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 inhibitors improve nerve biochemistry, function, and structure in diabetic animals and increase nerve conduction in diabetic patients. Nevertheless, it has been difficult to demonstrate a benefit from these agents in patients with clinically overt diabetic neuropathy. Direct measurement of the nerve tissue penetration and biochemical and biological potency of these compounds is essential to fully understand and evaluate their effectiveness. Human sural nerve biopsies obtained from diabetic neuropathic patients undergoing treatment with an aldose reductase inhibitor revealed a reduction in intermediates of the polyol pathway. Specific morphologic lesions that correlate with the degree of clinical and electrophysiologic impairment also were identified. Morphologic evaluation of sural nerve biopsies obtained after aldose reductase inhibitor treatment suggests that these biochemically effective compounds ameliorate clinically relevant structural lesions in patients with diabetic neuropathy.
J Diabetes Complications
PMID:Effects of aldose reductase inhibitors on the progression of nerve fiber damage in diabetic neuropathy. 156 56

In tissues susceptible to damage from chronic diabetes, excess glucose is metabolized by aldose reductase (AR) to sorbitol. Originally, AR-catalyzed sorbitol formation (and accumulation) was found in the diabetic lens; the cataractogenicity of this process was proven by preventing cataract formation with an AR inhibitor (ARI). These findings were extended to the hypothesis that, in diabetic tissues, excessive intracellular sorbitol formation initiates a cascade of metabolic abnormalities which gradually progress to loss of functional and structural integrity. The pivotal role of AR as a trigger for such abnormalities was established by preventing their occurrence in diabetic animals treated with an ARI. By inference, this led to the concept that inhibition of AR should prevent, arrest, and, possibly, reverse the development of late diabetic sequelae. In addition to motivating drug-oriented research, the ARI concept provided a rationale for the use of ARIs as experimental tools to probe the pathogenesis of diabetic complications. By helping to elucidate the metabolic, functional, and structural ramifications of the AR-catalyzed disposal of excess glucose in diabetic schemes, and in addition, by helping to define the applicability of animal models for the study of early functional pathogenic alterations occurring in diabetic subjects, ARIs may enable the discrimination in diabetic tissue of arrestible and reversible from the irreversible abnormalities.
J Diabetes Complications
PMID:Aldose reductase inhibitors as pathobiochemical probes. 156 55

A polyol-pathway related perturbation of myo-inositol metabolism has been invoked in the pathogenesis of diabetic complications, including retinal microvasculopathy. Previous studies have demonstrated a beneficiary effect of aldose reductase inhibition on basement membrane thickening of retinal microvessels in diabetic animals. In the present study we demonstrate a significant but partial effect on basement membrane thickening following myo-inositol supplementation. Qualitative structural changes, such as nodular swellings, fibrillar changes and basement membrane projections were not effected by myo-inositol supplementation, suggesting that although abnormal myo-inositol tissue levels may play a role in basement membrane thickening, other factors may be of primary pathogenetic importance.
Diabetes Res Clin Pract 1992 Apr
PMID:The effect of myo-inositol treatment on basement membrane thickening in the BB/W-rat retina. 157 27

1,2,4-Triazolidine-3,5-diones and the 3,5-isoxazolidinedione were observed to be potent inhibitors of rat lens aldose reductase activity. In vivo in streptozotocin-diabetic rats, selected agents at 20 mg/kg/day, orally for 21 days reduced significantly the sorbitol levels of rbc, lens and sciatic nerves, suggesting that these derivatives may have some usefulness to treat clinical complications of diabetes mellitus.
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PMID:Potential aldose reductase inhibitors: 1,2,4-triazolidine-3,5-diones and 2-(3,4,5-trimethoxybenzoyl)-4,4-diethyl-3,5-isoxazolidinedione . 158 96

