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)

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.
 ...
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

We report a patient, a twin, with diabetes mellitus whose hyperglycemic state fluctuated during the course of the pregnancy and the subsequent delivery. She was diagnosed as having slowly progressive IDDM because of her clinical course and the findings of serum positive ICA/CF, positive HLA-DR4 and disconcordance of diabetes mellitus with her identical twin. Insulin therapy was not initially needed in the first two years because the endogenous insulin secretion was not completely reduced. After two years of insulin therapy the patient became pregnant. Her glycemic control was remarkably improved without changes in dietary intake and insulin dosage. After delivery glycemic control deteriorated after delivery with the occurrence of postpartum thyroiditis. Urinary excretion of CPR was increased during pregnancy but decreased after delivery. ICA/CF in serum were persistently detected in the whole observation period. It seems that the improved glycemic control during pregnancy was caused by the reduction in the autoimmune reaction and the deterioration in glycemic control during the postpartum period was induced by the acceleration of the autoimmune reaction by the same mechanism of postpartum autoimmune thyroiditis.
Diabetes Res Clin Pract 1991 Sep
PMID:Insulin-dependent diabetes mellitus in which glycemic control was improved during pregnancy but deteriorated after delivery with the occurrence of postpartum thyrotoxicosis: a case report. 195 84

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.
 ...
PMID:Ponalrestat: a potent and specific inhibitor of aldose reductase. 210 33

Thirty diabetics who had been receiving ordinary insulin were switched to S-lente insulin, a new mixture of four parts semilente and six parts ultralente insulin. Eight times a day, we measured the glucose, insulin, and C-peptide (CPR) in their blood. Those with more than 250 mg/dl postprandial glucose were designated group A (18 patients) and the other were designated group B (12 patients). Group A diabetics experienced a significant decrease in fasting blood glucose levels whereas group B did not. S-lente improved the daily blood glucose profiles of 72% of group A and 25% of group B. It slightly reduced the sum of the daily blood glucose in group A and did not affect those of group B. The M-value fell significantly in group A but not in group B. Changes in this value correlated significantly with those of blood glucose determination sums. The sums of the determinations of free plasma insulin and CPR remained unaffected by the new insulin. It is concluded that S-lente insulin controls the blood glucose of diabetics whose postprandial blood glucose cannot be controlled by ordinary insulin.
Diabetes Res Clin Pract 1990 Jan
PMID:Effect of a new lente insulin on diabetics. 230 90

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.
 ...
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.
 ...
PMID:A superfamily of NADPH-dependent reductases in eukaryotes and prokaryotes. 250 40

Electromechanical dissociation (EMD) is the presenting rhythm in approximately 17% of all prehospital cardiorespiratory arrests. Yet, we know comparatively little about the demographic profile of these patients. The purpose of this study was to review historical and resuscitative parameters to help create a demographic profile. For a 6-year period of time from January 1st, 1980 to December 31st, 1985, 503 adult patients presented to a prehospital system in non-traumatic, nonpoisoned, cardiorespiratory arrest with an initial rhythm of electromechanical dissociation. The overall average response time was 6.1 +/- 3.2 min. Sixty percent of the patients were witnessed arrests and 65% had bystander initiated CPR. Forty-six percent of the patients had a cardiac history: myocardial infarction 13%, CHF 11% and other 21%. Other pertinent past medical history included diabetes 15%, COPD 10% and seizures 3%. The average age was 69.8 +/- 13.7 years. Fifty-seven percent were male. Forty-three percent were on cardiac medication including: digoxin, 24%; nitroglycerin, 12%; potassium supplements, 9%; propranolol, 8%; isordil, 6%; quinidine, 3%; nitropaste, 3%; and other cardiac medications, 15%. One hundred forty-eight (29%) patients developed a pulse at some time during resuscitative efforts, of these 17 (3.4%) patients responded with a pulse immediately after intubation. The mean time of resuscitation to sustaining pulse was 20 +/- 11 min and the mean resuscitation time to sustaining pressure was 22 +/- 11 min. Nineteen percent were successfully resuscitated, defined as a conveyance of a patient with a pulse and a rhythm to an emergency department. Four point four percent were saved, defined as a patient discharged alive from the hospital. Approximately 53% of the successfully resuscitated patients and 45% of the save patients were determined to have a probable respiratory event as the primary etiology of their arrest. This study attempts to provide some insight into the demographic profile of the patients in EMD.
 ...
PMID:Electromechanical dissociation: six years prehospital experience. 254 33

