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

Decreased sciatic nerve myo-inositol content and Na+-K+-ATPase activity have been associated with slowing of motor nerve conduction in the acutely diabetic rat and have been invoked as possible pathogenic factors in diabetic peripheral neuropathy. Aldose reductase inhibitors prevent these abnormalities in peripheral nerves of the streptozocin (STZ)-diabetic rat. Whether an analogous biochemical abnormality occurs in the autonomic nervous system and plays a role in the development of diabetic autonomic dysfunction is unknown. Therefore we examined the effect of 8 wk of untreated STZ diabetes and administration of 20 mg X kg-1 X day-1 of the aldose reductase inhibitor sorbinil on myo-inositol level and Na+-K+-ATPase activity in rat superior cervical ganglia. Both myo-inositol concentration and Na+-K+-ATPase activity were reduced in ganglia from untreated STZ-diabetic rats, and sorbinil administration prevented these abnormalities. Thus, a sorbinil-responsive metabolic defect involving myotional abnormalities in the somatic and autonomic nervous systems in diabetes.
Diabetes 1986 Oct
PMID:Decreased myo-inositol content and Na+-K+-ATPase activity in superior cervical ganglion of STZ-diabetic rat and prevention by aldose reductase inhibition. 301 4

Slowing of nerve conduction, a hallmark of both experimental and human diabetic neuropathy, is improved or corrected by aldose reductase inhibitors such as sorbinil. Animal experiments suggest that a myo-inositol-related defect in nerve sodium-potassium adenosine triphosphatase (ATPase) is responsible for the acute reversible slowing of nerve conduction in diabetes mellitus. This myo-inositol-related defect is at present viewed as a cyclic metabolic defect. Aldose reductase inhibitors have been shown to restore to normal both the myo-inositol content and the sodium-potassium ATPase activity of nerve. This suggests that the acute effects of aldose-reductase inhibitors on nerve conduction in both diabetic animals and human patients may be modified by the correction of an underlying myo-inositol-related defect of nerve sodium-potassium ATPase. Furthermore, this myo-inositol-related defect may contribute to other biochemical, functional and structural abnormalities of diabetic peripheral neuropathy.
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PMID:Sorbitol, myo-inositol and sodium-potassium ATPase in diabetic peripheral nerve. 302 50

During the past decade, our appreciation of the original experiments with myo-inositol supplementation in diabetic rats has greatly expanded. The effects of myo-inositol on nerve conduction are now explained by concepts that were largely unappreciated in 1976, including the fundamental role of phosphoinositide metabolism in cell regulation and the importance of the activity of sodium-potassium-ATPase in nerve conduction. Aldose reductase inhibitors firmly link defects in myo-inositol metabolism to activation of the polyol pathway in diabetes; the resulting "sorbitol-myo-inositol hypothesis" has been extended from its application to the lenses and peripheral nerves to most of the tissues involved with diabetic complications. These biochemical mechanisms provide a new framework within which to explore the complex interactions between hyperglycemia and the vascular, genetic, and environmental variables in the pathogenesis of diabetic complications. It is anticipated that these endeavors will result in the appearance of new classes of therapeutic agents, the first of which--the aldose reductase inhibitors--has emerged from the laboratory and is now undergoing extensive clinical testing. These efforts are very likely to result in the appearance of new treatment methods that may dramatically lighten the burden of chronic complications in patients with diabetes.
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PMID:Sorbitol, phosphoinositides, and sodium-potassium-ATPase in the pathogenesis of diabetic complications. 302 58

