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)

Erythrocyte sodium pump activity, osmotic fragility, and thiol status were measured in genetically hyperglycemic (db/db) mice and compared with their nondiabetic littermates (db/m). The data showed no major differences in these parameters. However, erythrocytes from streptozotocin (Stz)-induced diabetic rats had significantly lower activity of sodium pump and thiols with an almost fourfold increase in osmotic fragility as compared with erythrocytes from nondiabetic rats. Sorbinil (an aldose reductase inhibitor) treatment of Stz-diabetic rats normalized all these lesions, suggesting a key role for polyol pathway. However, sorbitol levels in erythrocytes from db/db and db/m mice were undetectable. The data suggest that in db/db mice, the relative lack of polyol pathway, a potential consumer of NADPH, may provide erythrocytes with optimal NADPH for glutathione reductase system, thus maintaining normal GSH levels even at the height of hyperglycemia. Thus, the genetically hyperglycemic mice may serve as a useful model to study diabetes related complications without involving polyol pathway.
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PMID:Erythrocyte sodium-potassium ATPase activity and thiol metabolism in genetically hyperglycemic mice. 131 May 17

Lucigenin-enhanced chemiluminescence was examined as an index of neutrophil superoxide production in four groups of 20 subjects: controls with/without infection and type 1 diabetics with/without infection. At 5 mM glucose there was no significant difference in chemiluminescence output between neutrophils from the four groups (P greater than 0.01). Increasing the in vitro glucose concentration from 5 to 20 mM produced an 8.75% reduction in superoxide in the combined control groups, compared with a 21.45% reduction in the diabetic subjects (P less than 0.01). With the addition of an aldose reductase inhibitor (Statil, ICI) to neutrophils from diabetic subjects, the suppression caused by an increase in glucose concentration to 20 mM was reduced to 4.5%. This value was similar to the controls (P greater than 0.01). Neutrophil aldose reductase activity, measured in 28 diabetic subjects was 0.024 +/- 0.003 U/10(8) cells (mean +/- SE). There was a significant correlation between aldose reductase activity and superoxide suppression (P less than 0.01, r = 0.64). These results suggest that aldose reductase is responsible for reduced superoxide production in diabetic patients and the addition of an aldose reductase inhibitor to the diabetic neutrophil restores superoxide output to control values.
Diabetes Res Clin Pract 1992 Feb
PMID:The influence of aldose reductase on the oxidative burst in diabetic neutrophils. 131 60

In view of the possible implication of multifactorial mechanisms in the pathogenesis of diabetic neuropathy, the aldose reductase inhibitor (ARI), Statil, which ameliorates abnormal sorbitol or myo-inositol metabolism in diabetic nerves, and the prostaglandin E1 (PGE1) analogue, OP1206.alpha CD (OP), which improves diabetic vascular derangements, were administered simultaneously for 2 months to streptozocin (STZ)-induced diabetic rats with 5 months' duration of diabetes, and the effects on sciatic motor nerve conduction velocity (MNCV), Na(+)-K(+)-adenosine triphosphatase (ATPase) activity, and morphology of myelinated nerve fibers (MNF) were compared with the effects of a monotherapy with OP. The combination regimen ameliorated abnormal nerve sorbitol and myo-inositol levels and normalized decreased MNCV and enzyme activity. In contrast, neither sorbitol nor myo-inositol metabolism was ameliorated, and only insufficient improvement of MNCV and morphology of MNF was obtained with a monotherapy with OP. In addition, the combination therapy reversed both a decrease in the percent of large MNF and an increase in the percent of small MNF in diabetic rats, whereas a monotherapy with OP reversed only a decrease in the percent of large MNF. The results might suggest that a multiple-drug therapy with different mechanisms of action has greater effects on diabetic neuropathy than a single-drug therapy and is worthy of clinical consideration.
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PMID:A combination of the aldose reductase inhibitor, statil, and the prostaglandin E1 analogue, OP1206.alpha CD, completely improves sciatic motor nerve conduction velocity in streptozocin-induced chronically diabetic rats. 132 Jan 79

The effects of a new aldose reductase inhibitor (ARI), (2S,4S)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-ca rboxamide (SNK-860), on the slowing of motor nerve conduction velocity (MNCV) and metabolic abnormalities in sciatic nerve were investigated in acute streptozotocin (STZ)-induced diabetic rats. MNCV in the diabetic rats was significantly slower 2 weeks after STZ injection. In the following 2 weeks, treatment with SNK-860 improved MNCV in a dose-dependent manner. The efficacy of 1 mg/kg SNK-860 was equipotent to that of 20 mg/kg sorbinil. Four weeks after STZ injection, increases in sorbitol levels, decreases in myo-inositol levels, and reductions in Na+, K(+)-adenosine triphosphatase (ATPase) activity were observed in sciatic nerves of diabetic rats. Administration of SNK-860 for 14 days beginning 2 weeks after the induction of diabetes inhibited these metabolic abnormalities in a dose-dependent manner. SNK-860 restored all of these parameters to normal levels at a dose of 2 mg/kg. In addition, close correlations were observed between MNCV and sorbitol levels (r = -.95) and between MNCV and myo-inositol levels (r = .93) in the sciatic nerve; a close correlation was also observed between sorbitol and myo-inositol levels in the sciatic nerve (r = -.86). Therefore, it is suggested that the effect of SNK-860 on the slowing of MNCV results from normalizing the above-mentioned metabolic abnormalities in the sciatic nerve of diabetics. Thus, SNK-860 may be useful in the treatment of diabetic neuropathy.
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PMID:Effects of a new aldose reductase inhibitor, (2S, 4S)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-ca rboxamid e (SNK-860), on the slowing of motor nerve conduction velocity and metabolic abnormalities in the peripheral nerve in acute streptozotocin-induced diabetic rats. 132 19

