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

Many of the complications of diabetes seem to be due to aldose reductase (aldehyde reductase 2, ALR2) catalysing the increased conversion of glucose to sorbitol. Therapy with aldose reductase inhibitors (ARIs) could, therefore, decrease the development of diabetic complications. (2,6-Dimethylphenylsulphonyl)nitromethane (ICI 215918) is an example from a newly discovered class of ARIs, and we here describe its kinetic properties. Preparations of bovine lens ALR2 exhibit biphasic kinetics with respect to glucose and various inhibitors including ICI 215918. The inhibitor sensitive form (ALR2S) has a higher affinity for glucose than does the inhibitor insensitive form (ALR2I). Only ALR2S was characterized in detail because ALR2I activity is very low at physiological levels of glucose and is difficult to measure with accuracy. Aldehyde reductase (ALR1) is the most closely related enzyme to ALR2. Inhibition of ALR1 was, therefore, investigated in order to assess the specificity of ICI 215918. The values of Ki and Kies (dissociation constants for inhibitor from enzyme-inhibitor and enzyme-inhibitor-substrate complexes, respectively) for ICI 215918 with bovine kidney ALR1 and bovine lens ALR2S have been determined. When glucose is varied, the compound is an uncompetitive inhibitor of ALR2S (Kies = 0.10 microM and Ki is much greater than Kies), indicating that ICI 215918 associates with an allosteric site on the enzyme. These kinetic characteristics would cause a decrease in the concentration required to give 50% inhibition when glucose levels rise during hyperglycaemia. ICI 215918 is a mixed noncompetitive inhibitor of ALR1 (Ki = 10 microM and Kies = 1.8 microM) when glucuronate is varied. Thus, the compound has up to 100-fold specificity in favour of ALR2S relative to ALR1. Therapeutic interest has now centred upon at least three distinct structural types of ARIs: spirohydantoins, acetic acids and sulphonylnitromethanes. Using one representative of each type, we have demonstrated kinetic competition for inhibition of ALR2S. This observation strongly suggests that the different inhibitors use overlapping binding sites.
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PMID:(2,6-Dimethylphenylsulphonyl)nitromethane: a new structural type of aldose reductase inhibitor which follows biphasic kinetics and uses an allosteric binding site. 195 30

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

Aldehyde reductase [EC 1.1.1.2] and aldose reductase [EC 1.1.1.21] are monomeric NADPH-dependent oxidoreductases having wide substrate specificities for carbonyl compounds. These enzymes are implicated in the development of diabetic complications by catalyzing the reduction of glucose to sorbitol. Enzyme inhibition as a direct pharmacokinetic approach to the prevention of diabetic complications resulting from the hyperglycemia of diabetes has not been effective because of nonspecificity of the inhibitors and some appreciable side effects. To understand the structural and evolutionary relationship of these enzymes, we cloned and sequenced cDNAs coding for aldose and aldehyde reductases from human liver and placental cDNA libraries. Human placental aldose reductase (open reading frame of 316 amino acids) has a 65% identity (identical plus conservative substitutions) to human liver and placental aldehyde reductase (open reading frame of 325 amino acids). The two sequences have significant identity to 2,5-diketogluconic acid reductase from corynebacterium, frog rho-crystallin, and bovine lung prostaglandin F synthase (reductase). Southern hybridization analysis of human genomic DNA indicates a multigene system for aldose reductase, suggesting the existence of additional proteins. Thus, the aldo-keto reductase superfamily of proteins may have a more significant and hitherto not fully appreciated role in general cellular metabolism.
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PMID:The aldo-keto reductase superfamily. cDNAs and deduced amino acid sequences of human aldehyde and aldose reductases. 249 33

Aldose reductase (AR) is implicated in some of the disabling complications of diabetes, including neuropathy, retinopathy and cataracts. Our studies are aimed at further clarifying the role of AR in diabetes and facilitating the design of new classes of potent, specific AR inhibitors by gaining an understanding of the protein structure of AR. To this end, we have determined the complete protein sequence of rat lens AR using cDNA analysis and primer extension of mRNA. By comparing protein sequences, we have found that the structural relatedness (41% to 57%) among the vertebrate proteins, aldose reductase, aldehyde reductase, prostaglandin F synthase and the frog lens protein rho-crystallin can now be extended to prokaryotes by the inclusion of Corynebacterium 2,5-diketo-D-gluconate reductase. This more distantly related protein shares 30-40% identity with the vertebrate enzymes. Sequence alignments reveal that 18% of the amino acids are completely conserved in all members of the superfamily, many of them in clusters, suggesting that they mark important structural features such as the nucleotide binding site and substrate binding site. rho-Crystallin, which is structurally related to this superfamily of NADPH-dependent reductases, does not appear to reduce PGH2, PGD2, xylose or glyceraldehyde to any appreciable extent. It does, however, bind NADPH.
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PMID:A superfamily of NADPH-dependent reductases in eukaryotes and prokaryotes. 250 40

We report a case of limbic encephalopathy clinically characterized by a progressive amnestic syndrome and many EEG seizures mainly localized on the left temporal area. Biological investigations revealed diabetes mellitus and a syndrome of inappropriate antidiuretic hormone secretion (IADH). Haemodynamic and metabolic studies by positron-emission tomography showed an important increase in cerebral blood flow (CBF) and cerebral metabolic rate of oxygen on the left anterior temporal region precisely where the electrical seizures were recorded. Nine months later, severe disorders of memory and a dramatic decrease in CBF and CMRO2 on the same area region were present. At autopsy, a small size oat cell bronchial carcinoma was found with metastases in two small adjacent lymph nodes. Neuropathological examination showed atrophy (neuronal loss, protoplasmic gliosis) in the amygdala; where there was in addition an area of nodular gliosis. The hippocampus and parahippocampal gyrus lesions were severe on the left and moderate on the right side. The authors discuss the nosology of their case in the paraneoplastic syndromes and, with a review of the literature, the role of ADH and cellular hyperactivity in the pathogenesis of specifically localized neuronal alterations.
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PMID:[Paraneoplastic limbic encephalopathy, inappropriate ADH secretion and recurrent subclinical epileptic seizures. Clinical, anatomo-pathological and metabolic correlations by positron emission tomography]. 282 90

