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)

Non-insulin-dependent diabetes mellitus is frequently associated with premature atherosclerosis. Abnormalities in lipid and lipoprotein metabolism contribute to the increased risk of coronary heart disease. One of the most common lipid abnormalities in non-insulin-dependent diabetes mellitus is hypertriglyceridaemia. In the present paper, the authors review the metabolism of triglyceride-rich lipoproteins, with special emphasis on the post-prandial state. Several studies have demonstrated that levels of atherogenic post-prandial lipoproteins are increased in patients with non-insulin-dependent diabetes mellitus. An increased supply of glucose and free fatty acids contributes to overproduction of very low-density lipoproteins, increasing the burden of triglyceride-rich lipoproteins on the common lipolytic pathway at the level of lipoprotein lipase. Low lipoprotein lipase activity and increased amounts of lipolysis-inhibiting free fatty acids further impair lipolysis of post-prandial lipoproteins. The clearance of atherogenic remnants is also delayed in non-insulin-dependent diabetes mellitus. There is evidence that a relative hepatic removal defect exists, secondary to impaired remnant-receptor interaction and increased competition with very low density lipoprotein remnants. Correction of the increased post-prandial lipaemia in non-insulin-dependent diabetes mellitus is advisable, as it may contribute to attenuation of the risk on premature atherosclerosis. When dietary measures and hypoglycaemic agents have failed to achieve acceptable lipid levels, lipid-lowering drugs should be advised. Fibric acids and hydroxymethyl-glutaryl coenzyme A (HMG CoA) reductase inhibitors are the drugs of choice.
 ...
PMID:Triglyceride-rich lipoproteins in non-insulin-dependent diabetes mellitus: post-prandial metabolism and relation to premature atherosclerosis. 890 18

Treatment of hypercholesterolemia with HMG-CoA-reductase inhibitors has revolutionized medical intervention towards the prevention of coronary artery disease. There is a wide sprectrum of patients with diverse underlying clinical conditions that may benefit from treatment using these agents. These include patients with multiple risk factors, individuals following major vascular events, and those with special conditions that are associated with accelerated atherosclerosis. The latter include patients with severe, dominantly inherited hypercholesterolemia, patients with major organ dysfunction such as chronic renal failure, and individuals after transplantation. Multimodality intervention includes behavior modification and mechanical as well as pharmacological treatment. It is aimed at several important targets: cholesterol reduction, control of hypertension and diabetes, improvement of myocardial contractility, reduction of infarct size, and control of hemostasis. Most of these patients require multiple drugs, which may interact at the pharmacodynamic (efficacy and safety) as well as pharmacokinetic levels. These potential interactions should be considered while planning and implementing preventive measures for an individual as well as for the community. The beneficial effects and the potential hazardous interactions between HMG-CoA reductase inhibitors and other medications are presented and discussed using two models: heterozygous familial hypercholesterolemia and major organ transplantation. Although there is a partial overlap in the medications used for the treatment of these two conditions, some of them differ. The interaction between HMG-CoA reductase inhibitors and other cholesterol-lowering agents, mainly fibrates, is discussed in the first model summarizing data from controlled clinical trials. The interaction with cyclosporin A is presented using the second model. A potential benefit of fluvastatin, as compared with other currently available HMG-CoA reductase inhibitors, which may be related to its relatively short plasma half-life and low systemic exposure, is discussed.
 ...
PMID:Targeted prevention of coronary artery disease: pharmacological considerations in multimodality treatment. 890 72

