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)

Aldose reductase inhibitors (A.R.I.s), developed as potentially therapeutic agents for the treatment of complications of long-term diabetes, were found to be potent inhibitors of aldose reductase (ALR2) partially purified from bovine retina (IC50 values: Statil 0.89 microM, Sorbinil 2 microM, M79175 greater than 1 microM). These compounds varied, however, in their ability to inhibit hexonate dehydrogenase (ALR1), a closely related enzyme isolated from the same source (IC50 values: Statil greater than 1 microM, Sorbinil 3.9 microM, M79175 0.18 microM). Statil and Sorbinil were active against ALR2 at very low concentrations (approx. 5% inhibition at 100 pM), but did not inhibit ALR1 at less than or equal to 10 nM. In contrast, M79175 (structurally very similar to Sorbinil) and M7HEQ (a flavonoid) were preferential inhibitors of ALR1. Valproate, a compound of value in the treatment of epilepsies, was a poor inhibitor of ALR2 (18% at 1 mM). Furthermore, valproate was found to be a relatively poor inhibitor of ALR1, particularly in comparison with M79175.
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PMID:Inhibition of hexonate dehydrogenase and aldose reductase from bovine retina by sorbinil, statil, M79175 and valproate. 309 Oct 36

Neuropathy and retinopathy are two potentially serious late complications of diabetes. There is accumulating evidence that the development of these conditions is closely related to increased activity of the polyol pathway, which occurs in certain tissues as a consequence of long term hyperglycaemia. Symptomatic diabetic neuropathy may appear as one of many forms and is frequently accompanied by pain. Diabetic retinopathy is a progressive degeneration of the retina that represents one of the major causes of blindness in the developed world. A good prognosis for either of these conditions is believed to rely on early diagnosis and optimisation of glycaemic control as they become less reversible with progression of cellular damage. A new approach to the treatment of these and other late complications of diabetes may be offered by recently developed drugs, such as sorbinil, that inhibit the enzyme aldose reductase. In various animal models of late complications of diabetes sorbinil and other aldose reductase inhibitors have been shown to reverse some of the biochemical and physiological changes believed to underlie these complications. These include prevention or reversal of the accumulation of sorbitol and depletion of myo-inositol in nerve, lens and renal glomeruli. Sorbinil also counteracts the slowing of nerve conduction velocities, reverses the structural changes of Sipple stages I and II cataracts and prevents proteinuria in diabetic rats. Orally administered sorbinil is absorbed rapidly and reaches steady state plasma concentrations after 6 to 10 days' administration. Its elimination half-life is long (38-52 hours) and much greater than that of another aldose reductase inhibitor, tolrestat (10-12 hours). Within the dose range 50-250 mg about one-third of administered sorbinil appears in the urine as unchanged drug. In the small number of clinical studies of diabetic patients with neuropathies sorbinil has demonstrated limited therapeutic effects. There is now a requirement for studies of its prophylactic use and its therapeutic use in patients with diabetic neuropathy in the early stages of development.
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PMID:Aldose reductase inhibitors and late complications of diabetes. 309 44

Sorbinil, an aldose reductase inhibitor, was examined as a therapeutic agent to arrest and/or reverse proteinuria in 'type 1' insulin-dependent BB rats having spontaneous diabetes mellitus. Prior to sorbinil treatment, diabetic rats exhibited hyperglycemia and increased urinary excretion of urobilinogen, glucose and protein. To assess proteinuria, 24-hour urine samples were analyzed for both total protein and individual components between 30,000 and 100,000 daltons. Daily oral administration of sorbinil (20 mg/kg body weight) was initiated and the aforementioned parameters reevaluated after 1, 2 and 4 months. Results indicated that after 1 month of sorbinil treatment, urobilinogen was normalized in all diabetic BB rats (n = 12), whereas urinary protein excretion was either diminished (67%) or remained constant (16%), despite persistence of hyperglycemia and glycosuria. These therapeutic effects were sustained after 2 months of sorbinil treatment. After 4 months, protein excretion was normalized (6.56 +/- 3.34 mg/24 h), despite persistence of hyperglycemia and glycosuria (n = 12); in marked contrast, 6 untreated rats continued to exhibit proteinuria (17.76 +/- 2.59 mg/day). Sorbinil diminished albumin and a series of urinary proteins between 30,000 and 100,000 daltons, suggesting that sorbinil may represent a therapeutic approach to manage diabetic nephropathy as indicated by diminution of proteinuria.
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PMID:Reversal of proteinuria by sorbinil, an aldose reductase inhibitor in spontaneously diabetic (BB) rats. 312 36

