Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

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.
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PMID:Targeted prevention of coronary artery disease: pharmacological considerations in multimodality treatment. 890 72

Cytosolic and mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthases were first recognized as different chemical entities in 1975, when they were purified and characterized by Lane's group. Since then, the two enzymes have been studied extensively, one as a control site of the cholesterol biosynthetic pathway and the other as an important control site of ketogenesis. This review describes some key developments over the last 25 years that have led to our current understanding of the physiology of mitochondrial HMG-CoA synthase in the HMG-CoA pathway and in ketogenesis in the liver and small intestine of suckling animals. The enzyme is regulated by two systems: succinylation and desuccinylation in the short term, and transcriptional regulation in the long term. Both control mechanisms are influenced by nutritional and hormonal factors, which explains the incidence of ketogenesis in diabetes and starvation, during intense lipolysis, and in the foetal-neonatal and suckling-weaning transitions. The DNA-binding properties of the peroxisome-proliferator-activated receptor and other transcription factors on the nuclear-receptor-responsive element of the mitochondrial HMG-CoA synthase promoter have revealed how ketogenesis can be regulated by fatty acids. Finally, the expression of mitochondrial HMG-CoA synthase in the gonads and the correction of auxotrophy for mevalonate in cells deficient in cytosolic HMG-CoA synthase suggest that the mitochondrial enzyme may play a role in cholesterogenesis in gonadal and other tissues.
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PMID:Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase: a control enzyme in ketogenesis. 1005 25

Serum coenzyme Q10 (CoQ10: 2-(3,7,11,15,19,23,27,31,35,39-decamethyl-2,6,10,14,18,22,26,30,34 ,38 -tetracontadecaenyl)-5,6-dimethoxy-3-methyl-1,4-benzoquinone, CAS 303-98-0) and cholesterol levels were measured to assess the effect of cholesterol-lowering therapy in patients with non-insulin-dependent diabetes mellitus (NIDDM). Twenty healthy volunteers, 97 NIDDM patients and 2 patients with familial hypercholesterolemia were studied. None had overt heart failure or any other heart disease. Mean serum CoQ10 concentrations were significantly (p < 0.01) lower in diabetic patients with normal serum cholesterol concentrations, either with or without administration of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (HMG-CoA RIs) including simvastatin (normal: 0.91 +/- 0.26 (mean +/- SD) mumol 1(-1); diabetic with HMG-CoA RI: 0.63 +/- 0.19; diabetic without HMG-CoA RI: 0.66 +/- 0.21). CoQ10 concentrations were higher (1.37 +/- 0.48, p < 0.001) in diabetic patients with hypercholesterolemia. Simvastatin or low density lipoprotein apheresis decreased serum CoQ10 concentrations along with decreasing serum cholesterol. Oral CoQ10 supplementation in diabetic patients receiving HMG-CoA RI significantly (p < 0.001) increased serum CoQ10 from 0.81 +/- 0.24 to 1.47 +/- 0.44 mumol 1(-1), without affecting cholesterol levels. It significantly (p < 0.03) decreased cardiothoracic ratios from 51.4 +/- 5.1 to 49.2 +/- 4.7%. In conclusion, serum CoQ10 levels in NIDDM patients are decreased and may be associated with subclinical diabetic cardiomyopathy reversible by CoQ10 supplementation.
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PMID:Effect of treatment with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on serum coenzyme Q10 in diabetic patients. 1033 51