Neuropathy is the most common and perhaps the most devastating complication associated with diabetes. Although many theories regarding the pathogenesis of diabetic neuropathies have been proposed, the most popular theory focuses on the accumulation of sorbitol in the nerve cell through the "polyol pathway." Treatment for diabetic neuropathy remains inadequate. Newer agents such as the aldose reductase inhibitors show some promise in halting and perhaps reversing the pathogenesis of this complication; however, these agents remain investigational. Currently, the most reasonable approach involves the use of agents to control pain and other symptoms associated with this progressive disease.
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PMID:Drug therapy of diabetic neuropathy. 158 3

Aldose reductase, the first enzyme of the polyol pathway, has been related to the pathogenesis of diabetic complications. The regulation of the enzyme in diabetes patients, however, has not yet been clarified. We recently reported that the activity of aldose reductase was increased in erythrocytes of insulin-dependent diabetes mellitus patients but short-term hyperglycemia did not affect the enzyme activity. It is still unclear, however, whether or not the increase in the enzyme activity is caused by long-term hyperglycemia and thus would be seen equally in both type I (insulin-dependent diabetes mellitus) and type 2 (non-insulin-dependent diabetes mellitus) individuals. To further clarify these issues we measured erythrocyte aldose reductase activity in 46 type I patients and 30 type II patients who had variable glucose control and in 16 nondiabetic subjects. We compared the enzyme activity with plasma glucose levels and hemoglobin A1c levels. The results show that erythrocyte aldose reductase activity is increased in both type I and type II patients as compared with nondiabetic subjects (7.1 +/- 0.3 U/L and 6.8 +/- 0.4 U/L erythrocytes versus 5.6 +/- 0.2 U/L erythrocytes, p less than 0.001 and p less than 0.01, respectively), but there were no significant differences between the two groups of diabetic patients. The enzyme activity varied by approximately four times among the diabetic individuals but there was no correlation between the enzyme activity and plasma glucose or hemoglobin A1c levels. We conclude that the increased activity of erythrocyte aldose reductase seen in diabetes is not related to hyperglycemia.
J Diabetes Complications
PMID:No correlation between glycemic control and an increase in erythrocyte aldose reductase activity in type I and type II diabetic patients. 161 Nov 34

The potential of the aldose reductase inhibitor ponalrestat (600 mg daily) to ameliorate diabetic neuropathy was evaluated in 259 diabetes mellitus patients with peripheral neuropathy (defined by abnormal vibration perception threshold and abnormal peroneal motor conduction velocity) in a double-blind placebo-controlled clinical trial running for 18 months. Overall, no beneficial effect of ponalrestat on vibration perception thresholds, nerve conduction velocities, and nerve action potential amplitudes was detected. Because vibration perception thresholds and conduction velocities in median, peroneal, and sural nerves did not deteriorate in the placebo group, the potential of ponalrestat to prevent the expected deterioration in peripheral nerve function that occurs with an increased duration of diabetes was not tested. Patients with an abnormal heart rate reaction to standing (abnormal 30:15 ratio; n = 84) on ponalrestat did not deteriorate in this autonomic nerve function test as shown in those on placebo. In conclusion, ponalrestat did not improve peripheral nerve function in diabetes mellitus patients with signs of peripheral neuropathy, although it did ameliorate a deterioration in autonomic nerve function in diabetic patients with signs of autonomic neuropathy.
J Diabetes Complications
PMID:Peripheral and autonomic nerve function in 259 diabetic patients with peripheral neuropathy treated with ponalrestat (an aldose reductase inhibitor) or placebo for 18 months. United Kingdom/Scandinavian Ponalrestat Trial. 161 Nov 36