The etiology of diabetic osteopenia has not been established. The value of serum osteocalcin (BGP) as a marker of the bone abnormalities and the possible role of the polyol pathway in diabetic osteopenia were investigated. Three groups of rats were studied over 7 weeks: group D (n = 12), rats with streptozotocin (55 mg/kg)-induced diabetes given saline by gavage; group DS (n = 12), rats with streptozotocin-induced diabetes given the aldose reductase inhibitor sorbinil (25 mg/kg) daily by gavage; and group C (n = 6), saline-injected controls. Circulating levels of ionized calcium, BGP, amino-terminal PTH, and glucose were measured on days 0, 7, 14, 28, and 49. Tibial bone specimens were examined for the presence of aldose reductase by immunocytochemistry and by histomorphometry after tetracycline labeling. Diabetic rats with or without sorbinil treatment failed to gain weight [group D, 234 +/- 26 g; group DS, 217.0 +/- 40 g; group C, 310 +/- 33 g (mean +/- SD)]. Serum BGP levels decreased significantly in the diabetic rats within 7 days and remained lower throughout the study. BGP values on day 7 were: group D, 47.7 +/- 4.9 ng/ml; group DS, 65.9 +/- 5.5 ng/ml; and group C, 90.4 +/- 4 ng/ml (mean +/- SEM). Serum PTH levels were similar in all groups, except for day 49, when an increase in the D group was observed. Bone histomorphometry showed decreased bone remodeling in the D group, which confirmed the serum BGP findings. Aldose reductase was detectable in the small blood vessels and in bone itself. Sorbinil failed to influence the biochemical or bone histomorphometric abnormalities associated with diabetes. Serum BGP may be a valuable marker for the decreased bone remodeling in insulinopenic diabetes.
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PMID:Bone mineral metabolism in experimental diabetes mellitus: osteocalcin as a measure of bone remodeling. 313 94

Long term and acute effects of glucose on myo-inositol (MI) uptake were studied in primary cultures of bovine retinal pigment epithelial (RPE) cells. RPE cells were grown under low (5 mM) or high (20, 40, or 50 mM) glucose levels in the growth medium for up to 18 days. The concentrative capacity of confluent RPE cells to accululate [3H]MI (10 microM) was reduced up to 41% as the glucose concentration in the growth medium increased. When the growth medium glucose was switched from 5 to 40 mM, or vice versa, the capacity of cells to accumulate MI was reversed. Treatment of cells grown in 40 or 50 mM glucose with 0.1 mM Sorbinil (an aldose reductase inhibitor) minimally reversed the ability of cells to accumulate MI. RPE cells, grown in 5 mM glucose, were incubated with 10-60 mM D-glucose or its nonmetabolizable analogues (acute effect). Kinetics of MI uptake inhibition by alpha-methyl glucose according to Dixon plots were characteristic of competitive inhibition (Ki = 28 mM). MI uptake was strongly inhibited by phlorizin. The ability of RPE cells to bind 5 microM [3H]phlorizin also was reduced by increased glucose levels in the growth medium. These studies indicated that MI and glucose shared the same transporter system. Glucose in the incubation medium directly interfered with MI binding to the transporter. High glucose feeding of the cells also down-regulated the transporter density. The uptake and function of solutes such as MI in tissues that operate on the glucose carrier system may be severely impaired in diabetes.
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PMID:Regulation of uptake of inositol by glucose in cultured retinal pigment epithelial cells. 314 98

Sciatic nerve glucose, sorbitol, fructose and myo-inositol levels were measured over a 24-week period in rats made diabetic using a single intraperitoneal injection of streptozotocin at 45 mg kg-1 body weight. In addition, the effect of the aldose reductase inhibitor Sorbinil (Pfizer Ltd) at 25 mg kg-1 day-1 in reversing the accumulation of nerve polyols following 8 weeks of diabetes was investigated. Following induction of diabetes 47, 471 and 456% increases and a 43% decrease in sciatic nerve glucose, sorbitol, fructose and myo-inositol concentrations (mumol g-1 wet weight) respectively, were observed by day 14. Over the remainder of the experimental course untreated diabetic control animals demonstrated relatively consistent elevations in sciatic nerve glucose, sorbitol and fructose. Although a significant, progressive reduction in sciatic nerve myo-inositol to 30% of onset values was observed over the first 84 days of the study, this was followed by a spontaneous partial recovery (31%) over the remainder of the experimental course. However, sciatic nerve myo-inositol levels at the end of the study were still significantly lower than onset values (P less than 0.01). Sorbinil treatment, initiated after 8 weeks of diabetes, and without effect on sciatic nerve glucose levels, normalized sorbitol concentrations following 4, 8, or 12 weeks of treatment but only partially reversed the accumulation of fructose by 368, 161 and 199%, compared to age-matched non-diabetic control values, at the above times, respectively. Mean myo-inositol levels were progressively increased following Sorbinil treatment over the experimental period, although the increase was only significant, compared to results from untreated diabetic animals, at weeks 4 and 16.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Increased nerve polyol levels in experimental diabetes and their reversal by Sorbinil. 314 96