Recent lipid intervention studies led to the implementation of lipid lowering therapy in the cardiovascular risk management. These secondary as well as primary prevention studies share the effect of HMG-CoA-reductase inhibition. Despite varying product properties there seem to be no major differences in risk reduction between the drugs. One could argue the main action of the statins, lipid lowering, is the most prominent mode of action. A new study (AirForce/Texas Coronary Atherosclerosis Prevention Study) extended that to patients with relatively low total cholesterol levels (mean 221 mg/dl with a slightly lowered LDL-C of 37 mg/dl, LDL-C of 150 mg/dl) successfully treated with lovastatin in primary prevention. That supports the concept to reach lipid levels as low as possible in the longer term, even if the absolute clinical event reduction in primary prevention is not so impressive. On the contrary, in secondary prevention: in the AVERT-study in patients with a 82% mean stenosis in one vessel PTCA-treated patients with conventional drug therapy were compared to such without PTCA and aggressive lipid lowering therapy (resulting LDL-C 77 mg/dl). One could be surprised that the "intervention group" was not better, though representing the usual clinical procedere. Interestingly, borderline significant (p < 0.046 at a level of significance of p < 0.045), results were in favor for the drug treated group. Such data could, if confirmed in further investigations, change cardiovascular disease management to aggressive lipid lowering prior to or instead invasive management, especially in initial therapy of CVD and diabetes mellitus type II.
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PMID:[Statins--attaining goal values--with reference to recent studies]. 1040 6

In clinical trials, all lipid-lowering agents have been associated with mild, asymptomatic elevations of alanine aminotransferase (ALT) and asparate aminotransferase enzymes. This, along with the fact that 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors are hepatotoxic in some animals, led the US Food and Drug Administration (FDA) to recommend monitoring of liver enzymes for all lipid-lowering agents, except the bile acid sequestrants. Because the drugs act by different mechanisms, ALT elevations may be a pharmacodynamic effect related to lipid lowering, rather than a direct effect of the drug. Animal studies support this assumption. ALT elevations of 3 times the upper limit of normal occur in <3% of patients in clinical trials of lipid-lowering drugs. The elevations are transient and often dose-related, and they usually revert to normal while continuing therapy and have never been associated with hepatotoxicity. Confounding factors include alcohol, acetaminophen, and pre-existing liver disease, such as chronic hepatitis C and type II diabetes with fatty liver, which are both associated with mild, intermittent elevations of ALT. The more important issue is whether or not lipid-lowering agents are hepatotoxic. There are case reports of hepatotoxicity (cholestasis, jaundice, hepatitis, chronic active hepatitis, fatty liver, cirrhosis and acute liver failure) with all of the drugs, except cholestyramine. To date there are just 5 cases of documented liver failure linked to lovastatin. There is no evidence that monitoring reduces the rate of hepatotoxicity. Mild elevations of ALT that occur with many drugs, including HMG-CoA reductase inhibitors, do not predict hepatotoxicity. Liver enzyme elevations appear to be a class characteristic of lipid-lowering agents. Hepatotoxicity is a rare idiosyncratic reaction, occurring only with sustained released nicotinic acid.
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PMID:Defining patient risks from expanded preventive therapies. 1085 89

In cardiovascular pharmacotherapy, the main focus is now on statins (HMG-CoA-reductase inhibitors) because of their antihyperlipidaemic and antiatherogenic effect. They are suggested to be beneficial also in senile dementia, stroke and osteoporosis and they can reduce incidence of ventricular arrhythmias in patients with cardioverter-defibrillator. In chronic heart failure, statins should be used with caution since reduced cholesterol levels relate to impaired survival. As an alternative to statins and fibrates, niacin therapy may be considered. ACE inhibitors are of proven benefit for patients with left ventricular dysfunction after acute myocardial infarction; however, in long-term treatment, their protective activity is not superior to that of beta-blockers, diuretics and clonidine. Ca-channel antagonists slightly increase the incidence of cardiovascular complications but reduce the incidence of stroke in high-risk patients. Biventricular pacing has been used with success in patients with severe heart failure and conduction disturbances, and the first permanent artificial ventricle was implanted to a patient with irreversible terminal heart failure in summer 2000. Cardiospecific troponin I may be an uninvasive marker of a procoagulant status indicating e.g. graft failure after cardiac transplantation; T-cadherin belongs to the cell-adhesion molecules and has a role in maintenance of cellular contacts which are critical for the vessel wall architecture. Etamoxir, originally developed for the treatment of diabetes II, has recently been shown to be a potential novel drug for heart failure. Routine use of nitric oxide after congenital heart surgery lessens the risk of pulmonary hypertensive crises.
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PMID:[Cardiology 2000]. 1137 23

