Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In recent studies we have demonstrated a marked increase in albumin permeation of new vessels formed by angiogenesis (in subcutaneous tissue) in the diabetic milieu. Likewise, lysyl oxidase-mediated collagen cross-linking is markedly increased in the scar tissue associated with angiogenesis. The present studies were undertaken to determine whether sorbinil, a chemical inhibitor of aldose reductase that has been shown to prevent and reverse diabetic cataracts and neuropathy, also could prevent the vascular permeability and collagen cross-linking changes in this model. Vascular permeation by 125I-BSA, collagen cross-linking, and tissue levels of sorbitol, myo-inositol, and scyllo-inositol were assessed in male Sprague-Dawley rats 3 wk after injection of streptozocin and induction of angiogenesis and collagen synthesis in polyester fabric implanted subcutaneously. Sorbinil (approximately 25 mg/kg/day) added to the diet of diabetic rats reduced the diabetes-induced increases in albumin permeation by 80%, completely prevented diabetes-induced changes in tissue levels of sorbitol and myo-inositol, and markedly reduced diabetes-induced changes in tissue levels of scyllo-inositol. In contrast, sorbinil had no effect on plasma glucose levels or collagen solubility (an index of collagen cross-linking). These observations indicate that increased vascular permeability associated with diabetes is linked to imbalances in sorbitol/inositol metabolism. These findings also indicate that diabetes-induced increases in vascular permeability and in collagen cross-linking are independent phenomena and diabetes-induced increases in vascular permeability are largely preventable by treatment with an aldose reductase inhibitor in the face of high plasma glucose levels.
Diabetes 1985 Jul
PMID:Sorbinil prevents diabetes-induced increases in vascular permeability but does not alter collagen cross-linking. 400 87

11 patients with severely painful diabetic neuropathy previously unresponsive to numerous drugs were treated with an aldose reductase inhibitor ('Sorbinil'--Pfizer CP 45, 634); 8 also received a placebo. Response was assessed according to a 0-20 graphic rating scale for pain and by tests for motor and sensory nerve conduction velocities (NCV) and cardiac autonomic nerve function. 8 patients had moderate to marked relief of symptoms, generally beginning on the 3rd or 4th day of medication, 2 had equivocal responses, and 1 had no change. Each of 4 patients with diabetic amyotrophy reported striking improvement in pain and mild to moderate improvement in proximal leg muscle strength; 2 of these noticed improved sensory perception in their feet. Objective evidence of improved muscle strength was obtained in each of these 4 patients and of improved sensation in 3. On stopping medication, pain worsened in 7 of 8 responders, although generally with some delay, suggesting a carry over effect. During the course of treatment autonomic nerve function improved significantly in 6 of 7 patients tested and across the group, and NCV improved in 4 of 7 tested. Both of these variables deteriorated after withdrawal of the drug. A correlation between NCV response and clinical response was apparent. Very little toxicity was observed. These observations suggest that aldose reductase inhibitors may be important in the treatment of symptomatic somatic and autonomic neuropathies complicating diabetes.
 ...
PMID:Treatment of severely painful diabetic neuropathy with an aldose reductase inhibitor: relief of pain and improved somatic and autonomic nerve function. 613 1

This investigation was designed to determine whether the aldose reductase inhibitor Sorbinil prevented the development of or reversed defects of nerve conduction and axonal transport in streptozotocin-diabetic rats. Untreated diabetes of either 3 or 6 wk duration caused a fall in sciatic motor nerve conduction velocity (MNCV) of 6-9 m/s (P less than 0.001) and significantly reduced the accumulation of axonally transported choline acetyltransferase activity against a 24-h sciatic nerve crush. These functional defects were associated with accumulation of sorbitol and depletion of myo-inositol in the sciatic nerve. Treatment with Sorbinil (25 mg/kg/day, p.o.) throughout the period of diabetes prevented the development of all these abnormalities in both 3- and 6-wk diabetic groups. In a second study, three groups of rats were subject to 3 wk untreated diabetes followed by Sorbinil treatment (as above) for 1, 2, or 3 wk to determine whether the abnormalities expected from 3 wk of untreated diabetes could be reversed. One week of treatment significantly elevated both MNCV and choline acetyltransferase accumulation (P less than 0.05). The longer treatments progressively ameliorated these defects such that the group that received Sorbinil for the second 3 wk of a 6-wk diabetic period gave values that were similar to controls and to diabetic rats that had been given Sorbinil throughout their diabetes. Sorbitol accumulation was markedly reduced by only 1 wk of Sorbinil treatment, but the normalization of myo-inositol levels required 2 wk of treatment. These findings indicate that Sorbinil treatment in diabetic rats prevented and reversed both Sorbitol accumulation and depletion of nerve myo-inositol in the sciatic nerve.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1984 May
PMID:Prevention and reversal of defective axonal transport and motor nerve conduction velocity in rats with experimental diabetes by treatment with the aldose reductase inhibitor Sorbinil. 620 76