Fresh intact human cataracts (derived from patients with mature-onset diabetes mellitus and from nondiabetic patients), normal human lenses between 2 and 71 years old and lenses derived from 1.5- to 5-kg rabbits were incubated in Earle's media containing enriched 13C-glucose (5 and 15 mM). 31P NMR organophosphate profiles were obtained at the start and end of each incubation. Sorbinil was added to one of each pair of selected lenses, both incubated with 13C-glucose. All the lenses were frozen after 4h of incubation and were subsequently assayed by 13C NMR spectroscopy. The results demonstrate significant sorbitol generation only in young lenses which can be inhibited by Sorbinil. None of the older normal and cataractous human lenses or the mature-onset diabetic cataracts were capable of generating measurable sorbitol levels although they all showed active glucose metabolism and their organophosphate profiles demonstrated normal high-energy phosphate levels. Increased sugar phosphate levels were usually found in the mature-onset diabetic cataracts. Although our NMR spectroscopy is only sensitive to 10(-3) M levels, such concentrations of sorbitol are required to exert their osmotic effects. These data indicate that high sorbitol levels can only be generated in young human and rabbit lenses and correlate well with the age-related changes in aldose reductase activity in these lenses.
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PMID:Sorbitol generation and its inhibition by Sorbinil in the aging normal human and rabbit lens and human diabetic cataracts. 323 92

Increased flux of glucose through the polyol pathway with resultant resultant accumulation of tissue sorbitol is implicated in the pathogenesis of the chronic complications of diabetes. Sorbinil is a potent inhibitor of aldose reductase (the first enzyme in the polyol pathway) and has been shown to normalize sorbitol levels in relevant tissues (eg, nerve, kidney, lens) of experimentally-induced diabetic animals. The purpose of this study was to identify a relatively noninvasive method of monitoring the intrinsic (or biochemical) efficacy of sorbinil in diabetic man. Specifically, the objective was to identify a readily accessible tissue that would be reflective of polyol pathway activity and the activity of sorbinil in clinically relevant but less accessible tissues. Based on several previous studies, which demonstrated that sorbitol accumulation in human red blood cells (RBCs) was a function of ambient glucose concentrations, either in vitro or in vivo, our investigations were conducted to determine if RBC sorbitol accumulation would correlate with sorbitol accumulation in lens and nerve tissue of diabetic rats; the effect of sorbinil in reducing sorbitol levels in lens and nerve tissue of diabetic rats would be reflected by changes in RBC sorbitol; and sorbinil would reduce RBC sorbitol in diabetic man.
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PMID:Applicability of red blood cell sorbitol measurements to monitor the clinical activity of sorbinil. 351 21

Aldose reductase is implicated in the pathogenesis of sugar cataracts; therefore, inhibition of this enzyme subsequent to cataractogenesis may represent a therapeutic approach for the restoration of lens physiology despite the persistence of diabetes or galactosemia. In the present study, the effect of aldose reductase inhibition subsequent to stage-I cataract formation was investigated in the galactose-maintained rat. Our results indicated that despite continuation of galactose feeding the aldose reductase inhibitor, Sorbinil, a spirohydantoin, arrested further progression and promoted a reparative process. Quantitative analysis of scanning electron micrographs indicated that the afflicted lens regions were contained and their cellular components stabilized with regard to fiber hydration and interdigitation. The reparative process involved: decrease in lens dulcitol, gradual recovery of fiber thickness and partial restoration of lens myo-inositol content. At this stage of cataractogenesis, despite continuance of galactose feeding, the effects of Sorbinil treatment were comparable to the reparative process achieved by restoration of a normal diet.
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PMID:Reversal of stage-I sugar cataract by Sorbinil, an aldose reductase inhibitor. 392 28

In a recently developed animal model, we investigated the pathogenesis of diabetic vascular disease and demonstrated that 125I-albumin permeation is markedly increased in new "granulation tissue" vessels formed in subcutaneous tissue after the onset of diabetes. The studies described in this report were undertaken to examine the effects of an aldose reductase inhibitor on diabetes-induced increases in vascular permeability in this animal model. 125I-albumin permeation was assessed 3 weeks after the subcutaneous implantation of sterile preweighed polyester fabric (to stimulate angiogenesis) in diabetic male Sprague-Dawley rats, in controls, and in diabetic rats given sorbinil approximately 12 or approximately 25 mg/kg/d mixed in ground rat chow. Sorbinil administration prevented the diabetes-induced increase in vascular permeability by approximately 60% at the lower dose and by approximately 80% at the higher dose without affecting body weight or plasma glucose levels. Diabetes-induced changes in tissue levels of sorbitol, myo-inositol, scyllo-inositol, and chiro-inositol were also prevented by the high dose of sorbinil (data were not obtained for the lower dose). These observations are consistent with evidence linking diabetic cataracts and neuropathy to imbalances in sorbitol/inositol metabolism and support the hypothesis that diabetic vascular disease as well as neuropathy and cataracts are mediated by excess metabolism of glucose through the polyol pathway. Furthermore, these observations suggest that increased vascular permeability associated with diabetic microangiopathy in humans may be prevented by inhibitors of aldose reductase without the need to normalize blood glucose levels.
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PMID:Diabetes-induced increases in vascular permeability and changes in granulation tissue levels of sorbitol, myo-inositol, chiro-inositol, and scyllo-inositol are prevented by sorbinil. 395 7


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