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

The relationship between the polyol pathway and sugar cataracts has been studied extensively using streptozotocin-induced diabetic rats and galactose fed rats as animal models for insulin-dependent diabetes mellitus (IDDM). In these models, sugar cataracts progress quickly, leading to rapid lenticular polyol accumulation in the early stages of cataract formation. In 1992, a new animal model of non-insulin-dependent diabetes mellitus (NIDDM), the Otsuka Long-Evans Tokushima Fatty (OLETF) rat, was established. In the present study, we examined both biochemical and morphological changes in the lenses of the OLETF rats to determine whether these changes reflect those associated with diabetic cataract formation and to clarify their relationship with the polyol pathway. For the biochemical analysis, we measured the enzyme activity of aldose reductase (AR) and sorbitol dehydrogenase (SDH) and the sorbitol levels using 20, 40 and 60 week old OLETF or control Long-Evans Tokushima Otsuka (LETO) rats. Enzyme activities of AR and SDH, which were lower in 20 week old OLETF rats than in LETO rats, were increased in 60 week old OLETF rats. The lenticular sorbitol level of the OLETF rats was similar to the control level at 20 weeks of age, but it was markedly increased at 40 weeks of age, and slightly decreased at 60 weeks of age compared with rats at 40 weeks but not compared with controls. Slight lens fiber swelling was observed in the anterior and/or posterior subcapsular regions of 40 week old OLETF rats, accompanying elevated sorbitol level and slightly increased SDH activity in the lens. Swelling and liquefaction of lens fibers were observed in the subcapsular and supranuclear region of 60 week old OLETF rats, as well as decreased lenticular sorbitol, and markedly increased SDH activity compared with rats at 40 weeks. AR activity was also increased causing the elevation of sorbitol in lenses of OLETF rats during the early stages of cataract formation. Despite differences in the etiology of diabetes mellitus, the strain of rat and the rate of disease progression in the OLETF rat model compared with other diabetic models, the present results support the theory that the polyol pathway via AR is a factor in the development of sugar cataracts.
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PMID:Biochemical and morphological changes during development of sugar cataract in Otsuka Long-Evans Tokushima fatty (OLETF) rat. 1152 Jan 12

Aldose reductase (AR) and sorbitol dehydrogenase (SDH) are the enzymes constituting the polyol pathway, an alternate route of glucose metabolism. A wealth of experimental data has indicated the involvement of the polyol pathway in the pathogenesis of diabetic complications. However, there has been surprisingly little research on the relative abundance of SDH to AR in the tissues affected in diabetes. We therefore developed a competitive RT-PCR system to simultaneously determine the mRNA levels of these two enzymes in small amounts of samples, and studied their expression in Schwann cells isolated from adult rat sciatic nerves. Although both AR and SDH mRNA were expressed in the Schwann cells, the levels of SDH cDNA were much lower than those of AR cDNA. The induction of AR mRNA expression in the Schwann cells under hyperosmotic conditions was similarly detected by Northern blot analysis and our competitive RT-PCR method. The RT-PCR system developed in this study may be a useful tool in ascertaining the relative contributions of AR and SDH to the metabolic derangements resulting from the acceleration of polyol pathway activity in the target organ of diabetic complications.
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PMID:Analysis of gene expression of aldose reductase and sorbitol dehydrogenase in rat Schwann cells by competitive RT-PCR method using non-homologous DNA standards. 1173 99

In the traditional system of medicine, Ayurveda, several spices and herbs are thought to possess medicinal properties. Among the spices, turmeric rhizomes (Curcuma longa. Linn.) are used as flavoring and coloring agents in the Indian diet everyday. In this research, we studied the effect of turmeric and its active principle, curcumin, on diabetes mellitus in a rat model. Alloxan was used to induce diabetes. Administration of turmeric or curcumin to diabetic rats reduced the blood sugar, Hb and glycosylated hemoglobin levels significantly. Turmeric and curcumin supplementation also reduced the oxidative stress encountered by the diabetic rats. This was demonstrated by the lower levels of TBARS (thiobarbituric acid reactive substances), which may have been due to the decreased influx of glucose into the polyol pathway leading to an increased NADPH/NADP ratio and elevated activity of the potent antioxdiant enzyme GPx. Moreover, the activity of SDH (sorbitol dehydrogenase), which catalyzes the conversion of sorbitol to fructose, was lowered significantly on treatment with turmeric or curcumin. These results also appeared to reveal that curcumin was more effective in attenuating diabetes mellitus related changes than turmeric.
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PMID:Efficacy of turmeric on blood sugar and polyol pathway in diabetic albino rats. 1185 20