The effect of streptozotocin diabetes of 4-week duration on the adrenergic motor transmission and on the nonadrenergic, noncholinergic, inhibitory transmission in the rat anococcygeus was investigated by recording contractile and relaxant activity of isolated muscle preparations taken from diabetic and age-matched control animals. The neurogenic contractile responses to electrical field stimulation were significantly reduced in the preparations from diabetic rats. The inhibitory transmission remained unaffected in the diabetic rats. Concentration--response curves showed no change in sensitivity of the diabetic anococcygei to noradrenaline. The maximum tension generated was also similar in preparations from diabetic and nondiabetic animals. The contractile responses to electrical field stimulation were significantly greater in preparations from diabetic rats treated for 4 weeks with either sorbinil (20 mg.kg-1.day-1 orally) or myo-inositol (667 mg.kg-1.day-1 orally) when compared with the untreated diabetic controls; the sensitivity to noradrenaline was identical in all three groups. It is concluded that streptozotocin diabetes causes a significant reduction of adrenergic contractile responses of the anococcygeus to electrical field stimulation by a prejunctional mechanism, and the reduction can be prevented by treating the animals with the aldose reductase inhibitor sorbinil or with myo-inositol.
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PMID:Effect of streptozotocin diabetes on motor and inhibitory transmission in rat anococcygeus. 133 14

This study was designed to determine whether deficient substance P in the sciatic nerve of diabetic rats was associated with a similar reduction in calcitonin gene-related peptide and whether the depletion of either or both peptides could be affected by insulin treatment or by aldose reductase inhibition. Substance P and calcitonin gene-related peptide were measured as immunoreactivities in the same nerve extracts. The sciatic nerve content of substance P was significantly reduced in diabetic rats (0.063 +/- 0.011; all data are mean +/- 1 standard deviation in ng peptide/mg nerve protein; n = 9 for all groups) compared to controls (0.093 +/- 0.026). The calcitonin gene related peptide content was similarly reduced (2.14 +/- 0.49) compared to controls (3.78 +/- 1.21). Tight glycaemic control with insulin prevented completely the deficit in both peptides (substance P = 0.096 +/- 0.021, calcitonin gene-related peptide = 4.66 +/- 0.92). Treatment with the aldose reductase inhibitor, imirestat, corrected the substance P deficit (0.08 +/- 0.018) and attenuated the calcitonin gene-related peptide (3.55 +/- 1.03) depletion seen in the untreated diabetic animals. This indicates that the polyol pathway may play a role in the peptide status of the sciatic nerve. Regression analysis of all data gave r2 = 0.53, indicating a comparable effect of diabetes and the treatments on both peptides.
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PMID:Depletion of substance P and calcitonin gene-related peptide in sciatic nerve of rats with experimental diabetes; effects of insulin and aldose reductase inhibition. 137 69

Diabetes is known to be associated with an increase in aldose reductase activity, platelet hyperaggregability, lipid peroxidation, and cataract formation. A molecule, D-myo-inositol 1,2,6-trisphosphate (PP-56), derived from phytic acid, could in principle, by supplying myoinositol to tissues and acting as an antioxidant, counteract some of the manifestations of diabetes. Thus, the effects of PP-56 on platelet aggregation, fatty acids, and polyols were investigated in uncontrolled streptozotocin-induced diabetes in rat in relation to cataract and lipid peroxidation. A decrease in the response of platelet aggregation to thrombin and ADP (P less than 0.05, P less than 0.001) and in the level of sorbitol and the ratio sorbitol/myo-inositol (P less than 0.01) in platelets was observed in the rats treated by PP-56 for 7-8 weeks. These beneficial effects were associated with an incidence of cataract reduced by 26 to 44% (P less than 0.05 to P less than 0.001) depending on the duration of treatment. They were also accompanied by a significant lower plasma level of malondialdehyde (P less than 0.05), and, more markedly, of conjugated dienes (P less than 0.001) as well as an increase in platelet lipids of the 20:4(n-6)/20:3(n-6) ratio, an index of delta 5 desaturase activity. PP-56 appears to modulate fatty acid desaturases and aldose reductase in platelets and delay by a few weeks the development of cataract in this acute model of diabetes.
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PMID:Effect of D-myo-inositol on platelet function and composition and on cataract development in streptozotocin-induced diabetic rats. 138 35