The increased incidence of thyroiditis reported to occur in diabetes has also been observed in long-term galactose-fed dogs where it is reduced by the administration of aldose reductase inhibitors. Since this suggests that thyroidal changes are linked to the abnormal accumulation of sugar alcohols (polyols), present studies were conducted to confirm the presence of aldose and aldehyde reductases in dog thyroid through isolation and characterization. Aldose and aldehyde reductases were isolated from dog thyroid by a series of chromatographic steps which included gel filtration on Sephadex G-100, affinity chromatography on Matrex Gel Orange A and chromatofocusing on Mono P. A third, labile NADPH-reductase was partially purified by gel filtration on Sephadex G-100, affinity chromatography on Matrex Green A and hydroxylapatite chromatography on BIO-GEL HT. The kinetic properties of aldose and aldehyde reductases and their susceptibility to inhibition by aldose reductase inhibitors are similar to those of dog kidney aldose and aldehyde reductases. However, the levels of aldose reductase present in thyroid are extremely low compared to the levels of aldehyde reductase. A third NADPH-dependent reductase, tentatively identified as glyceraldehyde reductase, is also present in dog thyroid. This novel enzyme utilizes NADPH to reduce DL-glyceraldehyde and is clearly distinct from the other aldo-keto reductases in molecular weight, substrate specificity, inhibition by aldose reductase inhibitors and immunological properties. In summary aldose reductase, aldehyde reductase and a third novel glyceraldehyde reductase, all of which can utilize glyceraldehyde as substrate, have been identified and characterized in dog thyroid. Only aldose and aldehyde reductases, which can catalyze the production of polyols and were inhibited by aldose reductase inhibitors, appear to be linked to thyroiditis.
 ...
PMID:NADPH-dependent reductases in dog thyroid: comparison of a third enzyme "glyceraldehyde reductase" to dog thyroid aldehyde reductase. 892 Jun 36

Recent reports suggest that excess amounts of sugar alcohol are linked to leukocyte dysfunctions associated with diabetes. As the polyol pathway has not been firmly established in leukocytes, we have investigated NADPH-dependent reductases and sugar alcohol formation in dog leukocytes. NADPH-dependent reductase activity was observed with DL-glyceraldehyde as substrate in both mononuclear and polymorphonuclear leukocytes isolated from dog. By chromatofocusing, this activity corresponded primarily to aldehyde reductase rather than aldose reductase. The enzymatic conversion of glucose to the sugar alcohol sorbitol in leukocytes was confirmed in vitro by 19F nuclear magnetic resonance (NMR) spectroscopy using 3-deoxy-3-fluoro-D-glucose as substrate. The NMR spectrum obtained after incubation with 10 Mm 3-deoxy-3-fluoro-D-glucose at 37 degrees C for 24 h displayed newly formed 3-deoxy-3-fluoro-D-sorbitol and 3-deoxy-3-fluoro-D-fructose peaks with both mononuclear and polymorphonuclear leukocytes. Sugar alcohol production in leukocytes from galactose-fed dogs was also observed in vivo. Galactitol accumulation was consistently observed by gas chromatography to occur in mononuclear cells while only trace amounts of galactitol were observed in polymorphonuclear leukocytes. Activation of NADPH oxidase activity in neutrophils isolated from galactose-fed dogs by zymosan was also significantly reduced compared to that of nongalactosemic control dogs. These results indicate that glucose is converted to fructose through sorbitol in both mononuclear and polymorphonuclear leukocytes despite the observations that these cells primarily contain aldehyde reductase rather than aldose reductase. In vivo, sugar alcohol accumulation in mononuclear cells is greater than in polymorphonuclear leukocytes.
J Diabetes Complications
PMID:Polyol pathway and NADPH-dependent reductases in dog leukocytes. 897 81

Mild hyperhomocysteinemia has been identified as a risk factor for arterial disease and for venous thrombosis. Individuals homozygous for the thermolabile variant of the methylene tetrahydrofolate reductase gene (MTHFR) which results from a common mutation Ala677-->Val and is found in 5-15% of the general population, have significantly elevated plasma homocysteine levels and may account for one of the genetic risk factors in vascular disease. We have analyzed the prevalence of MTHFR-T homozygotes in patients with arterial disease or venous thrombosis. We studied 191 patients with arterial disease and 127 individuals with venous thrombosis and compared with 296 unmatched controls. The results showed that there was a high prevalence of homozygotes for the mutated MTHFR-T allele among a group of patients with arterial disease (19%) in the absence of hyperlipoproteinemia, hypertension, and diabetes mellitus when compared to controls (4%), odds ratio of 5.52 (95% C.I., 2.27 to 13.51). The prevalence of homozygotes among patients with venous thrombosis was 11%, odds ratio of 2l93 (95% C.I., 1.23 to 7.01). The risk of venous thrombosis remained high, odds ratio of 2.63, even after we excluded 27 patients with hereditary thrombophilia (e.g. factor V Leiden, dysfibrinogenemia, deficiency of protein C, protein S, antithrombin III, or factor XII) from the 127 overall cases with venous thrombosis. These data support the hypothesis that being a homozygote for the MTHFR-T is a risk factor for the development of arterial disease and also for venous thrombosis.
 ...
PMID:The mutation Ala677-->Val in the methylene tetrahydrofolate reductase gene: a risk factor for arterial disease and venous thrombosis. 918 84