Diabetes causes increased oxidative stress, which is thought to play an important role in the pathogenesis of various diabetic complications. However, the source of the hyperglycemia-induced oxidative stress is not clear. It was found that the polyol pathway is the major contributor to oxidative stress in the lenses and nerves of diabetic mice. The first enzyme in the pathway, aldose reductase (AR), reduces glucose to sorbitol, which is then converted to fructose by sorbitol dehydrogenase (SDH). Transgenic mice that overexpress AR specifically in their lenses showed a significant increase in oxidative stress when they became hyperglycemic, as indicated by a decrease in GSH and an increase in malondialdehyde in their lenses. Introducing an SDH-deficient mutation into these transgenic mice significantly normalized the GSH and malondialdehyde levels. These results indicate that both enzymes of the polyol pathway contributed to hyperglycemia-induced oxidative stress in the lens. In the wild-type mice, diabetes caused a significant decrease in GSH in their sciatic nerves, indicative of oxidative stress. In the AR null mutant mice, diabetes did not lead to any decrease in the nerve GSH level. These results indicate that similar to the situation in the lens, AR is also the major contributor to hyperglycemia-induced oxidative stress in the nerve. Although increased flux of glucose through the polyol pathway leads to diabetic lesions in both the lenses and nerve, the mechanisms may be different. AR-induced osmotic stress seems to be the cause of diabetic cataract, whereas AR-induced oxidative stress is probably the cause of neuronal dysfunction.
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PMID:Contribution of polyol pathway to diabetes-induced oxidative stress. 1287 37

Sorbitol dehydrogenase (SDH), a member of the medium-chain dehydrogenase/reductase protein family and the second enzyme of the polyol pathway of glucose metabolism, converts sorbitol to fructose strictly using NAD(+) as coenzyme. SDH is expressed almost ubiquitously in all mammalian tissues. The enzyme has attracted considerable interest due to its implication in the development of diabetic complications and thus its tertiary structure may facilitate the development of drugs for the treatment of diabetes sufferers. Modelling studies suggest that SDH is structurally homologous to mammalian alcohol dehydrogenase with respect to conserved zinc binding motif and a hydrophobic substrate-binding pocket. Recently, the three-dimensional (3-D) structure of a mammalian SDH was solved, and it was found that while the overall 3-D structures of SDH and alcohol dehydrogenase are similar, the zinc coordination in the active sites of the two enzymes is different. The available structural and biochemical information of SDH are currently being utilized in a structure-based approach to develop drugs for the treatment or prevention of the complications of diabetes. This review provides an overview of the recent advances in the structure, function and drug development fields of sorbitol dehydrogenase.
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PMID:Sorbitol dehydrogenase: structure, function and ligand design. 1496 27

The initiation of sugar cataract formation by the aldose reductase catalyzed accumulation of sorbitol in diabetic rats, and its prevention by the administration of aldose reductase inhibitors at the onset or early stages of diabetes, has been well established. In contrast, the inhibition of sorbitol dehydrogenase by 4-[4-(N,N-dimethylsulfamoyl)piperazino]-2-hydroxymethylpyrimidine (SDI-1) has been observed to increase the onset in severity of sugar cataract formation in diabetic rats. Two analogs of SDI-1 have been synthesized, where the 4-(2-hydroxymethyl)pyrimidine ring has been replaced with either a 4-(2,6-dimethoxy)-pyrimidine ring or a 2-pyrimidine ring. Neither compound, 2-[4-(N,N-dimethylsulfamoyl)piperazino]-pyrimidine (SRA-1) or 4-[4-(N,N-dimethylsulfamoyl) piperazino]-2,6-dimethoxypyrimidine (SRA-2), demonstrated significant sorbitol dehydrogenase or aldose reductase inhibition. Oral administration of these compounds to streptozotocin diabetic rats, however, delayed cataract formation without reducing the levels of hyperglycemia or lens polyol.
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PMID:Anticataract activity of analogs of a sorbitol dehydrogenase inhibitor. 1532 Oct 28