This study examined the effect of an aldose reductase inhibitor (Sorbinil, CP 45634, Pfizer, Sandwich, Kent, United Kingdom) on the metabolite profile of the lens during the first week after induction of diabetes with alloxan. The lens content of sorbitol, fructose, glycerol 3-phosphate, and glucose 6-phosphate was, respectively, 0.33 +/- 0.03, 0.55 +/- 0.05, 0.10 +/- 0.01, and 0.074 +/- 0.006 mumol/g (means +/- SEM) in the control group rising to 12.2 +/- 0.52, 3.20 +/- 0.10, 0.76 +/- 0.10, and 0.200 +/- 0.009 in lenses from alloxan-diabetic rats. Sorbinil treatment (40 mg/kg) decreased the lens content of sorbitol to 0.60 +/- 0.06, fructose to 0.85 +/- 0.08, and glycerol 3-phosphate to 0.36 +/- 0.03 mumol/g; glucose 6-phosphate remained unchanged. Significantly, the lens content of glutathione was decreased to 60% of the normal value in the diabetic group, but was sustained at normal levels with Sorbinil treatment. The ATP content of the lens was not altered by diabetes or Sorbinil treatment at this time interval. Sorbinil has no significant effect on the above metabolites in the normal rat lens. The effect of Sorbinil in restoring normal levels of glutathione and glycerol 3-phosphate may be a potentially important facet of the action of this drug. The interlocking of metabolic pathways by the redox state of NAD+/NADH and NADP+/NADPH, their derangement in diabetes, and the wider effects of Sorbinil on the network of reactions in the lens are discussed.
Diabetes 1983 May
PMID:The effect of an aldose reductase inhibitor (Sorbinil) on the level of metabolites in lenses of diabetic rats. 640 81

Two major metabolic perturbations, increased polyol (sorbitol) pathway activity and reduced tissue myo-inositol content, are induced in peripheral nerve by hyperglycemia. Although they are commonly invoked as alternative biochemical pathogenetic mechanisms for diabetic neuropathy, their possible interrelationship has never been adequately explored. Therefore, we studied the effect of polyol pathway blockade with sorbinil, a specific inhibitor of aldose reductase, on nerve myo-inositol content in acutely streptozotocin-diabetic rats. Sorbinil administration completely prevented the fall in nerve myo-inositol, thereby implicating increased polyol pathway activity as a likely factor in the fall in nerve myo-inositol content in experimental diabetes.
Diabetes 1983 Nov
PMID:Polyol pathway activity and myo-inositol metabolism. A suggested relationship in the pathogenesis of diabetic neuropathy. 641 10

A possible relationship between increased sorbitol concentration and decreased myo-inositol concentration in peripheral nerves of diabetic rats has been examined. To this end, sorbinil, an aldose reductase inhibitor, was used either to prevent or reverse elevation of nerve sorbitol concentration in diabetic rats. Sorbinil treatment at 20 mg . kg-1 . day-1 prevented elevation of nerve sorbitol levels in early diabetes and reduced sorbitol concentration from 2.38 to 0.51 mumol/g in rats diabetic for 10 weeks. This treatment reduced the increase in nerve fructose concentration and prevented the reduced myo-inositol concentration found in diabetic rat nerve (control 3.63, diabetic 2.40, diabetic/sorbinil, 3.56 mumol/g). Sorbinil treatment did not prevent a significant slowing of motor-nerve conduction velocity at 10 weeks although treatment reduced the extent of slowing. Sorbinil treatment at 25 mg . kg-1 . day-1 reduced elevated sorbitol and fructose concentrations in diabetic in diabetic rat nerve and normalised myo-inositol concentration. Myo-Inositol treatment at 650 mg . kg-1 . day-1 did not affect the elevated concentrations of sorbitol, fructose or glucose in peripheral nerves of diabetic rats, but it did restore reduced myo-inositol concentration. Both sorbinil and myo-inositol treatment partially reversed the slowing of motor-nerve conduction velocity in diabetic rats. These results are discussed in relation to the involvement of sorbitol and myo-inositol metabolism in the aetiology of diabetic neuropathy.
 ...
PMID:Myo-inositol and sorbitol metabolism in relation to peripheral nerve function in experimental diabetes in the rat: the effect of aldose reductase inhibition. 641 13