One-third of diabetic patients are affected by peripheral neuropathy (PDN) in which the main aetiopathogenetic mechanism seems to be the high blood and nerve glucose content. The results of some long term trials, such as the Diabetes Control and Complications Trial (DCCT) and Stockholm studies, showed clearly that the maintenance of near-normal blood glucose levels and haemoglobin (Hb)A1c below 7.5% with intensive insulin treatment represents the best approach to primary and secondary prevention of the late diabetic complications, including PDN. After 5 years of such treatment DCCT reported that the development of clinical PDN was reduced by 64%. On the other hand, various and important problems still exist in identifying an efficacious aetiological therapy for PDN. In fact, while on the basis of current knowledge we have 2 possibilities for treatment of the pain, optimisation of glycaemic and HbA1c values and correct use of tricyclic antidepressants, none of the various substances tested has proven to be efficacious for PDN. Gangliosides, aldose-reductase inhibitors, including tolrestat, gamma-linolenic acid, levacecarnine (acetyl-L-carnitine) and antioxidants, were all shown to be of poor efficacy and often with significant adverse effects. The maintenance of near-normal glycaemic equilibrium seems currently to be the best way not only to prevent PDN but also to treat it. In the near future more long term trials, with very clear inclusion and exclusion criteria for recruitment, are needed to assist in identifying an efficacious treatment for PDN.
 ...
PMID:Peripheral diabetic neuropathy. Current recommendations and future prospects for its prevention and management. 927 3

Thyroid hormone is known to affect androgen metabolism, however, there are few studies in which alterations of androgen metabolism are simultaneously examined in patients with clinical thyroid disorders. In this study, we investigated the alterations of thyroid hormone and androgens before and during treatment in patients with hyperthyroidism. Fifteen female patients with hyperthyroidism due to Graves' disease were studied. From these patients, blood samples were obtained before treatment and at 1 month (M), 2M, 3M, 4M and 6M after beginning of treatment. Concentrations of free T4(FT4), free T3(FT3), testosterone (T), androstenedione (delta 4A), dihydrotestosterone (DHT), 5 alpha-androstane-3 alpha, 17 beta-diol(3 alpha-diol) and androsterone (AD) and sex hormone binding globulin (SHBG) were measured by radioimmunoassays (RIAs) or immunoradiometric assay (IRMA). As normal controls, ten healthy women were also studied. Before treatment concentrations of DHT (mean +/- SD: 3.35 +/- 0.78 nmol/L), 3 alpha-diol (0.78 +/- 0.11 nmol/L), AD (6.73 +/- 0.64 nmol/L) and SHBG (184.9 +/- 68.1 nmol/L) were significantly elevated compared with those of normal controls. T and delta 4A levels were not significantly different from normal values. DHT/T ratio indicating 5 alpha-reductase activity was 4.62 +/- 2.55 and significantly higher than that in normal controls. At 2 months after beginning of treatment with anti-thyroid drugs, thyroid function (FT4 and FT3) became normal and at 3 months after beginning of treatment, DHT, 3 alpha-diol, AD and DHT/T ratio decreased to normal range. SHBG level was gradually decreased, however still higher than that of the normal control group at 6 months after beginning of treatment. There was a time lag in recovery between serum androgen levels and SHBG level.
Exp Clin Endocrinol Diabetes 1997
PMID:Serum androgen levels in hyperthyroid women. 943 33

