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

We investigated the effects of novel aldose reductase inhibitors, M16209 (1-(3-bromobenzo[b]furan-2-ylsulfonyl)hydantoin) and M16287 (1-(3-chlorobenzo[b]furan-2-ylsulfonyl)hydantoin), on neuropathy in streptozotocin-induced (STZ) diabetic rats. Both compounds (3-100 mg/kg per day, p.o.) dose dependently improved the decreased motor nerve conduction velocity in the sciatic nerve during a 14-day treatment period. These compounds also partially ameliorated the diabetes-induced histological changes in the sciatic nerve. A distinct increase in sorbitol content and a slight decrease in myo-inositol content was observed in the sciatic nerve of STZ diabetic rats, and the sorbitol accumulation was dose dependently suppressed by treatment with M16209 and M16287. Treatment started at an earlier period was more effective in the suppression of sorbitol accumulation. There was a significant correlation between motor nerve conduction velocity and nerve sorbitol content, whereas there was none between motor nerve conduction velocity and myo-inositol content. The present study indicates that M16209 and M16287 are potent aldose reductase inhibitors expected to be useful for the treatment of diabetic complications.
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PMID:Effects of novel aldose reductase inhibitors, M16209 and M16287, on streptozotocin-induced diabetic neuropathy in rats. 182 68

One of the earliest histopathological signs of diabetic retinopathy is a selective loss of intramural pericytes from retinal capillaries. In the present study, the retinal vessels of rats with streptozotocin-induced diabetes (STZ Wistar) and rats with genetically-induced insulin dependent diabetes mellitus (BB Wistar) and non-insulin dependent diabetes mellitus (SHR/N-corpulent) were examined after 6 to 8 months duration for diabetes-related retinal microangiopathies. The SHR/N-corpulent (cp) rats were fed a 54% sucrose diet, whereas the STZ Wistar and BB Wistar rats were fed laboratory chow for 32 to 36 weeks. In all the diabetic rats, the retinal capillaries in enzyme-digested flat mounts exhibited an increase in periodic-acid-Schiff (PAS) staining and loss of pericytes compared to their respective euglycemic controls. Pericyte "ghosts", like those defined in human diabetes as intramural pockets lacking normal cell contents, were documented by high resolution micrographs in all the diabetic rats. Endothelial cell proliferation, capillary dilation, and varicose loop formation were noted in some of the diabetic rats. Hence, similar capillary lesions were found in very different groups of diabetic rats. The findings suggest that a chronic high tissue concentration of glucose is the underlying factor which triggers pathogenesis in the pericyte. Hyperglycemia-induced activation of endogenous aldose reductase of the polyol pathway is probably the initial insult, but other factors such as advanced glycosylation products may affect the final outcome.
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PMID:Degenerated intramural pericytes ('ghost cells') in the retinal capillaries of diabetic rats. 182 96

Direct investigation of the polyol pathway is rarely possible in studies of human diabetes. A spectrophotometric assay has been developed for the measurement of aldose reductase and sorbitol dehydrogenase activity in the neutrophil. Neutrophil aldose reductase activity was increased in patients with Type 1 diabetes with complications (median 40 (interquartile range 28-48) u, where 1 unit of enzyme activity = nmol NADPH min-1 10(8)-cells-1) compared with those without complications (20 (16-36) u, p less than 0.01) and normal control subjects (20 (8-36) u, p less than 0.01). In Type 2 diabetes, patients with complications also had higher aldose reductase activity (40 (28-52) u) than those without complications (24 (16-36) u, p less than 0.01). There were no differences between patients without complications and normal control subjects. Sorbitol dehydrogenase activity was decreased in diabetic patients (p less than 0.02) but not significantly different between diabetic patients with and without complications.
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PMID:Neutrophil aldose reductase activity and its association with established diabetic microvascular complications. 183 May 28