The formation of excess sugar alcohol mediated by aldose reductase (AR) and its intracellular accumulation in lens with resultant hydration is thought to be the initiating mechanism in the pathogenesis of diabetic and galactosemic cataracts. AR is also involved in other diabetic complications including retinopathy and neuropathy. Therefore, there is heightened interest in developing effective AR inhibitors (ARIs) for possible clinical use in human diabetes. However, the evaluation of these drugs for potential clinical use requires that the compounds be evaluated in appropriate target tissues since AR from different tissues is known to exhibit differential susceptibility to ARIs. The relative efficacy of ARIs in human lens epithelium (HLE) and human retinal pigment epithelium (HRPE) was studied by measuring the degree of inhibition of galactitol formation at various concentrations of ARI following incubation of cells in high galactose media for 72 hrs. Regardless of the structural characteristics of the ARIs investigated, higher doses were required to inhibit polyol synthesis in HRPE as compared to HLE cells. Based on ED50 values, dose required for 50% inhibition, the order of potencies against both HLE and HRPE enzymes was AL-4114 greater than AL-3152 greater than AL-1576 greater than tolrestat greater than statil greater than sorbinil. Since some ARIs are known to be bound to plasma proteins, it is conceivable that the observed differences in ED50 values could be due to differential binding to serum proteins in the culture medium. This possibility was examined by employing cultures of dog lens epithelium (DLE). These cells, which synthesize much higher levels of galactitol than HLE and HRPE, could be maintained in serum-free media for short periods (4 hrs) of time. The results, which demonstrate that the extent of polyol inhibition was the same in the presence or absence of serum, suggest that the differences in the potency of the inhibitors may reflect their inherent activity against AR in HLE and HRPE cells.
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PMID:The efficacy of aldose reductase inhibitors on polyol accumulation in human lens and retinal pigment epithelium in tissue culture. 140 94

To evaluate the activation of the sorbitol pathway in cardiac muscle in diabetic rats, we measured sorbitol, fructose, and myo-inositol content in cardiac tissue obtained from control and streptozotocin-diabetic rats, with or without an 8-week insulin treatment, using gas chromatography-mass spectrometry (GC-MS). Cardiac fructose and sorbitol content in 10-week diabetic rats increased by 60-fold and 3.9-fold of those of control rats, respectively (P less than .001). In contrast, cardiac myo-inositol content in 10-week diabetic rats decreased to 56% (P less than .025) of the control value. The abnormalities in cardiac fructose, sorbitol, and myo-inositol content were completely normalized by the 8-week insulin treatment, which was initiated 2 weeks after the induction of diabetes. There was no difference in cardiac aldose reductase activity between control and diabetic rats. However, cardiac sorbitol dehydrogenase activity in diabetic rats was 151% (P less than .005) higher than that of control rats, although hepatic sorbitol dehydrogenase activity was not different between the two groups. These results indicate that the sorbitol pathway is significantly activated in cardiac tissue obtained from streptozotocin-induced diabetic rats, which results in the marked cardiac accumulation of fructose.
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PMID:Increase in cardiac muscle fructose content in streptozotocin-induced diabetic rats. 140 91

These studies were undertaken to investigate the relationship between regional hemodynamic and hemorheological changes in the microvasculature of diabetic rats. Diabetes was induced in male Sprague-Dawley rats by injection of streptozotocin (55 mg/kg body wt). Control rats were injected with vehicle (sodium citrate buffer). A subgroup of diabetic rats was treated with an aldose reductase inhibitor (sorbinil) added to the diet in an amount to provide a daily dose of approximately 0.2 mmol.kg-1.day-1. Three weeks later all animals were anesthetized with thiobutabarbital sodium (Inactin, 100 mg/kg injected intraperitoneally) for assessment of blood flow (by injection of 15 microns microspheres) and regional hematocrit (determined by isotope-dilution techniques using 51Cr-labeled red blood cells and 125I-labeled bovine serum albumin) in selected tissues. The hematocrit in arterial blood samples was identical (approximately 46%) in controls and in diabetics. Regional hematocrits were much lower than arterial hematocrits in control rats and ranged from approximately 20% in ocular tissues, sciatic nerve, diaphragm, and skin to approximately 30% in brain, skeletal muscle, heart, and fat. Hematocrits of diabetic rats were markedly increased in ocular tissues, sciatic nerve, and skin but not in brain, heart, or skeletal muscle. These increases in regional hematocrit were associated with increases in blood flow and were largely prevented by sorbinil. Diabetes induced significant decreases in the mean transit times for whole blood and erythrocytes in all tissues examined except brain, retina, and skin.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Concurrent increases in regional hematocrit and blood flow in diabetic rats: prevention by sorbinil. 141 21


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