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)

Acetyl-L-carnitine (ALC) has been shown to facilitate the repair of transected sciatic nerves. The effect of ALC (50 mg/kg/d) on the diminished nerve conduction velocity (NCV) of rats with streptozotocin (STZ)-induced hyperglycemia of 3 weeks' duration was evaluated. The aldose reductase inhibitor, sorbinil, which is reported to normalize the impaired NCV associated with experimental diabetes, was used as a positive control. Aldose reductase inhibitors are thought to have an effect by decreasing peripheral nerve sorbitol content and increasing nerve myo-inositol. Treatment of STZ-diabetic rats with either ALC or sorbinil resulted in normal NCV. Sorbinil treatment was associated with normalized sciatic nerve sorbitol and myo-inositol; ALC treatment did not reduce the elevated sorbitol levels, but sciatic nerve myo-inositol content was no different from nondiabetic levels. Both ALC and sorbinil treatment of STZ-diabetic rats were associated with a reduction in the elevated malondialdehyde (MDA) content of diabetic sciatic nerve, indicating reduced lipid peroxidation. The beneficial effects of sorbinil and ALC on the altered peripheral nerve function associated with diabetes were similar, but their effects on the polyol pathway (frequently implicated in the pathogenesis of peripheral neuropathy) were different.
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PMID:Acetyl-L-carnitine corrects the altered peripheral nerve function of experimental diabetes. 775 19

We investigated the stimulatory effect of M16209 (1-(3-bromobenzo[b]furan-2-yl-sulfonyl)hydantoin), a novel aldose reductase inhibitor, on insulin secretion using isolated, perfused pancreases of rats. In the pancreases from normal rats, M16209 (100 microM) greatly augmented glucose-stimulated insulin secretion, but showed no effect on unstimulated insulin secretion at 2.8 mM glucose. In contrast, gliclazide (10 microM), a sulfonylurea, strongly enhanced both glucose-stimulated and unstimulated insulin secretion. Sorbinil and epalrestat, potent aldose reductase inhibitors, had no stimulatory effect on insulin secretion. M16209 (100 microM) improved appreciably the decreased insulin response to 22.2 mM glucose and enhanced slightly unstimulated insulin secretion in the pancreases of rats with neonatally streptozotocin-induced, non-insulin-dependent diabetes mellitus (NIDDM). Gliclazide (10 microM), however, failed to affect the pancreases of NIDDM rats. Furthermore, M16209 showed no appreciable effect on ATP-sensitive K(+)-channels in pancreatic beta-cells. These results suggest that M16209, unlike sulfonylureas, selectively enhances glucose-stimulated insulin secretion in both normal and NIDDM rats through a direct action on the pancreas. The site of action remains unknown, but the inhibition of aldose reductase or the ATP-sensitive K+ channels is unlikely to be involved.
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PMID:Effects of M16209 on insulin secretion in isolated, perfused pancreases of normal and diabetic rats. 778 99

Aldose reductase inhibitors, and particularly sorbinil, have been reported to prevent glomerular basement membrane thickening (GBMT) and albuminuria development in diabetic rats, but contradictory observations have been published. The aim of this study was to answer the following questions (i) is the corrective effect of sorbinil on GBMT, if confirmed, associated with an effect on collagen metabolism alterations? (ii) Is it associated with an effect on microvascular functional alterations? We therefore studied the influence of sorbinil on glucosyl-galactosyl-hydroxylysyl-glucohydrolase activity (GGHG; EC 3.2.1.107 which is involved in the catabolism of collagen disaccharide units), 3- and 4-hydroxyproline content and GBMT by ultrastructural morphometry in the kidney cortex of streptozotocin-diabetic rats after 5 months of disease. In parallel, the effects on albumin renal clearance and another functional alteration, the microvascular response to norepinephrine, were evaluated. We confirmed a corrective effect of sorbinil on both renal albumin clearance and GBMT. In the diabetic rats, sorbinil diminished the 3-hydroxyproline (but not the 4-hydroxyproline) content, whether expressed per mg protein or per total kidney cortex relative to body weight. Sorbinil reduced GGHG activity measured in the dialysed 10,000 g supernatant whether expressed per mg protein or per total kidney cortex; this activity has been shown to be increased in diabetes. Sorbinil also corrected the microvascular response to norepinephrine which is altered in diabetes.
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PMID:Renal and microvascular effects of an aldose reductase inhibitor in experimental diabetes. Biochemical, functional and ultrastructural studies. 809 87