Fifty obese (BMI = 40.1 +/- 1.5) subjects (21 men and 21 women; average age 38.6 +/- 3.8 years) were prescribed a 600 cal/day diet (carbohydrates 30 g, proteins 60 g, lipids 10 g). Thirty patients were also given benfluorex (three tablets/day) for six months (Group A), whereas the other 20 patients (Group B) were treated with the dietary measures only. Apart from grade II and III obesity, several patients suffered from dyslipidaemia (Group A: n = 10; Group B: n = 7), non-insulin-dependent diabetes mellitus (NIDDM) (Group A: n = 4; Group B: n = 3) or IGT (Group A: n = 8; Group B: n = 6). The usual blood and biochemical tests and clinical examinations were carried out on Days 0, 90 and 180, together with the OGTT and glucagon test to determine blood glucose levels, IRI and CPR. There was no statistical difference between the weight loss of Group A and that of Group B. In Group A there was a statistically significant reduction (p less than 0.001) in total cholesterol, triglycerides, total/HDL-cholesterol and beta/alpha-lipoproteins and a significant increase in HDL-cholesterol and alpha-lipoproteins (p less than 0.001), whereas in Group B only a significant reduction in triglycerides (p less than 0.001) was observed. In NIDDM patients treated with benfluorex, normalisation of basal blood glucose levels was accompanied by an improvement in the OGTT blood glucose curve which was statistically significant relative to Group B. Benfluorex was well tolerated by all patients and no adverse event was reported.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Effects of benfluorex in obese patients with metabolic disorders. 259 99

Imipramine metabolism has been studied in both type I (streptozotocin-induced insulin-deficient) and type II (genetically insulin-resistant) diabetes in mice. In both types of diabetes, the formation of imipramine N-oxide is increased. In type I diabetes, desmethyl- and 2-hydroxyimipramine are additionally increased. The inhibition of imipramine metabolism by anti-cytochrome P-450 reductase antibodies led to the conclusion that cytochrome P-450-dependent monooxygenases are not involved in the N-oxidation of imipramine. This metabolic route is only supported by the flavin monooxygenase, whose activity is increased by diabetes. The pharmacological implications of altered imipramine metabolism in diabetic states are discussed in relation to the drug metabolism in human diabetes.
 ...
PMID:Effects of genetic or chemically induced diabetes on imipramine metabolism. Respective involvement of flavin monooxygenase and cytochrome P-450-dependent monooxygenases. 288 26

The effect of chemically-induced diabetes on the hepatic microsomal mixed-function oxidase system and the activation of chemical carcinogens was investigated in animals treated with streptozotocin (STZ). In order to distinguish between the effects of the diabetogenic chemical per se and that of the diabetic state, groups of STZ-treated animals received either nicotinamide simultaneously with STZ to prevent the onset of diabetes, or daily treatment with insulin in order to reverse the effects of diabetes. STZ-treated animals exhibited higher pentoxyresorufin O-dealkylase, ethoxy-resorufin O-deethylase, ethoxycoumarin O-deethylase, aniline p-hydroxylase and NADPH-cytochrome c reductase activities; similarly, increases were seen in cytochrome P-450 and b5 levels. All of these effects were prevented by nicotinamide and, at least partly, antagonised by insulin therapy. Treatment of animals with STZ markedly increased the activation, by liver microsomes in vitro, of Trp-P-1 and Trp-P-2 to mutagens, the effect being totally preventable by nicotinamide and successfully antagonised with insulin therapy. The diabetic animals were similarly more efficient in activating MeIQ but the effect was not preventable by nicotinamide or reversed by insulin. In contrast no changes were seen in the activation of IQ and only a modest increase in the case of MeIQx. It is concluded that diabetes may modulate the metabolic activation of some chemical carcinogens, presumably by changing the ratio of the various cytochrome P-450 isoenzymes.
 ...
PMID:Streptozotocin-induced diabetes modulates the metabolic activation of chemical carcinogens. 297 97


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>