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

1. The present study was designed to investigate if the aldose reductase inhibitor ponalrestat is capable of preventing the impairment of the response of ornithine decarboxylase (ODC) to nerve crush in streptozotocin (STZ)-diabetic rats. 2. ODC activity was measured in the dorsal root ganglia of crushed and uncrushed contralateral sciatic nerve of non-diabetic, ponalrestat-treated non-diabetic, STZ-diabetic and ponalrestat-treated STZ-diabetic rats. 3. Twenty four hours after crush, a significant (P less than 0.001) increase in the ratio of ODC activity in ganglia of crushed relative to uncrushed nerves was found in non-diabetic but not in diabetic rats, as expected. In the ponalrestat-treated diabetic rats the ratio was significantly higher (P less than 0.001) than that in the untreated diabetic rats and was not different from that in the non-diabetic group. 4. Ponalrestat also significantly decreased absolute levels of ODC activity in ganglia of uncrushed nerves from diabetic and non-diabetic animals. Despite the near-normal induction of ODC activity by nerve crush in the ponalrestat-treated diabetic animals, absolute ODC activity remained lower than that in ganglia of uncrushed nerves from non-diabetics. 5. We conclude that ponalrestat is able to prevent the impaired induction of ODC in experimental diabetes. The results, however, call into question the relationship between impaired ODC induction and diabetes-induced defects in nerve regeneration, which are insensitive to ponalrestat.
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PMID:Impaired induction of nerve ornithine decarboxylase activity in the streptozotocin-diabetic rat is prevented by the aldose reductase inhibitor ponalrestat. 212 96

There is controversy over the efficacy of aldose reductase inhibitors in preventing the development of peripheral nerve lesions in experimental diabetes. This study was designed to show whether long-term (28-wk) inhibition of aldose reductase by ponalrestat influences structural changes in peripheral sensory nerve in rats with chronic streptozocin-induced diabetes. Sciatic nerve levels of sorbitol and fructose were significantly reduced but not completely normalized by ponalrestat treatment. myo-Inositol levels, which tended to decrease in diabetic rats, were significantly increased by ponalrestat treatment and exceeded the level in nondiabetic control rats (P less than 0.01). Ponalrestat treatment significantly increased nerve conduction velocity over the 28 wk of treatment (P less than 0.05), but levels remained well below those of control rats. Structural analysis of sural nerve of diabetic rats disclosed significant preventive effects of ponalrestat on the reduction in myelinated nerve fiber size and fiber occupancy. Axon-fiber size ratio was also preserved in the ponalrestat-treated group. However, diffuse deposition of glycogen and increased glycogenosomes within axons were not influenced by ponalrestat treatment. In contrast to the effect on myelinated nerve fibers, morphometry of unmyelinated nerve fibers did not reveal a significant effect of ponalrestat treatment. These results suggest that chronic treatment with an aldose reductase inhibitor has beneficial effects on the peripheral sensory nerve of experimentally diabetic rats. The effects were primarily on myelinated rather than unmyelinated nerve fibers.
Diabetes 1990 Jun
PMID:Effects of long-term aldose reductase inhibition on development of experimental diabetic neuropathy. Ultrastructural and morphometric studies of sural nerve in streptozocin-induced diabetic rats. 214 Aug 2