Activation of protein kinase C (PKC) has been linked to the development of secondary diabetes complications. However, the underlying molecular mechanisms remain unclear. We examined the contribution of aldose reductase, which catalyzes the first, and the rate-limiting, step of the polyol pathway of glucose metabolism, to PKC activation in vascular smooth muscle cells (VSMCs) isolated from rat aorta and exposed to high glucose in culture. Exposure of VSMCs to high glucose (25 mmol/l), but not iso-osmotic mannitol, led to an increase in total membrane-associated PKC activity, which was prevented by the aldose reductase inhibitors tolrestat or sorbinil or by the ablation of aldose reductase by small interfering RNA (siRNA). The VSMCs were found to express low levels of sorbitol dehydrogenase, and treatment with the sorbitol dehydrogenase inhibitor CP-166572 did not prevent high-glucose-induced PKC activation. Stimulation with high glucose caused membrane translocation of conventional (alpha, beta1, beta2, and gamma) and novel (delta and epsilon) isoforms of PKC. Inhibition of aldose reductase prevented membrane translocation of PKC-beta2 and -delta and delayed the activation of PKC-beta1 and -epsilon, whereas membrane translocation of PKC-alpha and -gamma was not affected. Treatment with tolrestat prevented phosphorylation of PKC-beta2 and -delta. High glucose increased the formation of diacylglycerol (DAG) and enhanced phosphorylation of phospholipase C-gamma1 (PLC-gamma1). Inhibition of aldose reductase prevented high glucose-induced DAG formation and phosphorylation of PLC-gamma1 and PLC-beta2 and -delta. Inhibition of phospholipid hydrolysis by D609, but not by the synthetic alkyl-1-lysophospholipid 1-O-octadecyl-2-O-methyl-rac-glycerophosphocholine, or edelfosine, prevented DAG formation. Treatment with sorbinil decreased the levels of reactive oxygen species in high-glucose-stimulated VSMCs. Hence, inhibition of aldose reductase, independent of sorbitol dehydrogenase, appears to be effective in diminishing oxidative stress and hyperglycemic changes in signaling events upstream to the activation of multiple PKC isoforms and PLC-gamma1 and may represent a useful approach for preventing the development of secondary vascular complications of diabetes.
Diabetes 2005 Mar
PMID:Requirement of aldose reductase for the hyperglycemic activation of protein kinase C and formation of diacylglycerol in vascular smooth muscle cells. 1573 61

We have developed an animal model of diabetic sympathetic autonomic neuropathy which is characterized by neuroaxonal dystrophy (NAD), an ultrastructurally distinctive axonopathy, in chronic streptozotocin (STZ)-diabetic rats. Diabetes-induced alterations in the sorbitol pathway occur in sympathetic ganglia and therapeutic agents which inhibit aldose reductase or sorbitol dehydrogenase improve or exacerbate, respectively, diabetes-induced NAD. The sorbitol dehydrogenase inhibitor SDI-711 (CP-470711, Pfizer) is approximately 50-fold more potent than the structurally related compound SDI-158 (CP 166,572) used in our earlier studies. Treatment with SDI-711 (5 mg/kg/day) for 3 months increased ganglionic sorbitol (26-40 fold) and decreased fructose content (20-75%) in control and diabetic rats compared to untreated animals. SDI-711 treatment of diabetic rats produced a 2.5- and 4-5-fold increase in NAD in the SMG and ileal mesenteric nerves, respectively, in comparison to untreated diabetics. Although SDI-711 treatment of non-diabetic control rat ganglia increased ganglionic sorbitol 40-fold (a value 8-fold higher than untreated diabetics), the frequency of NAD remained at control levels. Levels of ganglionic sorbitol pathway intermediates in STZ-treated rats (a model of type 1 diabetes) and Zucker Diabetic Fatty rats (ZDF, a genetic model of type 2 diabetes) were comparable, although STZ-diabetic rats develop NAD and ZDF-diabetic rats do not. SDI failed to increase diabetes-related ganglionic NGF above levels seen in untreated diabetics. Initiation of Sorbinil treatment for the last 4 months of a 9 month course of diabetes, substantially reversed the frequency of established NAD in the diabetic rat SMG without affecting the metabolic severity of diabetes. These findings indicate that sorbitol pathway-linked metabolic alterations play an important role in the development of NAD, but sorbitol pathway activity, not absolute levels of sorbitol or fructose per se, may be most critical to its pathogenesis.
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PMID:A potent sorbitol dehydrogenase inhibitor exacerbates sympathetic autonomic neuropathy in rats with streptozotocin-induced diabetes. 1575 58