Diabetes complicates 2-3% of all pregnancies and is associated with an increase in both perinatal morbidity and mortality, though reasons for these adverse outcomes are unknown. Estrogen biosynthesis is a critical factor during pregnancy and is carried out in the placenta via aromatase (cytochrome P450 19A1), which catalyzes the conversion of C-19 androgens to C-18 estrogens. Previous studies have shown that hormones such as insulin-like growth factors and insulin regulate aromatase activity when studied in vitro. Interestingly, levels of these hormones are altered in patients with diabetes. Thus, we hypothesized that the presence of maternal diabetes may alter placental aromatase activity and thus estrogen biosynthesis, possibly serving as one factor in the adverse outcomes of babies born to mothers with diabetes. To this end, we measured the production of 19-hydroxyandrostenedione, 19-oxoadrostenedione and estrone in 30 placental tissues from diabetic patients, using [7-3H]androst-4-ene-3,17-dione as a model substrate for aromatase (P450 19A1). A statistical difference was detected in the percentage of 19-oxoandrostenedione formed between the overt and control groups (P < 0.05). Additionally, NADPH P450-reductase levels were measured in these same tissues to determine whether alterations in this enzyme necessary for aromatase activity could be affected by diabetes. No differences in reductase levels were detected among the patient groups. However, a statistical correlation was found between NADPH P450-reductase activity and the formation velocities of all three estrogen products (P < 0.05). Thus, it appears that the presence of diabetes does not affect placental aromatase activity.
 ...
PMID:The effects of diabetes on placental aromatase activity. 944 16

Patients with diabetes mellitus (DM), type 1 and type 2, have an increased risk of coronary heart disease as a result of accelerated atherosclerosis. Dyslipidemia, often found in these patients, plays an important role in this process. This study investigates the efficacy and safety of lipid-lowering therapy with pravastatin, a 3-HMG-Coenzym A reductase inhibitor in hypercholesterolemic type-1 and type-2 diabetic patients. Of 49 patients (22 type-1 DM and 27 type-2 DM), 24 patients were treated with pravastatin, 20 mg/day, and 25 patients with placebo. After 24 weeks, total cholesterol (TC) was decreased by 22.2%, low-density lipoprotein (LDL) cholesterol by 25.8% and triglycerides (TG) by 13.6%. Pravastatin treatment did not induce a significant change in high-density (HDL) cholesterol levels. No differences in effects of pravastatin treatment on serum lipids and lipoproteins were found with respect to the diabetes type. No serious side effects occurred and pravastatin treatment did not cause any deterioration in glycemia control. The data suggest that pravastatin is effective and safe in the treatment of dyslipidemia in both type-1 and type-2 diabetic patients.
 ...
PMID:Pravastatin in diabetes-associated hypercholesterolemia. 945 75

Oxidative stress and dyslipidaemia are key features of diabetes mellitus and may be involved in mediating the vascular endothelial dysfunction associated with this disease. The aim of this study was to examine the effect of dietary lipid-lowering and antioxidant agents on vascular endothelial function and oxidative stress. Diabetic male Sprague-Dawley rats (i.v. streptozotocin, 45 mg/kg) were fed for 4 weeks on a standard diet or on a diet supplemented with either the lipid-lowering antioxidant probucol (1% w/w in diet) or the 3-hydroxy 3-methylglutaryl coenzyme-A (HMG-CoA) reductase inhibitor simvastatin (0.01% w/w in diet). Responses to noradrenaline, acetylcholine, and sodium nitroprusside were assessed in small mesenteric arteries (mean internal diameter 300+/-5 microm, n = 80) mounted on a small vessel myograph. Plasma concentrations of total cholesterol and triglycerides were significantly raised in standard-fed diabetic rats and significantly reduced in probucol and simvastatin-fed diabetic rats 8-epi-prostaglandin (PG)F2alpha, an indicator of oxidative stress, was raised in liver and aorta from diabetic rats compared to controls. Probucol supplementation reduced 8-epi-PGF2alpha in aorta and liver of diabetic rats but increased 8-epi-PGF2alpha content in plasma and aorta from control animals. The abnormal relaxation to acetylcholine in arteries from the diabetic rats (pEC550 diabetic 6.763+/-0.172 vs control 7.541+/-0.175; p < 0.05) was not improved by probucol or simvastatin. These data, therefore, do not support a role for oxidative stress or dyslipidaemia in mediating the impaired ACh-induced endothelium-dependent relaxation of small mesenteric arteries from the streptozotocin-diabetic rat.
 ...
PMID:Endothelial dysfunction in streptozotocin-diabetic rats is not reversed by dietary probucol or simvastatin supplementation. 949 48


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