To evaluate the role of excessive polyol pathway activity in the pathogenesis of nerve disorders in diabetes mellitus, nerve conduction velocity was measured in motor nerves of diabetic dogs given an aldose reductase inhibitor (Sorbinil) or placebo, and also in non-diabetic dogs made experimentally galactosaemic. The nerve conduction velocity slowly declined in the diabetic placebo group, becoming significantly less than normal by the fifth year of the study, and the decline was prevented by administration of the aldose reductase inhibitor. Non-diabetic dogs made galactosaemic by consuming a 30% galactose diet developed erythrocyte and nerve polyol concentrations many times greater than that of diabetic or normal animals, but the nerve conduction velocity remained normal throughout 5 years of study. These results in dogs suggest that aldose reductase inhibitors may prevent defective nerve conduction in long-term diabetes, and raise the possibility that excessive accumulation of polyol itself is not sufficient to produce the nerve defect in the absence of excessive polyol utilization.
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PMID:Nerve conduction and aldose reductase inhibition during 5 years of diabetes or galactosaemia in dogs. 816 47

The polyol pathway in diabetes is activated in tissues that are not dependent on insulin for glucose uptake. To examine the role of the polyol pathway in renal extracellular matrix accumulation, we incubated murine proximal tubule cells in either normal or high glucose concentration in the presence or absence of the aldose reductase inhibitor sorbinil. Rising medium glucose from 100 to 450 mg/dl for 72 hours increased cell sorbitol levels sevenfold. Addition of 0.4 mM sorbinil reduced sorbitol content to virtually undetectable levels as measured by gas chromatography. Sorbinil (0.1 to 0.2 mM) also reduced the secretion of collagens types IV and I in the high glucose concentration after 48 to 72 hours but had no appreciable effect in the normal glucose concentration. Concordantly, 0.1 mM sorbinil inhibited the high glucose-induced stimulation of alpha 1(IV) and alpha 2(I) mRNA levels without affecting levels in normal glucose concentration. To study the role of transcriptional activation of collagen genes, we transfected proximal tubule cells with a chloramphenicol acetyltransferase (CAT) reporter gene linked to the promoter and regulatory elements of alpha 1(IV) gene. CAT activity increased several-fold in the cells grown in the high versus normal glucose concentration; this transcriptional activation in culture media containing high glucose concentration was reduced by treatment of the cells with 0.1 mM sorbinil. Thus, high ambient glucose activates the polyol pathway in proximal tubule cells, and may mediate the high glucose-induced stimulation of gene expression for collagens types IV and I.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Polyol pathway mediates high glucose-induced collagen synthesis in proximal tubule. 819 67

Aldose reductase (AR) has been implicated in the etiology of the secondary complications of diabetes, and enzyme inhibitors have been proposed as therapeutic agents. While effectively preventing the development of diabetic complications in animals, results from clinical studies of AR inhibitors have been disappointing, possibly due to poor potency in man. To assist in the design of more potent and specific inhibitors, crystallographic studies have attempted to identify enzyme-inhibitor interactions. Resolution of crystal complexes has suggested that the inhibitors bind to the enzyme active site and are held in place through hydrogen bonding and van der Waals interactions formed within two hydrophobic pockets. To confirm and extend these findings we quantified inhibitor activity with single, site-directed, mutant, human AR enzymes in which the apolar active-site residues tryptophan 20, -79, -111 and phenylalanine 115 were replaced with alanine or tyrosine, decreasing the potential for van der Waals interactions. Consistent with molecular models, the inhibitory activity of Tolrestat, Sorbinil and Zopolrestat decreased 800-2000-fold when tested with the mutant enzyme in which Trp20 was replaced with alanine. Further, alanine substitution for Trp111 decreased Zopolrestat's activity 400-fold, while mutations to Trp79 and Phe115 had little effect on the activity of any of the inhibitors. The alanine mutation at Trp111 had no effect on Tolrestat's activity but decreased the activity of Sorbinil by about 1000-fold. These latter effects were unanticipated based on the number of non-bonded interactions between the inhibitors, Tolrestat and Sorbinil, and Trp20 and Trp111 that have been identified in the crystal structures. In spite of these unexpected findings, our results are consistent with the hypothesis that AR inhibitors occupy the enzyme active site and that hydrophobic interactions between the enzyme and inhibitor contribute to inhibitor binding stability.
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PMID:Probing the inhibitor-binding site of aldose reductase with site-directed mutagenesis. 976 Jan 69

Effects of 5 years administration of an aldose reductase inhibitor (Sorbinil) on renal structure and albumin excretion were evaluated in diabetic dogs. Glycemia, estimated by frequent measurements of HbA1, glycated plasma proteins and glucosuria, was kept comparable between the placebo- and Sorbinil-treated diabetic groups. Kidney structure was evaluated using morphometric techniques by light and electron microscopy, and excretion of immunoreactive albumin was measured yearly. Placebo-treated diabetic dogs developed nephromegaly, glomerular enlargement, increased mesangial volume, and basement membrane thickening during the 5 years of study, and by the fifth year, excreted greater than normal quantities of albumin. Sorbinil treatment prevented sorbitol accumulation in erythrocytes and tended to have a similar effect in renal cortex, but had no beneficial effect on renal structure or albuminuria. Experimental galactosemia, another model of polyol over-production, failed to produce nephromegaly, glomerular enlargement, or mesangial expansion in dogs even after 5 years of galactose-feeding. The results suggest that polyol over-production and/or accumulation per se are not sufficient to account for the nephromegaly, glomerular enlargement, or increased mesangial volume observed in diabetic dogs.
J Diabetes Complications
PMID:Aldose reductase and the development of renal disease in diabetic dogs. 1023 4