Vanadium compounds are potent in controlling elevated blood glucose levels in experimentally induced diabetes. However the toxicity associated with vanadium limits its role as therapeutic agent for diabetic treatment. A vanadium compound sodium orthovanadate (SOV) was given to alloxan-induced diabetic Wistar rats in lower doses in combination with Trigonella foenum graecum, a well-known hypoglycemic agent used in traditional Indian medicines. The effect of this combination was studied on lens morphology and glucose metabolism in diabetic rats. Lens, an insulin-independent tissue, was found severely affected in diabetes showing visual signs of cataract. Alterations in the activities of glucose metabolizing enzymes (hexokinase, aldose reductase, sorbitol dehydrogenase, glucose-6-phosphate dehydrogenase) and antioxidant enzymes (glutathione peroxidase, glutathione reductase) besides the levels of related metabolites, [sorbitol, fructose, glucose, thiobarbituric acid reactive species (TBARS) and reduced glutathione (GSH)] were observed in the lenses from diabetic rats and diabetic rats treated with insulin (2 IU/day), SOV (0.6 mg/ml), T. f. graecum seed powder (TSP, 5%) and TSP (5%) in combination with lowered dose of vanadium SOV (0.2 mg/ml), for a period of 3 weeks. The activity of the enzymes, hexokinase, aldose reductase and sorbitol dehydrogenase was significantly increased whereas the activity of glucose-6-phosphate dehydrogenase, glutathione peroxidase and glutathione reductase decreased significantly in lenses from 3 week diabetic rats. Significant increase in accumulation of metabolites, sorbitol, fructose, glucose was found in diabetic lenses. TBARS measure of peroxidation increased whereas the levels of antioxidant GSH decreased significantly in diabetic condition. Insulin restored the levels of altered enzyme activities and metabolites almost to control levels. Sodium orthovanadate (0.6 mg/ml) and Trigonella administered separately to diabetic animals could partially reverse the diabetic changes, metabolic and morphological, while vanadate in lowered dose in combination with Trigonella was found to be the most effective in restoring the altered lens metabolism and morphological appearance in diabetes. It may be concluded that vanadate at lowered doses administered in combination with Trigonella was the most effective in controlling the altered glucose metabolism and antioxidant status in diabetic lenses, these being significant factors involved in the development of diabetic complications, that reflects in the reduced lens opacity.
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PMID:Efficacy of lower doses of vanadium in restoring altered glucose metabolism and antioxidant status in diabetic rat lenses. 1588 58

Vanadium has been reported to have broad pharmacological activity both in vitro and in vivo. Vanadium compound, sodium orthovanadate, Na3VO4, is well known for its hypoglycaemic effects. However, Na3VO4 exerts these effects at relatively high doses (0.6 mg/ml) and exhibit several toxic effects. In the present study lower doses of Na3VO4 (0.2 mg/ml) are combined with Trigonella foenum graecum seed powder (TSP), another hypoglycaemic agent, to reduce its toxicity without compromising its antidiabetic potential. The efficacy of the lower doses of Na3VO4 has been investigated in restoring the altered glucose metabolism and histological structure in the sciatic nerves in 21 and 60 days alloxan diabetic rats. A portion of the glucose was found to be channelled from the normal glycolytic route to polyol pathway, evident by the reduced hexokinase activity and increased polyol pathway enzymes aldose reductase and sorbitol dehydrogenase activity causing accumulation of sorbitol and fructose in diabetic conditions. Ultrastructural observation of the sciatic nerve showed extensive demylination and axonal loss after eight weeks of diabetes induction. Blood glucose levels increased in diabetic rats were normalized with the lower dose of vanadium and Trigonella treatment. The treatment of the diabetic rats with vanadium and Trigonella prevented the activation of the polyol pathway and sugar accumulations. The sciatic nerves were also protected against the structural abnormalities found in diabetes with Trigonella foenum graecum as well as Na3VO4. Results suggest that lower doses of Na3VO4 may be used in combination with TSP as an efficient antidiabetic agent to effectively control the long-term complications of diabetes in tissues like peripheral nerve.
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PMID:Restoration of ultrastructural and biochemical changes in alloxan-induced diabetic rat sciatic nerve on treatment with Na3VO4 and Trigonella--a promising antidiabetic agent. 1618 85


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