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

Mounting evidence indicates that aldose reductase catalyzed reduction of excess glucose to sorbitol initiates the onset of certain diabetic complications. However, the kidney contains a large amount of aldehyde reductase, another NADPH-dependent reductase. The study was designed to assess the importance of these reductases to sugar alcohol (polyol) production in the kidney. To study the ability to reduce aldoses to polyols, both aldose and aldehyde reductases were purified from rat kidneys. Incubation studies with purified enzymes clearly demonstrated the polyol formation by both enzymes. Galactose feeding induced polyol accumulation in both medulla and cortex of the rat kidney. Al 1576, a potent inhibitor of both enzymes, reduced this polyol accumulation in both cortex and medulla, while the selective inhibitors Ponalrestat or FK 366 resulted in greater inhibition in medulla than cortex. These results suggest that kidney polyols may be generated by both aldose and aldehyde reductases and that aldehyde reductase contributes to polyol production in the kidney cortex, the predominant site of diabetes-linked kidney lesions.
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PMID:Rat kidney aldose reductase and aldehyde reductase and polyol production in rat kidney. 144 70

Diabetic nephropathy leading to kidney failure is a major complication of type I (insulin-dependent) diabetes mellitus and is associated with progressive proteinuria. In the present 6-month study, effects of two structurally dissimilar aldose reductase inhibitors (sorbinil and ponalrestat or Statil) were examined on prevention of proteinuria in insulin-dependent spontaneously diabetic BB rats and compared with age-matched BB resistant controls. Prior to aldose reductase inhibitor treatment, all diabetic BB rats exhibited hyperglycemia (> 300 mg/dl), glycosuria (> 2,000 mg/dl) and 24-hour urinary protein excretion ranging from 5.01 to 11.23 mg/day. After daily administration of ponalrestat (20 mg/kg) for 3 months, 24-hour urinary protein excretion was 11.53 +/- 1.76 mg/day in ponalrestat-treated rats, despite persistence of hyperglycemia (444 +/- 31 mg/dl) and glycosuria (> 2,000 mg/dl); by contrast, urinary protein excretion was 17.76 +/- 2.59 mg/day in the control group of untreated BB diabetic rats. Ponalrestat initially protected against excretion of an array of urinary proteins having molecular weights between 30,000 and 100,000 daltons. These effects sustained throughout the 4th month of treatment, tended to change toward valves in control rats by the 5th month. At the end of 6 months, ponalrestat-treated diabetic rats excreted 18.73 +/- 3.20 mg/day of protein, similar to valves in untreated BB diabetic rats; both demonstrated a 4-fold increase in urinary protein excretion when compared to age-matched BB resistant controls. Proteinuria was attributed to an increase in albumin and an array of proteins having molecular weights between 30,000 and 100,000 daltons.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Comparison of sorbinil and ponalrestat (Statil) diminution of proteinuria in the BB rat. 146 75

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. At 3 weeks, 6-7 months and 13-14 months, the vascular permeability in regions of brain, and in optic and sciatic nerves, were measured by maintaining radiotracers in the bloodstream--125I-albumin (100 min), [14C]sucrose (60 min) and 131I-albumin (5 min)--followed by tissue sampling and counting at termination. 131I-albumin estimated residual intravascular plasma. Diabetes of up to 13-14 weeks caused no measurable increase in the sucrose permeability of microvessels in eight different brain regions, in optic or in sciatic nerve. At 3 weeks of diabetes, sucrose permeability in all brain regions and in optic nerve was reduced relative to that in controls. Extravascular albumin entry into different regions of brain and optic nerve was insignificant and insensitive to diabetes, except in the hypothalamus and optic nerves where it was raised with increasing duration of diabetes. In sciatic nerve, extravascular albumin distribution was markedly increased by diabetes, but sucrose permeability was not demonstrably affected. At the level used in the diet, Ponalrestat reduced the sorbitol content of diabetic sciatic nerve but did not protect again the increased permeability to albumin.
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PMID:Permeability of blood-brain and blood-nerve barriers in experimental diabetes mellitus in the anaesthetized rat. 176 15