This study examined the preventative effect of an aldose reductase inhibitor, ponalrestat, on contractile properties of heart left ventricular papillary muscles in rats having streptozotocin induced diabetes for 13 weeks. Both contraction and relaxation were slowed by diabetes. The time to reach peak twitch tension was increased by 21%, and the time to relax to half peak tension was increased by 29% (p less than 0.01, respectively compared to normal control animals). With ponalrestat treatment, the increase in contraction time was only 11%, and relaxation was only slowed by 4% (p less than 0.05 and p less than 0.01, respectively compared to diabetic controls). Diabetes also reduced maximum rates of contraction (13%) and relaxation (19%) and prolonged the time taken to reach peak relaxation rate (36%, p less than 0.01). Ponalrestat had no effect on maximum contraction rates but was particularly effective in normalising relaxation rates (p less than 0.01). Deficiencies with diabetes were noted over a range of stimulation frequencies (0.1-4.0 Hz), and ponalrestat treatment was beneficial except at the highest rates. Diabetes and ponalrestat effects were observed over a temperature range of 25-37 degrees C. Ventricular sorbitol levels showed a 17-fold increase with diabetes (p less than 0.01) and this was reduced by 67% with ponalrestat (p less than 0.01). There were no changes in ventricular myo-inositol. It is possible that ponalrestat treatment prevented a defect in sarcoplasmic reticulum calcium handling which could be responsible in part for the deficits in contraction ability and mainly for the deficits in relaxation ability in diabetic cardiomyopathy, although this remains to be tested directly.
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PMID:Contractile properties of cardiac papillary muscle in streptozotocin-diabetic rats and the effects of aldose reductase inhibition. 250 12

Sorbitol levels were determined in lens of genetically obese (ob/ob) and diabetic (db/db) mice, as well as in lean mice (+/db, +/ob) made diabetic by administration of streptozotocin (STZ). Treatment of lean mice with STZ resulted in hypoinsulinemia, whereas the ob/ob and db/db mice were hyperinsulinemic. Hyperglycemia was present in STZ-treated +/db and +/ob mice and in db/db mice, whereas relative euglycemia was observed in ob/ob mice and untreated +/db and +/ob mice. Sorbitol levels were elevated in lens tissue of db/db mice and STZ-treated +/db. In contrast, no changes in sorbitol content were observed in ob/ob mice and +/ob mice treated with STZ, suggesting that aldose reductase activity in lens of this animal model is considerably less than that present in db/db mice. Oral treatment of db/db mice and STZ-treated +/db mice with Ponalrestat reduced hyperglycemia-induced sorbitol accumulation significantly in lens, indicating that aldose reductase inhibitors may ameliorate long-term complications associated with sorbitol accumulation in diabetes.
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PMID:The effect of ponalrestat on sorbitol levels in the lens of obese and diabetic mice. 251 Jul 26

Conduction deficits caused by 2-4 months diabetes were examined in one sensory and six motor nerve branches of mature rats. The effect of aldose reductase inhibitor (ponalrestat) treatment was assessed in preventative and reversal studies. The efficacy of 1% dietary myoinositol supplementation was also examined in a 2 month preventative group. Diabetes suppressed a maturation-related increase in conduction velocity in the interosseus nerve supplying foot muscles. This was unaffected by any treatment. Large conduction velocity reductions (22-29%) seen for fast nerves supplying four calf muscles and sensory saphenous nerves were prevented by ponalrestat treatment. In a reversal group, which had 2 months of diabetes followed by 2 months of treatment, restoration of conduction varied between nerves, ranging from 100% in sensory saphenous to 25% in soleus motor branches. Myo-inositol supplementation had little effect. Sciatic nerves accumulated the sugar alcohol sorbitol with diabetes. This was markedly reduced by treatment, and correlated with the conduction velocity improvement. There was a 40% reduction in nerve free myo-inositol levels after 2 months diabetes. Ponalrestat normalized myo-inositol in the short term but failed to do so in 4 month preventative and reversal groups. Myo-inositol treatment did not affect nerve levels. The data implicate the polyol pathway in the diabetic conduction velocity deficits seen in normally fast conducting motor and sensory nerves and suggest that aldose reductase inhibitor action does not depend on restoration of nerve myo-inositol levels.
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PMID:The effect of aldose reductase inhibition on the pattern of nerve conduction deficits in diabetic rats. 251 91