The effect of experimental diabetes on the activity of liver alcohol dehydrogenase was studied in males and females of two strains of rats. Alloxan diabetes of 8 weeks duration increased the activity of alcohol dehydrogenase in Sprague-Dawley males by about 50%. This effect was also observed in rats rendered diabetic with streptozotocin. However, there was no increase in the enzyme activity in female Sprague-Dawley rats. The magnitude of the increase was much less in diabetic Wistar-Kyoto males than in Sprague-Dawley males. Plasma concentrations of thyroxine were lower in diabetic animals than in controls, but this effect of diabetes did not correlate with changes in alcohol dehydrogenase activity. There was no reduction in plasma testosterone concentration in diabetic Sprague-Dawley rats. Growth hormone levels were not increased in the diabetic rats. The mechanism of the increase in liver alcohol dehydrogenase activity in diabetic male Sprague-Dawley rats is unknown.
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PMID:The effect of experimental diabetes on liver alcohol dehydrogenase activity in rats. 293 14

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

Previous work has shown that induction of a high-affinity NADPH-dependent nitrosodimethylamine demethylase (NDMAd) in liver microsomes occurs in rats due to fasting, ethanol consumption, and streptozotocin-induced diabetes. Several lines of observations suggest that this is due to the induction of specific cytochrome P-450 isozymes. Induction of P-450 species by ethanol has also been observed by other investigators. Since each of the above altered metabolic states has in common elevated levels of ketone bodies, the possible role of acetone, a known inducer of NDMAd, in the induction of the demethylase activity was investigated. Levels of endogenous acetone in fasted rats correlated (r = 0.72) with a three- to fourfold increase in NDMAd activity. However, a dose-response experiment showed endogenous levels of acetone to be capable of causing at most 40% of the induction in fasted rats. This suggests that other ketone bodies or factors may have contributed to the induction. The induction of NDMAd by ethanol was enhanced by alcohol dehydrogenase inhibitors pyrazole and acetaldehyde oxime, suggesting that ethanol, rather than its metabolites, was responsible for the induction.
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PMID:Studies on the mechanisms of induction of N-nitrosodimethylamine demethylase by fasting, acetone, and ethanol. 670 8

A new method was developed for the estimation of arginine vasopressin (AVP) in plasma and urine. Samples were extracted by a microcolumn of resin and assayed radioimmunologically using a highly sensitive antiserum to AVP. Ion-exchange resin, CG-50, H+ form, packed in a small column (diameter 4 mm, height 6 mm), was proved effective to remove the interfering substances and to concentrate the AVP in the sample. The application of 80% acid acetone successive to diluted HCl brought about a consistent recovery of AVP from the resin column. Recoveries were 66.4 +/- 8.5% for plasma and 85.4 +/- 9.7% for urine. In normal subjects plasma AVP levels were 3.9 +/ 0.3 pg/ml (mean +/- S.D.) in ambulatory states, 4.9 +/- ).6 after overnight fast, and 0.4 +/- 0.2 after water lading. High levels of 2.0 +/- 24.2 pg/ml were obtained in patinents with syndrome of inappropriate secretion of ADH (SIADH), low values of 0-1.8 pg/ml in diabetes inipidus. Urinary excretions of AVP were 117.4 +/- 59.4 ng/24/hr (mean +/- S.D.) in normal controls, 191 +/- 177.0/24 hr in SIADH, and 17.0 +/- 12.0/24 hr in diabetes insipidus.
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PMID:Radioimmunoassay of arginine vasopressin in human plasma and urine, a resin microcolumn method. 740 74

Transcellular shifts of water and changes in the physiology of water excretion are common in diabetes mellitus and its treatment. Recent evidence indicates that hyperglycemia in diabetic patients, but not in normal subjects, is characterized by elevations of circulating levels of arginine vasopressin (AVP; antidiuretic hormone, ADH). The role and importance of these observations remain to be defined since elevations of plasma AVP levels do not decrease water excretion in diabetic patients. Certain oral sulfonylureas, notably chlorpropamide and tolbutamide, are known to decrease renal free water clearance (CH2O), whereas insulin increases CH2O; the insulin and tolbutamide effects may be clinically trivial, whereas that of chlorpropamide is important. The hyponatremic effect of chlorpropamide may be exaggerated in diabetic patients by concomitant diuretic therapy. Euglycemia during chlorpropamide therapy appears to allow full expression of the action of chlorpropamide on CH2O; hyperglycemia with attendant osmotic diuresis protects chlorpropamide-treated patients against hyponatremia. Inhibition of prostaglandin synthesis with nonsteroidal anti-inflammatory agents enhances expression of the ADH effect on the kidney, but it does not appear to potentiate chlorpropamide hyponatremia. Two other oral sulfonylurea agents, tolazamide and glyburide, increase CH2O. Diazoxide is an antihypertensive thiazide which is antidiuretic as well as hyperglycemic. Thus, abnormalities of water metabolism are common in diabetes mellitus. Whether certain of these abnormalities are clinically important depends upon the presence of the osmotic diuresis of hyperglycemia and the pharmacology of diabetic management.
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PMID:Water metabolism in diabetes mellitus. 745 88


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