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)

Enzyme activities along the kynurenine pathway were assayed in the tissues of New Zealand white rabbits made diabetic with alloxan treatment and hypercholesterolemic with a high-cholosterol diet. Activities are expressed as nmoles of product forming per min per mg of protein and per g of fresh tissue. Liver tryptophan 2,3-dioxygenase (TDO) was present only in holoenzyme form. This activity decreased in diabetic-hyperlipidemic and hyperlipidemic rabbits in comparison with healthy animals. Small intestine indole 2,3-dioxygenase was markedly higher than liver TDO in all rabbit groups, but did not show any significant difference in the values among the three groups. Mitochondrial kynurenine 3-monooxygenase activity was higher in liver than in kidney, but were unchanged with respect to controls. Kynureninase showed similar specific activities in the liver and kidney among groups, whereas the activity per g of fresh tissue was significantly lower in the liver of hyperlipidemic and kidney of diabetic-hyperlipidemic rabbits than in healthy animals. Kynurenine-oxoglutarate transaminase and kynureninase showed lower values in kidney, but not in liver, of diabetic-hyperlipidemic rabbits. However, 3-hydroxyanthranilate 3,4-dioxygenase activity was reduced in both liver and kidney of diabetic-hypercholesterolemic and hyperlipidemic rabbits compared with controls. Instead, aminocarboxymuconate-semialdehyde decarboxylase (picolinic carboxylase) activity was significantly higher in diabetic-hyperlipidermic rabbits in comparison with hyperlypidemic and control rabbits. Therefore, in diabetic rabbits, there is an alteration of tryptophan metabolism at the level of 3-hydroxyanthranilic acid --> nicotinic acid step, which has the effect of reducing the biosynthesis of NAD in diabetes.
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PMID:Metabolism of tryptophan along the kynurenine pathway in alloxan diabetic rabbits. 1520 55

Despite their inherited nature, familial dyslipidemias show large intra- and interfamilial variability in phenotypic expression, clinical presentations, and levels of abnormalities of serum lipid fractions. Once diagnosed, patients shall be considered at high cardiovascular risk and treated as per secondary prevention National Cholesterol Education Program III guidelines. Comorbidity treatments (ie, obesity, diabetes, and hypertension) are imperative. Lifestyle interventions shall soon be concomitantly followed by lipid-regulating drugs. The major aspects of the above interventions are the following: 1) therapeutic lifestyle change: regular aerobic exercises, conventional low-fat, low-cholesterol, low refined but high complex carbohydrates diet, avoidance of unproven fad diets (ie, Atkins); 2) plant stanols and sterol esters, 3) high-potency statins (eg, rosuvastatin, simvastatin, atorvastatin); 4) addition of nicotinic acid, bile acid binders, fibrates, or ezetimibe pending on the lipid fraction affected; 5) statins are the starting drug of choice with these exceptions: in isolated low-density lipoprotein cholesterol, niacin or fibrates may be preferable; in isolated severe hypertriglyceridemic conditions, fibrates or fish oil may be preferable; in children with isolated elevation of low-density lipoprotein cholesterol, ezetimibe or bile acid binders may be preferable; when serum lipoprotein (a) elevation is the most notable abnormality, niacin may be chosen as the initial drug for its unique effect on this fraction. Plasmapheresis, intestinal shunts, or liver transplantation are to be considered in that order as last resorts if the above fails to accomplish serum lipid level goals.
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PMID:Treatment of Familial Hypercholesterolemia and Other Genetic Dyslipidemias. 1521 22

