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)

The objectives of this study were to determine the relationships among Type II diabetes (T2DM)-dependent elevations in platelet-derived reactive oxygen species (ROS), platelet-surface protein disulfide isomerase (psPDI) NO-releasing activity, and platelet aggregation and to evaluate the efficacy of rosuvastatin in normalizing these parameters in primary cells derived from a hamster model of prediabetic insulin resistance induced by fructose feeding. Platelets from rosuvastatin-treated non-fructose-fed (NFF) and fructose-fed (FF) hamsters were analyzed for aggregability and psPDI-denitrosation activity. Platelets from NFF animals treated with xanthine/xanthine oxidase (X/XO) were assessed for the same parameters and primary aortic endothelial cells (AEC) cultivated with a range of [rosuvastatin] +/- mevalonate were analyzed for ROS production. Platelets from FF hamsters displayed statistically significant enhanced ROS production, diminished psPDI-mediated NO-releasing activity, and hyperaggregability. Suggestively, platelets from NFF animals treated with X/XO displayed characteristics similar to platelets from FF animals. Rosuvastatin elicited a normalizing effect on all parameters measured in platelets from FF animals. Further, ROS production in primary AEC from FF animals could be blunted to that of NFF animals by concentrations of rosuvastatin in the range of those achieved in the bloodstream. Diminished psPDI-dependent NO-releasing activity and increased initial aggregation rates of FF platelets may result from elevated vascular ROS production under conditions of insulin resistance. Normalization of ROS production and platelet aggregation by rosuvastatin indicates its potential use as a vasculoprotective agent.
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PMID:Antioxidant and antiplatelet effects of rosuvastatin in a hamster model of prediabetes. 1718 32

Dyslipidaemia is an important risk factor for the development of chronic kidney disease (CKD) and cardiovascular disease (CVD). CKD generates an atherogenic lipid profile, characterised by high triglycerides, low high-density lipoprotein (HDL) cholesterol and accumulation of small dense low-density lipoprotein (LDL) particles, comparable to that in the metabolic syndrome. These changes are due specifically to the effects of CKD on key enzymes, transfer proteins and receptors involved in lipid metabolism. Dyslipidaemia is further compounded by dialysis, immunosuppressive drugs, and concomitant diseases such as diabetes mellitus. Post hoc analyses from large intervention trials suggest the benefit of statins in patients with early CKD, but prospective clinical trials in haemodialysis (HD) and renal transplant recipients have not conclusively shown improvements in hard cardiovascular end-points. The lack of efficacy of statins in late-stage CKD could be a consequence of other disease processes, such as calcific arteriopathy and insulin resistance, which are not modified by lipid-lowering agents. Despite uncertainty and pending the results of ongoing statin trials such as Study of Heart and Renal Protection (SHARP) and AURORA (A study to evaluate the Use of Rosuvastatin in subjects On Regular haemodialysis: an Assessment of survival and cardiovascular events), major international guidelines continue to support statin therapy in CKD and renal transplant patients to reduce cardiovascular risk burden. Because of increased risk of toxicity, particularly myopathy, statins and other lipid-regulating agents should be used cautiously in CKD and renal transplant recipients.
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PMID:Dyslipidaemia and cardiorenal disease: mechanisms, therapeutic opportunities and clinical trials. 1734 61

In diabetes the exposure of the vascular endothelium to high glucose levels results in increased oxidative insult and in vascular dysfunction. We have investigated the effects of rosuvastatin on oxidative stress and apoptosis induced in human umbilical vein endothelial cells (HUVECs) by constant and intermittent high glucose levels. HUVECs were incubated for 14 days in either low (5 mM) or high (20 mM) glucose concentrations, or intermittent high and low glucose on a daily basis. Constant high glucose levels increased p47-phox, p67-phox, and p22-phox expression [components of the Nicotinamide adenine dinucleotide phosphate [NAD(P)H] oxidase complex]; endothelial nitric oxide synthase, nitric oxide, and O(2)(-) production; nitrotyrosine, 8-hydroxy-2'-deoxyguanosine, and caspase-3 expression; and reduced Bcl-2 expression. These effects were significantly greater under intermittent compared to constant high/low glucose conditions. The effect of rosuvastatin (1 microM) in the presence or absence of mevalonate (200 microM) was evaluated in the cells under both constant and intermittent glucose conditions. Rosuvastatin almost normalized all these parameters. These effects of rosuvastatin were prevented when mevalonate was also added, demonstrating the link to inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase. These data suggest that rosuvastatin has the potential to prevent damage to and apoptosis of HUVECs induced by high glucose exposure, by reducing oxidative stress. The action of rosuvastatin on antioxidant pathways is related to the inhibition of the overexpression of components of NAD(P)H oxidase induced by the two conditions of high glucose.
J Diabetes Complications
PMID:The protective effect of rosuvastatin in human umbilical endothelial cells exposed to constant or intermittent high glucose. 1819 Oct 76