In a prospective cohort study, the authors examined risk factors for progression of distal symmetric polyneuropathy (DSP) in type 1 (insulin-dependent) diabetes mellitus. The study population consisted of participants in the Sorbinil Retinopathy Trial, a randomized trial of aldose reductase inhibition among patients aged 18-56 years with type 1 diabetes mellitus of 1-15 years' duration. Diagnosis of DSP was based on standardized clinical neurologic evaluation. A total of 407 participants who did not have definite DSP at randomization and had at least one follow-up visit were included in the analysis. Stepwise Cox proportional hazards models were used to examine the independent contribution of baseline variables to progression of DSP. During follow-up (median, 40 months), 68 participants (17%) showed progression to definite DSP. After adjustment for age and treatment assignment, independent predictors of progression to definite DSP were total glycosylated hemoglobin (relative risk (RR) for increase of one percentage point = 1.25; 95% confidence interval (CI) 1.12, 1.39), height (RR associated with being one inch (2.54 cm) taller = 1.15; 95% CI 1.05, 1.26), cigarette smoking (ever vs. never) (RR = 1.87; 95% CI 1.09, 3.21), and female gender (RR = 2.26; 95% CI 1.09, 4.67). These data indicate that, in addition to the previously established role for total glycosylated hemoglobin, other factors including height, cigarette smoking, and female gender may also be independent risk factors for progression of DSP in type 1 diabetes mellitus.
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PMID:Risk factors for progression of distal symmetric polyneuropathy in type 1 diabetes mellitus. Sorbinil Retinopathy Trial Research Group. 1058 75

The authors compared, in the context of diabetic retinopathy, alternative methods of quantifying the extent to which disease progression in one eye increases the risk of subsequent progression in the other eye. Data were gathered on 478 US patients with insulin-dependent diabetes mellitus who participated in the 1983-1988 Sorbinil Retinopathy Trial and were followed up for a median of 41 months. During that time, diabetic retinopathy progressed in 93 right eyes and 77 left eyes. Crude incidence rates of progression for right eyes were 7.7 times higher after the left eye had progressed and, for left eyes, were 4.4 times higher after the right eye had progressed. In eye-specific proportional hazards models that adjusted for increasing rates of progression over time and for baseline risk factors, the comparable relative risks associated with progression in the other eye were 2.6 (95% confidence interval (CI): 1.5, 4.7) for right eyes and 1.4 (95% CI: 0.72, 2.9) for left eyes. Two alternative proportional hazards models that included data on both eyes and accounted for their correlation produced estimated relative risks of 1.9 (95% CI: 1.2, 2.9) and 2.7 (95% CI: 1.8, 3.5), respectively. The more complex models for joint survival integrate information on both eyes and provide more stable estimates than do separate analyses of right or left eyes.
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PMID:Methods to quantify the relation between disease progression in paired eyes. 1085 35

Diabetes mellitus is frequently associated with the complications of cardiovascular disease. Activation of the aldose reductase (or polyol) pathway has long been implicated as an underlying factor for the development of many diabetic complications and indeed, treatment with aldose reductase inhibitors has been shown to prevent or reverse many of these diabetic complications. This study examines the effects of 14-day streptozotocin-induced diabetes on alpha1- and beta-adrenoceptor-mediated responses in rat isolated left and right atria. The effects of treatment with the aldose reductase inhibitor (ARI) sorbinil were also studied. A positive inotropic response was observed to both isoprenaline and phenylephrine in left atria. Diabetes of 14 days duration resulted in a supersensitivity of these tissues to the beta-adrenoceptor agonist in comparison with controls, while responses to the alpha1-adrenoceptor agonist were unaltered. Spontaneously beating right atria from diabetic rats was found to have a depressed resting rate compared with control tissues, although positive chronotropic beta-adrenoceptor-mediated responses were not affected by diabetes. Phenylephrine produced alpha1-adrenoceptor-mediated chronotropic responses in right atrial tissues, and these were found to be enhanced in rats with diabetes. Treatment of diabetic rats with the ARI sorbinil was successful in preventing only one of the observed diabetes-induced changes in atrial function, namely the supersensitivity of left atria to isoprenaline. Sorbinil treatment did, however, alter responses of control left and right atria in a manner similar to diabetes. In conclusion, streptozotocin-induced diabetes of 14 days duration was found to cause a number of alterations in the functioning of both left and right atria. ARI treatment with sorbinil failed to prevent all but one of these changes, and in addition altered responses of atria from control rats, having a similar effect to that produced by diabetes. These data suggest that sorbinil may have effects in addition to, and independent of, aldose reductase inhibition in the cardiovascular system.
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PMID:The effects of streptozotocin-induced diabetes and aldose reductase inhibition with sorbinil, on left and right atrial function in the rat. 1087 46


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