The Adult Treatment Panel III (ATP III) of the National Cholesterol Education Program issued an evidence-based set of guidelines on cholesterol management in 2001. Since the publication of ATP III, 5 major clinical trials of statin therapy with clinical end points have been published. These trials addressed issues that were not examined in previous clinical trials of cholesterol-lowering therapy. The present document reviews the results of these recent trials and assesses their implications for cholesterol management. Therapeutic lifestyle changes (TLC) remain an essential modality in clinical management. The trials confirm the benefit of cholesterol-lowering therapy in high-risk patients and support the ATP III treatment goal of low-density lipoprotein cholesterol (LDL-C) <100 mg/dL. They support the inclusion of patients with diabetes in the high-risk category and confirm the benefits of LDL-lowering therapy in these patients. They further confirm that older persons benefit from therapeutic lowering of LDL-C. The major recommendations for modifications to footnote the ATP III treatment algorithm are the following. In high-risk persons, the recommended LDL-C goal is <100 mg/dL, but when risk is very high, an LDL-C goal of <70 mg/dL is a therapeutic option, ie, a reasonable clinical strategy, on the basis of available clinical trial evidence. This therapeutic option extends also to patients at very high risk who have a baseline LDL-C <100 mg/dL. Moreover, when a high-risk patient has high triglycerides or low high-density lipoprotein cholesterol (HDL-C), consideration can be given to combining a fibrate or nicotinic acid with an LDL-lowering drug. For moderately high-risk persons (2+ risk factors and 10-year risk 10% to 20%), the recommended LDL-C goal is <130 mg/dL, but an LDL-C goal <100 mg/dL is a therapeutic option on the basis of recent trial evidence. The latter option extends also to moderately high-risk persons with a baseline LDL-C of 100 to 129 mg/dL. When LDL-lowering drug therapy is employed in high-risk or moderately high-risk persons, it is advised that intensity of therapy be sufficient to achieve at least a 30% to 40% reduction in LDL-C levels. Moreover, any person at high risk or moderately high risk who has lifestyle-related risk factors (eg, obesity, physical inactivity, elevated triglycerides, low HDL-C, or metabolic syndrome) is a candidate for TLC to modify these risk factors regardless of LDL-C level. Finally, for people in lower-risk categories, recent clinical trials do not modify the goals and cutpoints of therapy.
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PMID:Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. 1524 16

Nicotinic acid effectively treats each of the common lipid abnormalities found in the metabolic syndrome, and much progress has recently been made in understanding its mechanisms of action. Early concern that nicotinic acid can precipitate or worsen diabetes has been eased with recent trials, which demonstrated its safety and effectiveness in insulin-resistant states. Furthermore, nicotinic acid prevents cardiovascular disease and death in persons with a high prevalence of risk factors for the metabolic syndrome. When used by an experienced physician and taken by a motivated patient, nicotinic acid can be safe and effective in treating the dyslipidemia of the metabolic syndrome.
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PMID:Management of the metabolic syndrome-nicotinic acid. 1526 97

The Adult Treatment Panel III (ATP III) of the National Cholesterol Education Program issued an evidence-based set of guidelines on cholesterol management in 2001. Since the publication of ATP III, 5 major clinical trials of statin therapy with clinical end points have been published. These trials addressed issues that were not examined in previous clinical trials of cholesterol-lowering therapy. The present document reviews the results of these recent trials and assesses their implications for cholesterol management. Therapeutic lifestyle changes (TLC) remain an essential modality in clinical management. The trials confirm the benefit of cholesterol-lowering therapy in high-risk patients and support the ATP III treatment goal of low-density lipoprotein cholesterol (LDL-C) <100 mg/dL. They support the inclusion of patients with diabetes in the high-risk category and confirm the benefits of LDL-lowering therapy in these patients. They further confirm that older persons benefit from therapeutic lowering of LDL-C. The major recommendations for modifications to footnote the ATP III treatment algorithm are the following. In high-risk persons, the recommended LDL-C goal is <100 mg/dL, but when risk is very high, an LDL-C goal of <70 mg/dL is a therapeutic option, ie, a reasonable clinical strategy, on the basis of available clinical trial evidence. This therapeutic option extends also to patients at very high risk who have a baseline LDL-C <100 mg/dL. Moreover, when a high-risk patient has high triglycerides or low high-density lipoprotein cholesterol (HDL-C), consideration can be given to combining a fibrate or nicotinic acid with an LDL-lowering drug. For moderately high-risk persons (2+ risk factors and 10-year risk 10% to 20%), the recommended LDL-C goal is <130 mg/dL, but an LDL-C goal <100 mg/dL is a therapeutic option on the basis of recent trial evidence. The latter option extends also to moderately high-risk persons with a baseline LDL-C of 100 to 129 mg/dL. When LDL-lowering drug therapy is employed in high-risk or moderately high-risk persons, it is advised that intensity of therapy be sufficient to achieve at least a 30% to 40% reduction in LDL-C levels. Moreover, any person at high risk or moderately high risk who has lifestyle-related risk factors (eg, obesity, physical inactivity, elevated triglycerides, low HDL-C, or metabolic syndrome) is a candidate for TLC to modify these risk factors regardless of LDL-C level. Finally, for people in lower-risk categories, recent clinical trials do not modify the goals and cutpoints of therapy.
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PMID:Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. 1529 92