Normotensive and spontaneously hypertensive rats fed a 30% galactose diet until 15-21 months of age developed significant (P less than 0.05) retinal capillary basement membrane thickening, compared with animals fed a standard test diet. Animals on the high galactose diet containing 250 mg/kg of the aldose reductase inhibitor, Sorbinil, did not develop basement membrane thickening. No cytologic abnormalities of pericytes or endothelial cells were noted, and pericyte:endothelial cell nuclear ratios did not differ in the various experimental groups. This model reproduces a characteristic lesion of diabetes mellitus in non-diabetic animals, and should facilitate study of the biochemical mechanisms of basement membrane thickening.
 ...
PMID:Galactose-induced retinal capillary basement membrane thickening: prevention by Sorbinil. 664 31

This study examined the effects of an aldose reductase inhibitor (CP 45634, Sorbinil, Pfizer, New York, New York) on the neuropathy of streptozotocin-induced diabetic rats. Sorbinil treatment for 4 wk reduced sciatic nerve sorbitol concentration and improved motor nerve conduction velocity in diabetes of 2-9 mo duration. It remains to be determined whether Sorbinil can prevent chronic diabetic neuropathy.
Diabetes 1982 Sep
PMID:The effect of aldose reductase inhibition on motor nerve conduction velocity in diabetic rats. 681 73

Abnormalities in corneal epithelial healing in diabetic patients have been described recently. Defects in corneal re-epithelialization in diabetic rats have been reported, and it was found that treatment with aldose reductase (AR) inhibitors effectively prevented these defects. Experiments using galactosemic rats to study further the role of AR in these defects, since AR is known to be the common factor involved in sugar cataractogeneses, are reported herein. Similar defects in corneal re-epithelialization in galactosemic rats as in diabetic rats were found. The delay in re-epithelialization was documented by computer planimetry. Light microscopy showed marked corneal stroma edema and wider intercellular spaces in the epithelium after complete re-epithelialization, while scanning electron microscopy revealed fewer filopodia projecting from the leading margin during the active migration stage. These defects were prevented by treating galactosemic rats with the aldose reductase inhibitor, Pfizer's Sorbinil. These suggest that AR plays a role in the defects in corneal re-epithelialization observed in diabetes.
 ...
PMID:Corneal re-epithelialization in galactosemic rats. 684 Oct 2

It has been demonstrated that activation of aldose reductase (AR; EC 1.1.1.21) in diabetic tissues plays an important role in the pathogenesis of diabetic complications. In the present study, the effects of non-enzymatic glycation of recombinant human AR (rhAR) on enzyme activity and affinity for its substrate (glyceraldehyde), co-factor (NADPH) and inhibitors (ARI; Sorbinil, Tolrestat, AL-1576 and Statil) were examined. Although rhAR was successfully non-enzymatically glycated with HPLC-purified [3H]D-glucose, the Michaelis constant (Km) and catalytic efficiency (Kcat/Km) for glyceraldehyde, the Km for NADPH and the inhibitor constant (Ki) for ARI did not change. These results suggest that the mechanism of AR activation and its insensitivity to inhibition observed in diabetic tissues cannot be attributed to its non-enzymatic glycation.
Diabetes Res Clin Pract 1995 Mar
PMID:The effect of non-enzymatic glycation on recombinant human aldose reductase. 755 97


<< Previous 1 2 3 4 5 6 Next >>