Besides hyperglycemia and hypertension, a recently recognized risk factor for diabetic retinopathy (DR) appears to be hyperlipidemia. While studies using earlier generation lipid lowering agents in DR were disappointing, a randomized trial using HMG-CoA Reductase Inhibitors has strong rationale, though hitherto not attempted. The aim of the present study was to compare the HMG-CoA Reductase Inhibitor, simvastatin, with placebo in patients having DR in a double-blind randomized placebo-controlled trial. Fifty patients with diabetes mellitus (Type 1 and 2) with good glycemic control and hypercholesterolemia and having DR (non-clinically significant macular edema and visual acuity 6/24 or better) in either or both eyes were randomized to simvastatin 20-mg per day or placebo, and were followed up for 180 days. On simvastatin therapy, total cholesterol and low-density lipoprotein cholesterol (LDL-C) decreased (P < 0.001, respectively), and the level of high-density lipoprotein cholesterol (HDL-C) increased (P < 0.001). VA improved in four patients using simvastatin, (not statistically different from placebo group) and worsening of VA occurred in seven patients in the placebo group and none in the simvastatin group (P = 0.009). Fundus fluorescein angiography and color fundus photograph showed improvement in one patient in the simvastatin group, while seven patients showed worsening in the placebo group (P = 0.009). The observations of the current study suggest that the HMG-CoA Reductase Inhibitor simvastatin significantly retards the progression of retinopathy in diabetic patients with hypercholesterolemia. The potential of this class of drugs for the primary prevention of DR and other microvascular complications needs to be explored further.
Diabetes Res Clin Pract 2002 Apr
PMID:Simvastatin retards progression of retinopathy in diabetic patients with hypercholesterolemia. 1187 15

Nutrient secretagogues can increase the production of succinyl-CoA in rat pancreatic islets. When succinate esters are the secretagogue, succinyl-CoA can be generated via the succinate thiokinase reaction. Other secretagogues can increase production of succinyl-CoA secondary to increasing alpha-ketoglutarate production by glutamate dehydrogenase or mitochondrial aspartate aminotransferase followed by the alpha-ketoglutarate dehydrogenase reaction. Although secretagogues can increase the production of succinyl-CoA, they do not increase the level of this metabolite until after they decrease the level of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). This suggests that the generated succinyl-CoA initially reacts with acetoacetate to yield acetoacetyl-CoA plus succinate in the succinyl-CoA-acetoacetate transferase reaction. This would be followed by acetoacetyl-CoA reacting with acetyl-CoA to generate HMG-CoA in the HMG-CoA synthetase reaction. HMG-CoA will then be reduced by NADPH to mevalonate in the HMG-CoA reductase reaction and/or cleaved to acetoacetate plus acetyl-CoA by HMG cleavage enzyme. Succinate derived from either exogenous succinate esters or generated by succinyl-CoA-acetoacetate transferase is metabolized to malate followed by the malic enzyme reaction. Increased production of NADPH by the latter reaction then increases reduction of HMG-CoA and accounts for the decrease in the level of HMG-CoA produced by secretagogues. Pyruvate carboxylation catalyzed by pyruvate carboxylase will supply oxaloacetate to mitochondrial aspartate aminotransferase. This would enable this aminotransferase to supply alpha-ketoglutarate to the alpha-ketoglutarate dehydrogenase complex and would, in part, account for secretagogues increasing the islet level of succinyl-CoA after they decrease the level of HMG-CoA. Mevalonate could be a trigger of insulin release as a result of its ability to alter membrane proteins and/or cytosolic Ca(2+). This is consistent with the fact that insulin secretagogues decrease the level of the mevalonate precursor HMG-CoA. In addition, inhibitors of HMG-CoA reductase interfere with insulin release and this inhibition can be reversed by mevalonate.
Diabetes 2002 Sep
PMID:The succinate mechanism of insulin release. 1219 57

