months, blood glucose being periodically monitored. Half the diabetic and control rats received the aldose reductase inhibitor, Ponalrestat, in their diet. At 3 weeks, 6-7 months and 13-14 months, the vascular permeability in regions of brain, and in optic and sciatic nerves, were measured by maintaining radiotracers in the bloodstream--125I-albumin (100 min), [14C]sucrose (60 min) and 131I-albumin (5 min)--followed by tissue sampling and counting at termination. 131I-albumin estimated residual intravascular plasma. Diabetes of up to 13-14 weeks caused no measurable increase in the sucrose permeability of microvessels in eight different brain regions, in optic or in sciatic nerve. At 3 weeks of diabetes, sucrose permeability in all brain regions and in optic nerve was reduced relative to that in controls. Extravascular albumin entry into different regions of brain and optic nerve was insignificant and insensitive to diabetes, except in the hypothalamus and optic nerves where it was raised with increasing duration of diabetes. In sciatic nerve, extravascular albumin distribution was markedly increased by diabetes, but sucrose permeability was not demonstrably affected. At the level used in the diet, Ponalrestat reduced the sorbitol content of diabetic sciatic nerve but did not protect again the increased permeability to albumin.
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PMID:Permeability of blood-brain and blood-nerve barriers in experimental diabetes mellitus in the anaesthetized rat. 176 15

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

Sorbitol-3-phosphate (S3P) and fructose-3-phosphate (F3P) are novel phosphorus compounds recently discovered and identified in the crystalline lens as well as other tissues. These phosphates increased with diabetes progression in streptozotocin-diabetic rat lenses. Treatment of these rats with an orally administered aldose reductase inhibitor eliminated S3P and intramuscularly injected insulin obliterated F3P. These results indicate that enzymes catalyzing S3P and F3P formation co-activate with aldose reductase activation and hyperglycemia, respectively.
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PMID:The effect of insulin and aldose reductase inhibition on the phosphate metabolism of streptozotocin-diabetic rat lens. 178 17

The polyol pathway has long been associated with diabetic retinopathy. Glucose is converted to sorbitol with the aid of the enzyme aldose reductase. Aldose reductase inhibitors can prevent changes induced by diabetes. A total of 30 patients with minimal background retinopathy were randomly divided into a ponalrestat-taking group and a placebo-taking group. All were followed for 6 months and twenty-three were followed for 12 months. The baseline microaneurysm count was 2.6 +/- 1.9 (mean +/- SD) for the ponalrestat group and 3.5 +/- 2.9 for the placebo group. At 6 months the counts were 3.1 +/- 3.5 and 2.9 +/- 3.6 and after 12 months 3.0 +/- 4.1 and 2.9 +/- 3.4. There is no statistically significant difference between the groups at 0, 6 or 12 months of study. The change in retinopathy severity level did not significantly differ between the two groups at either 6 or 12 months. Ponalrestat administration at a dosage of 600 mg daily for 12 months has no significant effect on the course of minimal retinopathy in diabetic patients.
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PMID:The effects of an aldose reductase inhibitor on the progression of diabetic retinopathy. 179 Jul 35

The effects of a new aldose reductase inhibitor, 7-fluoro-2-(N-methyl-N-carboxymethyl)sulfamoyl xanthone (BAL-ARI8, CAS 124066-40-6), on the diabetic complications of streptozotocin-induced diabetic rats were studied. The daily administration of BAL-ARI8 throughout the 8-week course of the experiment sharply decreased the sorbitol accumulation in the lens of the diabetic rats. The incidence of cataract formation was also reduced, being detected in only 45% of BAL-ARI8 treated animals, against the 100% of diabetic controls showing cataract after 8 weeks from diabetes onset. On the other hand, the serum glucose levels remained unchanged. In diabetic controls, there was about a 2.5-fold increase of the total protein urinary excretion during the 24 h. Treatment with BAL-ARI8 prevented up to 70% of this increase. Individual protein components were examined by polyacrylamide gel electrophoresis and quantitated by laser densitometric analysis. Diabetic-induced proteinuria primarily resulted from excretion of newly detected proteins with molecular weight in the range 30,000-60,000 D, together with an increase of albumin (25% of the total excretion) and the presence of new higher molecular weight proteins (greater than 66,000 D). BAL-ARI8 administration resulted in a shift of the protein profile back toward normality i.e. 73% of proteins with molecular weight below 30,000 D, 7.5% albumin and no proteins above 66,000 D. These results suggest that BAL-ARI8 may represent a therapeutic approach for the management of diabetic complications.
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PMID:Effects of a new aldose reductase inhibitor on diabetic complications in rats. 181 Feb 61


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