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

In diabetic cataracts aldose reductase initiates the cataractous process by converting glucose to sorbitol. The ensuing osmotic change, caused by sorbitol accumulation, adversely affects the lens permeability barrier so that the distribution within the lens of electrolytes, amino acids, and myo-inositol becomes grossly altered. These changes affect lens viability resulting in opacification. That aldose reductase triggers the process is shown by the fact that several structurally unrelated aldose reductase inhibitors prevent cataracts from occurring. Aldose reductase is also implicated in diabetic retinopathy and keratopathy. Aldose reductase functions in the retinal capillary pericytes, the cells first affected in microvascular abnormalities in diabetes. Additionally, retinal capillary basement membrane thickening can be prevented by aldose reductase inhibitors. Clinical trials are underway to determine the efficacy and safety of aldose reductase inhibitors in treatment of diabetic retinopathy.
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PMID:Aldose reductase in the diabetic eye. XLIII Edward Jackson memorial lecture. 309 7

Aldose reductase (AR) is an enzyme which catalyzes the transformation of D-glucose to sorbitol. Under non physiological conditions, like diabetes for example, the accumulation of polyols in the lens, sorbitol in particular, gives a basis to the osmotic hypothesis of cataract formation. AR inhibitors can protect against such accumulation. Oxidation of the constituents of the lens is a primary phenomenon in cataract formation, and some authors have suggested that the autoxidation of monosaccharides would originate the formation of cataract. For these authors, AR inhibitors would act by trapping the radical intermediates formed, inhibiting the denaturation of proteins in the organ and the lowering of glutathione. There classes of AR inhibitors can be distinguished: flavonoids and their related compounds, spirohydantoins--like sorbinil--and related compounds, and compounds with an acid function such as alrestatine. For each of these three classes, the authors try to establish the structure-activity relationship of the molecules. The possibility of a single site of interaction between AR and the different AR inhibitors is discussed. Differences in the inhibitory effect for a given compound between species, and for one species between tissues have been underlined.
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PMID:[Aldose reductase inhibitors]. 310 88

Aldose reductase [aldehyde reductase 2; alditol:NAD(P)+ 1-oxidoreductase, EC 1.1.1.21] catalyzes conversion of glucose to sorbitol. Although its activity is implicated in the progression of ocular and neurological complications of diabetes, the normal function of the enzyme in most cells is unknown. Both aldose reductase activity and substantial levels of sorbitol were previously reported in renal inner medullary cells. In this tissue, the extracellular NaCl concentration normally is high and varies considerably depending on the urine concentration. We report here on a line of renal medullary cells in which medium that is high in NaCl greatly increases both aldose reductase activity and intracellular sorbitol. In these tissue culture cells (and presumably also in the renal inner medulla), the intracellular sorbitol helps balance the osmotic pressure of elevated extracellular NaCl and thus prevents cellular dehydration.
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PMID:Induction of aldose reductase and sorbitol in renal inner medullary cells by elevated extracellular NaCl. 310 2

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

Before any clinical signs of diabetic retinopathy can be detected, two major histopathological lesions occur in the walls of retinal capillaries: basement membrane thickening; and loss of intramural pericytes (mural cells). A decrease in the number of pericyte to endothelial cell junctions also occurs under diabetic conditions and may result in subsequent proliferation of endothelial cells and microaneurysm formation. Aldose reductase inhibitors prevent all these diabetic microangiopathies of the retina in animal models of diabetes and are presently being tested in clinical trials on diabetic retinopathy. Utilization of aldose reductase inhibitors is a novel approach which would potentially provide a very effective diabetic therapy to be used in addition to insulin.
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PMID:Prevention of diabetes-related retinal microangiopathy with aldose reductase inhibitors. 315 Jun 50

Peripheral neuropathy in diabetes begins as a physiologic aberration related to hyperglycemia and its subsequent effects of endoneurial hypoxia, elevated sorbitol levels, and decreased myoinositol levels. Resultant decreases in sodium-potassium-adenosine triphosphatase levels ultimately lead to structural alterations at the nodes of Ranvier. Aldose reductase inhibitors and dietary myoinositol supplementation are being used in long-term clinical studies to monitor the possibility that they may prevent or reverse these abnormalities. In the meantime, symptomatic treatment remains the mainstay of management.
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PMID:Management of peripheral neuropathy in diabetes mellitus. Recent research findings and their therapeutic implications. 330 36


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