Disturbances in nitric oxide (NO) metabolism resulting in endothelial dysfunction play a central role in the pathogenesis of atherosclerosis in hypercholesterolemia and in individuals with type 2 diabetes. It is unclear whether lipid lowering therapy with HMG-CoA-reductase inhibitors might improve endothelial function in subjects with type 2 diabetes as it is demonstrated in non-diabetic subjects with hypercholesterolemia. We examined the influence of 0.2 mg and 0.8 mg cerivastatin on endothelial function in a multicenter, randomised, double-blind, and three-arm placebo-controlled clinical trial. Endothelial function was assessed by nitric oxide-dependent flow mediated vasodilatation (FMD) of the brachial artery. A total of 103 patients with type 2 diabetes were enrolled in the study. Bayer Company undertook a voluntary action to withdraw cerivastatin from market, therefore the study was terminated earlier. At this point 77 patients were randomised, of which 58 completed the study (mean age 60 +/- 8 years, HbA1c 7.4 +/- 0.9 %). At baseline mean FMD was disturbed in all three therapy arms (5.18 +/- 2.31 % in the placebo group, 3.88 +/- 1.68 in the 0.2-mg cerivastation group, and 4.86 +/- 2.25 in the 0.8-mg cerivastatin group). Despite a significant reduction in cholesterol and LDL-cholesterol-levels after 12 weeks of treatment (decrease in LDL-cholesterol - 26.8 +/- 13.9 % in the 0.2-mg group and - 40.3 +/- 16.0 % in the 0.8-mg group, p = 0.0001, ANCOVA) there was no difference in flow mediated vasodilatation (p = 0.52 and p = 0.56 vs. placebo, respectively, ANCOVA). HbA1c, CRP, and HDL-cholesterol did not change during the study. Furthermore no difference in safety profile between cerivastatin and placebo was found. Despite a significant improvement in lipid profile under statin therapy, no improvement of endothelial dysfunction in terms of nitric oxide bioavailability could be detected.
Exp Clin Endocrinol Diabetes 2005 Jun
PMID:Intense cholesterol lowering therapy with a HMG-CoA reductase inhibitor does not improve nitric oxide dependent endothelial function in type-2-diabetes--a multicenter, randomised, double-blind, three-arm placebo-controlled clinical trial. 1597 99

Simvastatin, a widely used 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitor, effectively reduced cardiac death and ischemic events in patients with coronary heart disease (CHD) and diabetes mellitus (DM). The mechanism of cardiovascular benefits of statins in DM remains unclear. We examined how simvastatin influences the levels of several in vivo markers for coagulation and fibrinolysis in 26 Type 2 DM patients. The diabetic patients received 20 mg/day of simvastatin up to 12 months. The levels of total cholesterol (TC), low density lipoprotein-cholesterol (LDL-c) and triglycerides in peripheral circulation of patients were significantly reduced after > or =6 weeks of simvastatin treatment. Levels of prothrombin fragment 1+2 (F1+2), factor VII, plasminogen activator inhibitor-1 (PAI-1) and tissue factor pathway inhibitor (TFPI) antigens, but not tissue plasminogen activator (tPA) antigen, in the pre-simvastatin plasmas of the diabetic patients were significantly higher than the levels found in plasmas of healthy subjects. Significant reductions in F1+2 and PAI-1 levels were evident > or =6 weeks after the diabetic patients received simvastatin. Levels of total tPA, TFPI, FVII, hemoglobin A1c, fasting blood glucose, and insulin in the diabetic patients' plasma were not significantly altered by simvastatin treatment. Positive correlations were found between PAI-1 versus TC, PAI-1 versus LDL-c, and FVII versus triglycerides in the plasmas of simvastatin-treated patients. The results suggest that simvastatin reduces in vivo prothrombinase activity and PAI-1 levels in type 2 DM patients. These actions may contribute to the protective properties of simvastatin against ischemic events in diabetic patients.
Diabetes Res Clin Pract 2005 Nov
PMID:Impact of simvastatin on hemostatic and fibrinolytic regulators in Type 2 diabetes mellitus. 1618 73


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