The polyol pathway has long been associated with diabetic retinopathy. Glucose is converted to sorbitol with the aid of the enzyme aldose reductase. Aldose reductase inhibitors can prevent changes induced by diabetes. A total of 30 patients with minimal background retinopathy were randomly divided into a ponalrestat-taking group and a placebo-taking group. All were followed for 6 months and twenty-three were followed for 12 months. The baseline microaneurysm count was 2.6 +/- 1.9 (mean +/- SD) for the ponalrestat group and 3.5 +/- 2.9 for the placebo group. At 6 months the counts were 3.1 +/- 3.5 and 2.9 +/- 3.6 and after 12 months 3.0 +/- 4.1 and 2.9 +/- 3.4. There is no statistically significant difference between the groups at 0, 6 or 12 months of study. The change in retinopathy severity level did not significantly differ between the two groups at either 6 or 12 months. Ponalrestat administration at a dosage of 600 mg daily for 12 months has no significant effect on the course of minimal retinopathy in diabetic patients.
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PMID:The effects of an aldose reductase inhibitor on the progression of diabetic retinopathy. 179 Jul 35

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

1. The responses of isolated left atria and papillary muscles to isoprenaline, forskolin and calcium have been examined in 3 week streptozotocin-diabetic rats and the effects of oral ponalrestat administration (25 mg kg-1 daily) on diabetes-induced changes in cardiac responsiveness investigated. 2. Three weeks after animals were made diabetic, cardiac responses to isoprenaline were enhanced and this was accompanied by an increase in the density of ventricular [3H]dihydroalprenolol binding sites. Treatment of animals with ponalrestat prevented the increase in cardiac beta-adrenoceptor responsiveness and receptor number. 3. Diabetes also enhanced the sensitivity of cardiac tissues to forskolin, an effect that was not prevented by the treatment of animals with ponalrestat. 4. Ponalrestat treatment increased the resting and maximum tensions developed by cardiac tissues from diabetic animals and increased the maximum tensions developed by tissues from control animals. Diabetes alone had no effect on resting or maximum developed tensions. 5. Ponalrestat therefore prevents the changes in beta-adrenoceptor density and responsiveness induced by short-term diabetes in the rat and also increases the tension developed by cardiac muscle, an effect observed in diabetic and normal animals.
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PMID:Diabetes-induced changes in cardiac beta-adrenoceptor responsiveness: effects of aldose reductase inhibition with ponalrestat. 184 72

The gut may be a site of early diabetic neuropathy in humans and rats. The latter may provide appropriate models of these conditions. Therefore, cholinergic function was examined in two gut smooth muscle preparations from control, 30-day, and 6-month streptozotocin-diabetic and similarly diabetic rats that had received continuous treatment with an aldose reductase inhibitor, ponalrestat. Responses of terminal ileum longitudinal muscle to transmural nerve stimulation were depressed in preparations from untreated 30-day diabetic animals. Responses to exogenous acetylcholine were also depressed, by at least the same extent, in preparations from both 30-day and 6-month diabetic groups. Ponalrestat treatment prevented both changes in the 30-day study but did not prevent a depression of responses to acetylcholine in the 6-month study. Neither diabetes nor ponalrestat affected responses of esophageal muscularis mucosa to electrical stimulation or to exogenous acetylcholine. These observations suggest a change in the smooth muscle and/or noncholinergic innervation rather than in the cholinergic nerves of the ileal preparation. Cholinergic function in the ileum did not, therefore, seem to be an appropriate model of diabetic neuropathy.
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PMID:Effects of diabetes on cholinergic transmission in two rat gut preparations. 189 95