The Adult Treatment Panel III (ATP III) of the National Cholesterol Education Program issued an evidence-based set of guidelines on cholesterol management in 2001. Since the publication of ATP III, 5 major clinical trials of statin therapy with clinical end points have been published. These trials addressed issues that were not examined in previous clinical trials of cholesterol-lowering therapy. The present document reviews the results of these recent trials and assesses their implications for cholesterol management. Therapeutic lifestyle changes (TLC) remain an essential modality in clinical management. The trials confirm the benefit of cholesterol-lowering therapy in high-risk patients and support the ATP III treatment goal of low-density lipoprotein cholesterol (LDL-C) <100 mg/dL. They support the inclusion of patients with diabetes in the high-risk category and confirm the benefits of LDL-lowering therapy in these patients. They further confirm that older persons benefit from therapeutic lowering of LDL-C. The major recommendations for modifications to footnote the ATP III treatment algorithm are the following. In high-risk persons, the recommended LDL-C goal is <100 mg/dL, but when risk is very high, an LDL-C goal of <70 mg/dL is a therapeutic option, ie, a reasonable clinical strategy, on the basis of available clinical trial evidence. This therapeutic option extends also to patients at very high risk who have a baseline LDL-C < 100 mg/dL. Moreover, when a high-risk patient has high triglycerides or low high-density lipoprotein cholesterol (HDL-C), consideration can be given to combining a fibrate or nicotinic acid with an LDL-lowering drug. For moderately high-risk persons (2+ risk factors and 10-year risk 10% to 20%), the recommended LDL-C goal is <130 mg/dL, but an LDL-C goal <100 mg/dL is a therapeutic option on the basis of recent trial evidence. The latter option extends also to moderately high-risk persons with a baseline LDL-C of 100 to 129 mg/dL. When LDL-lowering drug therapy is employed in high-risk or moderately high-risk persons, it is advised that intensity of therapy be sufficient to achieve at least a 30% to 40% reduction in LDL-C levels. Moreover, any person at high risk or moderately high risk who has lifestyle-related risk factors (eg, obesity, physical inactivity, elevated triglycerides, low HDL-C, or metabolic syndrome) is a candidate for TLC to modify these risk factors regardless of LDL-C level. Finally, for people in lower-risk categories, recent clinical trials do not modify the goals and cutpoints of therapy.
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PMID:Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. 1535 46

Nicotinic acid is a unique cholesterol modifying agent that exerts favorable effects on all cholesterol parameters. It holds promise as one of the main pharmacological agents to treat mixed dyslipidemia in metabolic syndrome and diabetic patients. The use of nicotinic acid has always been haunted with concerns that it might worsen insulin resistance and complicate diabetes management. We will discuss the interaction between phosphorous metabolism and carbohydrate metabolism and the possibility that worsening of insulin resistance could be related to a drug induced alteration in phosphorous metabolism, and the implications of that in medical management of diabetes and metabolic syndrome patients with mixed dyslipidemia.
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PMID:Are the effects of nicotinic acid on insulin resistance precipitated by abnormal phosphorous metabolism? 1551 Dec 97