The effect of a dietary supplement of an aldose reductase inhibitor (ponalrestat) or of myo-inositol on sodium transport into the rat brain and on concentrations of saccharide and polyols in cortical brain tissue and sciatic nerve was investigated in control rats and in streptozotocin-diabetic rats after a diabetes duration of 2 weeks. In untreated diabetes, the neocortical blood-brain barrier permeability for sodium decreased by 28% (3.4 +/- 0.4 vs 4.7 +/- 1.6 x 10(-5) ml/s g, mean +/- SD) as compared to controls. Levels of glucose, sorbitol and fructose increased in brain as well as in nerve tissues, whereas myo-inositol depletion was not demonstrable. Ponalrestat treatment of diabetic animals had no effect upon the decreased neocortical blood-brain barrier permeability to sodium (3.5 +/- 0.9 vs 4.7 +/- 1.1 x 10(-5) ml/s g) despite normalization of brain and nerve content of sorbitol and fructose. Myo-inositol supplementation of diabetic rats normalized sodium passage into the brain (4.2 +/- 1.1 vs 4.4 +/- 0.5 x 10(-5) ml/s g). Brain concentrations of monosaccharides and polyols were normalized as compared to the myo-inositol treated control group and nerve concentrations of glucose, sorbitol, and fructose were significantly increased. Myo-inositol treatment leads to a normalization of blood-brain barrier permeability; it is suggested that myo-inositol exerts a restituting effect upon Na+/K+-ATPase activity of the cerebral endothelial cells.
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PMID:Myo-inositol normalizes decreased sodium permeability of the blood-brain barrier in streptozotocin diabetes. 252 78

Rats with streptozotocin-induced diabetes have a decreased rate of sciatic nerve regeneration. We studied the effects on this defect of treatment with the aldose reductase inhibitor, ponalrestat (25 mg/kg per day via an endogastric tube). The nerves of diabetic rats were crush-injured at 5 weeks of diabetes and regeneration evaluated 7 days later with the pinch-reflex test. Ponalrestat treatment was started at day 3 after streptozotocin injection and was continued for the whole experimental period, i.e. until 6 weeks of diabetes. The treatment prevented effectively the accumulation of sorbitol and fructose in the nerves of diabetic rats, but was without effect on the sciatic nerve regeneration (controls 21.8 +/- 1.2 mm/7 days (mean +/- SEM, n = 6), untreated diabetics 15.8 +/- 1.8 (n = 7), ponalrestat-treated diabetics 16.2 +/- 1.0 (n = 10]. The results indicate that there is no connection between increased sorbitol pathway flux and impaired regeneration in streptozotocin diabetic rats.
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PMID:Impaired nerve regeneration in streptozotocin-diabetic rats. Effects of treatment with an aldose reductase inhibitor. 253 88

The binding capacity of ouabain to erythrocyte Na,K-ATPase was determined to analyze alterations in this enzyme activity in non-insulin-dependent diabetic patients. A significant (p less than 0.001) reduction of the binding capacity of ouabain was found in erythrocytes obtained from the diabetic patients with polyneuropathy (0.51 +/- 0.02 pmol/10(9) erythrocytes, m +/- SE, n = 14) as compared with the patients without neuropathy (0.67 +/- 0.02, n = 14) or age-matched control subjects (0.71 +/- 0.04, n = 11). Accordingly, the effect of an aldose reductase inhibitor (ARI; Ponalrestat) on erythrocyte Na,K-ATPase activity was studied following two or three months oral administration in seven of the diabetic patients with polyneuropathy. After treatment with Ponalrestat the mean binding capacity of ouabain was significantly increased from 0.53 +/- 0.04 to 0.57 +/- 0.03 (p less than 0.05 by paired t-test). Furthermore, enzyme kinetics showed that in normal subjects the apparent Km and Vmax of erythrocyte membrane Na,K-ATPase were 0.51 +/- 0.07 mM (n = 5, m +/- SE) and 7.19 +/- 0.27 nmol Pi/mg protein/min (n = 5, m +/- SE), respectively. The Vmax with 3 mM ATP was significantly (p less than 0.05) decreased in the diabetic patients with polyneuropathy as compared with age-matched control subjects. However, the apparent Km did not change. Finally, the in vitro effect of Ponalrestat was examined in erythrocyte membrane fractions from the diabetic patients with polyneuropathy. The activity of erythrocyte membrane Na,K-ATPase was found to be directly stimulated about 1.2 fold by the addition of pharmacological doses of Ponalrestat (10(-10), 10(-8), 10(-6) M).(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes Res 1989 Nov
PMID:Effect of aldose reductase inhibitor (Ponalrestat) on erythrocyte Na,K-ATPase activity in non-insulin-dependent diabetic patients with polyneuropathy. 256 96