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. Distribution of volumes of 131I-albumin (5 min) and 125I-albumin (100 min) were estimated in various tissues at 3 weeks, 6-7 months and 13-14 months of diabetes. The former space was assumed to represent the intravascular plasma space, while the latter was taken to include both the extravascular and intravascular albumin volumes in the kidney. In heart and skeletal muscle, equilibration between the specific activities of extravascular albumin and of plasma albumin was not assumed to be complete at 100 min. In the cortex and medulla of kidney, the extravascular albumin pool increased significantly at 13-14 months of diabetes (for both, P less than 0.01). Significantly increased entry of albumin into the interstitium occurred at 6 months (P less than 0.05) and at 13-14 months (P less than 0.01) in skeletal muscle, and at 13-14 months (P less than 0.05) in heart. The intravascular plasma volumes were not influenced by diabetes and the aldose reductase inhibitor had no effect at any time in either diabetic or control rats. These findings indicate increased movement of plasma albumin into the interstitium in the late phase of diabetes in the heart, skeletal muscle and in the kidney. Enlargement of the interstitial albumin pool is likely to affect the fluid balance between capillary and interstitium and may contribute to the effect of diabetes on the function of these organs.
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PMID:Albumin escape from microvessels in kidney, heart and skeletal muscle in experimental diabetes mellitus in the anaesthetized rat. 183 64

Aldose reductase activity can be measured in the neutrophil and it has been proposed that this may be a marker for risk of complications in diabetes. We have studied aldose reductase activity in neutrophil, nerve, and lens in diabetic patients undergoing sural nerve biopsy or cataract extraction. A correlation was demonstrated between lens and neutrophil aldose reductase activity (r = 0.53, p = 0.01) but no correlations were demonstrated between nerve aldose reductase activities and nerve morphometry, nerve function or neutrophil aldose reductase activity. No significant difference was found between neutrophil aldose reductase activities in groups of patients with severe neuropathy, or cataract, or no complications (24 (interquartile range 16-32) vs 24 (16-40) vs 24 (16-40) nmol NADPH min-1 10(8)-cells-1). In a group of 56 Type 1 diabetic patients screened within 6 years of diagnosis, multiple regression analysis failed to show any relationship between neutrophil aldose reductase activity and abnormalities of neurophysiological function. These results suggest that neutrophil aldose reductase activity cannot be used as a marker for the development of cataract or neuropathy in diabetes.
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PMID:Neutrophil aldose reductase activity as a potential marker for neuropathy and cataract in diabetes. 183 41

Sexual impotence is the main andrological complication of diabetes mellitus and is the consequence of nervous, vascular and psychological factors which act either separately or in association. An attempt to prevent this complication will be successful if performed early before impotence has became irreversible. Neuropathy-induced impotence can be prevented by obtaining a good metabolic control of diabetes and/or by using some specific drugs such as gangliosides and aldose reductase inhibitors. The vascular causes of erectile failure can be prevented by reducing or removing associated risk factors such as smoking, hypertension, obesity, hypercholesterolemia, sedentariness and insulin-resistance. Finally, correct information and reassurance of the patient and his partner can prevent the negative role played by psychological factors on the sexual dysfunctions complained by the diabetic subject.
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PMID:[Is it possible to prevent andrological complications in the diabetic patient?]. 183 28

The effects of aldose reductase inhibitors (ARIs) on the synthesis of prostacyclin (PGI2) by aortic rings from diabetic rats were examined. The ARIs studied were ONO-2235 and isoliquiritigenin, a new compound extracted from glycyrrhizae radix. The content of sorbitol in the sciatic nerve of diabetic rats induced by streptozotocin was significantly increased as compared with that of controls. This increase was significantly inhibited by the administration of an ARI. On the other hand, there was a marked decrease in the synthesis of PGI2 by the diabetic rats compared with the control rats. The decrease in PGI2 synthesis was significantly reversed by the administration of an ARI. Furthermore, the synthesis of PGI2 by the aortic rings was inversely correlated with the content of sorbitol in sciatic nerves. Those observations suggest that an ARI may have a beneficial effect on the vascular synthesis of PGI2 in diabetes mellitus.
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PMID:Effects of aldose reductase inhibitors on prostacyclin (PGI2) synthesis by aortic rings from rats with streptozotocin-induced diabetes. 184 7