Human L-xylulose reductase (XR) is an enzyme of the glucuronic acid/uronate cycle of glucose metabolism and is a possible target for treatment of the long-term complications of diabetes. In this study we utilised the molecular modelling program DOCK to analyse the 249,071 compounds of the National Cancer Institute Database and retrieved those compounds with high predicted affinity for XR. Several carboxylic acid-based compounds were tested and shown to inhibit XR. These included nicotinic acid (IC50=100 microM), benzoic acid (IC50=29 microM) and their derivatives. These results extend and improve upon the activities of known, commercially available inhibitors of XR such as the aliphatic fatty acid n-butyric acid (IC50=64 microM). To optimise the interaction between the inhibitor and the holoenzyme, the program GRID was used to design de novo compounds based on the inhibitor benzoic acid. The inclusion of a hydroxy-phenyl group and a phosphate to the benzoic acid molecule increased the net binding energy by 1.3- and 2.4-fold, respectively. The resultant compounds may produce inhibitors with improved specificity for XR.
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PMID:Structure-based discovery of human L-xylulose reductase inhibitors from database screening and molecular docking. 1559 53

Cardiovascular disease is the leading cause of mortality among people with diabetes mellitus, accounting for 70% of all deaths. As the prevalence of diabetes increases significantly worldwide, greater attention must be focused on preventing cardiovascular events in this group. One contributor to this increased event rate is the characteristic pattern of dyslipidemia in diabetic patients, consisting of elevated serum triglyceride levels, decreased high-density lipoprotein levels, and an increased proportion of small, dense, low-density lipoproteins. Several pharmacologic agents have been used to treat this dyslipidemia including HMG-CoA reductase inhibitors, fibric acid derivatives, niacin (nicotinic acid), thiazolidinediones, and fish oils, as well as other non-pharmacologic measures. Currently, the most extensive data for a reduction in cardiovascular events in patients with diabetes exist for HMG-CoA reductase inhibitors. The results of these trials indicate that HMG-CoA reductase inhibitor therapy should be considered for all patients with diabetes at sufficient risk for cardiovascular events, regardless of serum low-density lipoprotein-cholesterol level. Several ongoing trials of various pharmacologic agents should help clarify the role of these agents alone and in combination with HMG-CoA reductase inhibitors in the management of diabetic dyslipidemia.
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PMID:Management of diabetic dyslipidemia: need for reappraisal of the goals. 1572 39

Nicotinic acid has favorable effects on atherogenic dyslipidemia. However, in some patients who have diabetes, crystalline nicotinic acid decreases glycemic control; this effect could be due to a marked rebound of nonesterified fatty acids (NEFAs) observed after nicotinic acid suppression of lipolysis in adipose tissue. Recent reports have indicated that small doses of extended-release nicotinic acid do not cause a substantial decrease in glucose levels. Therefore, in this study, we examined whether 2 g/day of extended-release nicotinic acid abolishes the NEFA rebound that is reported with crystalline nicotinic acid. Seventeen men who had the metabolic syndrome (8 did not have type 2 diabetes and 9 did) were treated for 4 months. At baseline and at 4 months, measurements were made of plasma glucose, insulin, and NEFA during an oral glucose tolerance test. At 3 months, effects of extended-release nicotinic acid on NEFA levels and flux rates were determined on 3 separate days at 3 separate intervals after the final dose of nicotinic acid (4, 9, and 28 hours). Values obtained at 28 hours were taken as baseline (i.e., no nicotinic acid remaining in the circulation). After 4 hours (percent baseline), NEFA levels were -30% without diabetes and -37% with diabetes, and flux rates were -21% without diabetes and -25% with diabetes; after 9 hours, NEFA levels were 43% without diabetes and 50% with diabetes, and flux rates were 38% without diabetes and 70% with diabetes. Extended-release nicotinic acid did not abolish NEFA rebound. Nonetheless, the rebound was much less than previously reported for crystalline nicotinic acid. Moreover, after 4 months of nicotinic acid therapy, levels of NEFA, glucose, and insulin during the oral glucose tolerance test were not significantly different from those before institution of nicotinic acid therapy, suggesting minimal changes in insulin sensitivity.
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PMID:Influence of extended-release nicotinic acid on nonesterified fatty acid flux in the metabolic syndrome with atherogenic dyslipidemia. 1590 34


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