The objective of this study was to evaluate the effects of ponalrestat, an aldose reductase inhibitor, on the progression of diabetic retinopathy. In this study, 62 patients with diabetes mellitus underwent a double-masked placebo-controlled clinical trial comparing the effect of ponalrestat 600 mg per day with a placebo on the progression of diabetic retinopathy. Both groups were comparable in terms of age, gender distribution, diabetes duration, metabolic control, and presence and severity of diabetic retinopathy. Seven-field stereo fundus photographs were performed at 0 (baseline), 12, and 18 months; 49 patients completed the study (26 in the ponalrestat group and 23 in the placebo group). In both treatment groups, a significant progression of diabetic retinopathy as evaluated by the Early Treatment Diabetic Retinopathy Study classification was observed (Wilcoxon Rank-Sum Test, p less than 0.05). No difference was observed in the progression of retinopathy between the two treatment groups (p = 0.96). The number of microaneurysms increased in the two study groups (from 5.6 +/- 1.2 to 10.5 +/- 1.3 in the placebo group and from 10.3 +/- 1.4 to 12.7 +/- 1.4 in the ponalrestat group); however, the increase was statistically significant only in the placebo group (p less than 0.05). When the increase in the number of microaneurysms was evaluated by change of category of microaneurysm count, no significant difference was observed. We conclude that ponalrestat at a dose of 600 mg per day has no clinically significant effect on the progression of diabetic retinopathy.
J Diabetes Complications
PMID:The effect of the aldose reductase inhibitor, ponalrestat, on the progression of diabetic retinopathy. 161 Nov 37

This study describes reduced motor nerve conduction velocity and increased resistance to hypoxia-induced conduction failure in sciatic nerves of rats after four weeks of streptozotocin-induced diabetes (both effects were significant at p less than 0.05). These changes occurred in the absence of any deficit in the steady-state ouabain-sensitive adenosine triphosphatase (ATPase) activity of sciatic nerve endoneurial homogenates. The addition of 10 nmol/l insulin to endoneurial homogenates from control animals resulted in a 34% increase in ouabain-sensitive ATPase activity and a 19% reduction in ouabain-insensitive ATPase activity (both p less than 0.01). This stimulation of ouabain-sensitive ATPase activity by insulin did not occur in homogenates from diabetic rats. Treating diabetic rats daily with the aldose reductase inhibitor, imirestat (1 mg/kg) improved nerve conduction velocity (p less than 0.05) but was without effect upon the resistance to hypoxic conduction blockade or the deficit in insulin-stimulated ouabain-sensitive ATPase activity. These data suggest that in streptozotocin-diabetic rats the functional disorders of reduced motor nerve conduction velocity and increased resistance to hypoxic conduction blockade do not share a common aetiology and that impaired nerve conduction is not related to reduced maximal potential ouabain-sensitive ATPase activity.
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PMID:Aldose reductase inhibition with imirestat-effects on impulse conduction and insulin-stimulation of Na+/K(+)-adenosine triphosphatase activity in sciatic nerves of streptozotocin-diabetic rats. 165 57

Aldose reductase (EC 1.1.1.21) is implicated in the pathophysiology of diabetic complications. In this paper we determined the activities of aldose reductase and ATPases of the erythrocytes in 17 patients with Type 2 (non-insulin-dependent) diabetes mellitus (NIDDM). In the aldose reductase assay we used fluorometric method to avoid the disturbance of hemoglobin. With dihydronicotinamide adenine dinucleotide (NADH), we verified it was aldose reductase but not aldehyde reductase II that was activated in the erythrocytes of the patients with NIDDM. The aldose reductase activity of the erythrocytes in the patients was significantly higher (P less than 0.01) than that in the controls. The activity of Na+/K(+)-ATPase of the patients was significantly lower (P less than 0.01) than that of the controls. The activities of Ca(2+)-ATPase and Mg(2+)-ATPase on the erythrocyte membranes of the patients were similar to those of the controls. At the same time we measured the seven nucleotide concentrations in the erythrocytes of the patients. In this experiment we used ultrafiltration method, instead of acid precipitation to make it possible to determine dihydronicotinamide adenine dinucleotide phosphate (NADPH) and NADH. The concentrations of ATP, ADP and AMP were similar to those of the controls. The concentrations of NADPH, NAD+ and NADH in the erythrocytes of the patients were significantly lower (P less than 0.01, 0.05 and 0.05 respectively) than those of controls. The concentration of nicotinamide adenine dinucleotide phosphate (NADP+) in the patients was significantly higher (P less than 0.01) than that of controls.
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PMID:Activities of aldose reductase, ATPases, and nucleotide concentrations of erythrocytes in patients with type 2 (non-insulin-dependent) diabetes mellitus. 166 Dec 22


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