Microangiopathy is the major cause of death in Insulin Dependent Diabetes Mellitus. However, the pathogenesis of microangiopathy is still far from clear. This paper is a review of the literature on diabetic microangiopathy and discusses the current theories concerning its causes, prevention and treatment. The roles of abnormal glucose metabolism, protein glycosylation, genetic factors and puberty as well as the changes in vascular endothelium, capillary permeability and blood constituents, in the development of microangiopathy are discussed. The benefits of strict control of blood glucose concentrations are discussed along with the action of various pharmaceutical preparations such as aldose reductase inhibitors, hydroxyrutosides, pentoxifylline and free radical scavengers currently assessed in the prevention or treatment of diabetic microangiopathy.
Diabetes Res 1991 Jul
PMID:Microangiopathy in diabetes mellitus: I. Causes, prevention and treatment. 184 Oct 26

The effects of an aldose reductase (AR) inhibitor, elevated glucose and other compounds were evaluated on in vitro 2-[3H] myo-inositol (MI) uptake in cultured human endothelial cells (ECs). Significant AR activity was present in ECs (1,373 +/- 170 mumol/mg.min: incubated with 28 mM glucose for 48 hr). Since Na(+)-deprivation and the addition of Ouabain (5 mM) significantly reduced MI uptake, MI incorporation into ECs might be dependent on an active transport system via Na(+)-K+ ATPase activity. MI uptake was reduced significantly (21 +/- 6, 39 +/- 7% reduction) in the presence of excess glucose (27.5, 55 mM). However, addition of the AR inhibitor (ONO-2235 100 microM) prevented the glucose mediated inhibition of MI uptake (15 +/- 5, 21 +/- 6% reduction). These results suggest that inhibition of AR might prevent glucose-mediated toxicity via an increment of MI uptake.
Diabetes Res 1991 Oct
PMID:Effect of glucose and an aldose reductase inhibitor on myo-inositol uptake by cultured human endothelial cells. 184 13

A myo-inositol-related defect in nerve Na(+)-K(+)-ATPase in experimental diabetes has been invoked in the pathogenesis of diabetic neuropathy, but the mechanism linking altered myo-inositol metabolism and Na(+)-K(+)-ATPase regulation in diabetic nerve is uncertain. Decreased Na(+)-K(+)-ATPase in diabetic rat nerve is normalized by aldose reductase inhibitors or dietary myo-inositol, which preserve normal nerve myo-inositol content in vivo. Decreased Na(+)-K(+)-ATPase in diabetic rabbit nerve is acutely reversed by exposure to protein kinase C agonists in vitro. This study explored the relationship between the myo-inositol-sensitive and protein kinase C-agonist-sensitive Na(+)-K(+)-ATPase defects in diabetic rat nerve. Ouabain-sensitive ATPase activity was measured in an enriched membrane fraction isolated from nondiabetic, streptozocin-induced diabetic, and myo-inositol-supplemented streptozocin-induced diabetic rats before and after the membranes were exposed to protein kinase C agonists in vitro. The decreased ouabain-sensitive ATPase activity in plasma membranes from untreated diabetic rats was increased after exposure to two structurally unrelated protein kinase C agonists; the normal ouabain-sensitive ATPase in plasma membranes from myo-inositol-supplemented diabetic rats was unaffected by protein kinase C agonists. The nonadditivity and implied equivalence of the Na(+)-K(+)-ATPase defect corrected by myo-inositol in vivo and by protein kinase C agonists in vitro are consistent with the postulated existence of a deficient myo-inositol-dependent phospholipid-derived protein kinase C agonist (presumably diacylglycerol) in diabetic nerve that regulates nerve Na(+)-K(+)-ATPase either directly or via a protein kinase C mechanism.
Diabetes 1991 May
PMID:Normalization of Na(+)-K(+)-ATPase activity in isolated membrane fraction from sciatic nerves of streptozocin-induced diabetic rats by dietary myo-inositol supplementation in vivo or protein kinase C agonists in vitro. 185 Jul 4


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