Many of the complications of diabetes appear to be closely linked to increased conversion of tissue glucose to sorbitol which is catalysed by aldose reductase (aldehyde reductase 2, ALR2). Inhibition of ALR2 could, therefore, lead to a reduction in the development of diabetic complications. Ponalrestat ["Statil" (a trademark, the property of Imperical Chemical Industries PLC), "Prodiax" (a trademark, the property of Merck, Sharp and Dohme), ICI 128436, MK538] inhibits ALR2 from a number of sources. Until now, the mechanism of this inhibition has not been fully elucidated. In this paper, we present a detailed mechanism for inhibition of bovine lens ALR2 by ponalrestat. Treatment of humans with some ALR2 inhibitors leads to side-effects, some of which may result from interactions with other enzymes. Aldehyde reductase (ALR1) is probably the most closely related enzyme to ALR2. Inhibition of ALR1 from bovine kidney was, therefore, investigated in order to assess the specificity of ponalrestat. The values of Ki and Kies (apparent dissociation constants for inhibitor from enzyme-inhibitor and enzyme-inhibitor-substrate complexes, respectively) for the interactions of ponalrestat with ALR1 and ALR2 has been calculated by non-linear fitting of kinetic data. These values indicate that ponalrestat does not compete with binding of glucose of NADPH to ALR2, nor with binding of glucuronate or NADPH to ALR1. Lack of competition and the structural dissimilarity of substrates and inhibitor make it unlikely that ponalrestat will utilize substrate binding sites on other enzymes, and so produce undesirable side-effects via such a mechanism. Ponalrestat is a potent inhibitor (Ki = Kies = 7.7 nM) of ALR2 and follows a pure noncompetitive mechanism with respect to glucose. Efficacy, therefore, will not be decreased by development of hyperglycaemia. The compound is a mixed noncompetitive inhibitor of ALR1 when glucuronate is varied. The values of Ki and Kies are 60 microM and 3 microM, respectively, so that inhibition tends towards uncompetitive. The selectivity of ponalrestat in favour of ALR2, therefore, lies in the range 390 to 7,800-fold, being higher at lower concentrations of glucuronate. The high selectivity of ponalrestat in favour of ALR2 rather than ALR1 suggests that the compound is unlikely to inhibit other enzymes which have less homology with ALR2.
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PMID:Ponalrestat: a potent and specific inhibitor of aldose reductase. 210 33

To test the hypothesis that aldose reductase inhibition may prevent or delay the development of functional and structural neuropathy in the insulin-deficient diabetic Bio-Breeding rat (BB-rat), hyperglycemic rats were begun on the aldose reductase inhibitor (ARI) ponalrestat 25 mg/kg body wt soon after the onset of diabetes and followed for 4 or 6 mo. Ponalrestat treatment completely prevented the characteristic nerve conduction slowing and structural abnormalities of the node of Ranvier for 4 mo despite only partial preservation of axonal integrity. Ponalrestat treatment for 6 mo achieved a partial but significant prevention of nerve conduction slowing, axoglial dysjunction, and axonal degenerative changes. This incomplete but significant prevention of neuropathy by ponalrestat suggests that additional mechanisms besides polyol-pathway activation may be of importance in the pathogenesis of diabetic neuropathy. Alternatively, the dosage used in the present study may not have been sufficient to achieve a complete prevention. Despite the only partial protective effect of ARI treatment on degenerative peripheral nerve changes in hyperglycemic BB-rats, 6 mo of treatment resulted in a more than threefold increase in regenerating nerve fibers. These data suggest that prophylactic ARI treatment may be efficacious in delaying the development of diabetic neuropathy.
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PMID:Preventive effect of long-term aldose reductase inhibition (ponalrestat) on nerve conduction and sural nerve structure in the spontaneously diabetic Bio-Breeding rat. 211 Jan 89

Lens hydration was monitored by laser Raman spectroscopy in WBN/Kob rats which form spontaneous diabetes at about 1 yr of age and develop cataracts approximately 6 months after the onset of diabetes. Lens hydration in response to chronic hyperglycemic stress in these rats appeared predominantly in the cortical region while the hydration state in the nuclear region was fairly preserved. The 9-month treatment of similarly diabetic rats with the aldose reductase inhibitor Ponalrestat sufficiently suppressed lens hydration in the cortical and nuclear regions.
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PMID:Confirmation of lens hydration by Raman spectroscopy. 211 54


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