Six groups of rats were studied over a 12-week period: onset and end controls, untreated diabetics, ponalrestat-treated diabetics, insulin-treated diabetics, and diabetics treated with ponalrestat and insulin. The concentrations of glucose, sorbitol and fructose significantly increased and that of myo-inositol significantly decreased in the sciatic nerve of untreated diabetic animals. Ponalrestat administration completely normalized sorbitol levels and partially corrected fructose and myo-inositol concentrations without altering nerve glucose levels. The biochemical abnormalities were also corrected in both the insulin-treated and insulin and ponalrestat-treated diabetic animals. Myelinated fibre cross-sectional areas and axonal areas were significantly less in the tibial nerve of diabetic animals as compared with age-matched controls. Insulin treatment partially corrected the reduction in fibre and axonal area but teased fibre preparations showed an excess of axonal degeneration as compared with controls, untreated diabetics and ponalrestat-treated diabetics. Ponalrestat given alone or in conjunction with insulin therapy did not correct the reduction in fibre or axonal area and single isolated fibres from diabetic animals treated with ponalrestat and insulin showed a marked excess of axonal degeneration, probably related to hypoglycaemia. The study fails to reveal any significant beneficial effect of aldose reductase inhibition on the structural abnormalities in peripheral nerve in experimental diabetes.
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PMID:Ultrastructural observations on myelinated fibres in experimental diabetes: effect of the aldose reductase inhibitor ponalrestat given alone or in conjunction with insulin therapy. 296 41

Advanced glycation is an important pathogenic mechanism in the development of diabetic complications. However, other biochemical processes, such as the polyol pathway or lipid and protein oxidation which can interact with advanced glycation can also yield tissue fluorescence and may also be implicated in the genesis of diabetic microangiopathy. Aminoguanidine is an inhibitor of advanced glycation, but it is not known if all of its effects are mediated by this mechanism. The present study explores the relative contributions of aldose reductase, oxidative stress and advanced glycation on the development of aortic and renal fluorescence and urinary albumin excretion in streptozotocin diabetic rats. The study groups included non-diabetic (control), streptozotocin diabetic rats and diabetic rats receiving aminoguanidine, the anti-oxidants butylated hydroxytoluene and probucol and the aldose reductase inhibitor, ponalrestat. Serial measurements of glycaemic control and urinary albumin excretion were performed every 8 weeks. At 32 weeks, animals were killed, tissues removed and collagen extracted for measurement of fluorescence. Diabetic rats had increased fluorescence in aorta, glomeruli and renal tubules. Aminoguanidine prevented an increase in fluorescence at all three sites suggesting that diabetes-related tissue fluorescence is predominantly due to advanced glycation. Ponalrestat retarded fluorescence in aorta only and butylated hydroxytoluene attenuated fluorescence at the renal sites but not in the aorta. Diabetic rats had increased renal cortical sorbitol levels. Ponalrestat normalized renal cortical sorbitol levels but aminoguanidine did not affect this parameter. The only agent to decrease plasma thiobarbituric acid reactive substances was butylated hydroxytoluene. Diabetic rats developed albuminuria over the 32-week period.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The relative roles of advanced glycation, oxidation and aldose reductase inhibition in the development of experimental diabetic nephropathy in the Sprague-Dawley rat. 878 32


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