Calcific aortic stenosis (AS) is a progressive disease that has, until recently, been considered to be a degenerative and unmodifiable process induced by long-lasting mechanical stress. However, histopathologic studies have now demonstrated that the development and progression of calcific AS is based on an active process, sharing a number of similarities with atherosclerosis. Inflammation, lipid infiltration, dystrophic calcification, ossification, platelet deposition and endothelial dysfunction have been observed in both diseases. In addition, several studies have suggested that AS and atherosclerosis share a number of risk factors, such as hypercholesterolemia, elevated lipoprotein (a), smoking, hypertension and diabetes. These findings suggest that statin therapy could be beneficial in AS by its lipid-lowering and/or anti-inflammatory effects, as is the case in atherosclerosis. Although this concept has been supported by experimental work and by four retrospective clinical studies observing significantly slower rates of hemodynamic progression in statin-treated patients, a prospective randomized trial (Scottish Aortic Stenosis and Lipid Lowering Trial, Impact on Regression [SALTIRE]; 80mg of atorvastatin vs placebo) yielded a negative result. In contrast to the retrospective analyses, according to the study protocol, patients with hyperlipidemia had to be excluded in this trial. A recent prospective study (Rosuvastatin Affecting Aortic Valve Endothelium [RAAVE]) treating hypercholesteremic patients with rosuvastatin, found a significantly slower rate of progression in these patients compared with patients with normal cholesterol levels who were left untreated, suggesting that statin therapy may only be beneficial in patients with hyperlipidemia. Lipid-lowering therapy with statins can, therefore, currently only be recommended in this subgroup of patients with AS.
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PMID:Aortic sclerosis, aortic stenosis and lipid-lowering therapy. 1832 97

Morbidity and mortality in patients who have heart failure (HF) remains substantial, and new therapies are needed. Tantalizing evidence from experimental studies, retrospective analyses, and limited prospective clinical investigations have suggested that statin therapy may improve ventricular function, HF status, and clinical outcomes independently of HF etiology and through mechanisms other than statin effects on dyslipidemia. The Controlled Rosuvastatin in Multinational Trial in Heart Failure (CORONA) is the first prospective randomized clinical outcome trial with statins focused specifically on HF. Over a median follow-up of 33 months, there were no significant differences in the primary end point or in all-cause mortality, the rate of coronary events, effects on New York Heart Association class, or the rate of newly diagnosed diabetes. There were significant reductions in the number of cardiovascular hospitalizations and, in a post hoc analysis, in nonfatal ischemic events. The discrepancy between the results from previous observational studies and the results of the CORONA trial emphasizes the importance of prospective randomized clinical outcome trials.
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PMID:Randomized clinical outcome trials of statins in heart failure. 1843 3

Atherothrombosis of the coronary and cerebral vessels is understood to be a disorder of inflammation and innate immunity, as well as a disorder of lipid accumulation. From a vascular biology perspective, the processes of cellular adhesion, monocyte and macrophage attachment, and transmigration of immune cells across the endothelium are crucial steps in early atherogenesis and in the later stages of mature plaque rupture, particularly the transition of unstable plaque at the time of acute thrombosis. There is abundant clinical evidence demonstrating that many biomarkers of inflammation are elevated years in advance of first ever myocardial infarction (MI) or thrombotic stroke and that these same biomarkers are highly predictive of recurrent MI, recurrent stroke, diabetes, and cardiovascular death. In daily practice, the inflammatory biomarker in widest use is high-sensitivity C-reactive protein (hsCRP); when interpreted within the context of usual risk factors, levels of hsCRP <1, 1 to 3, and >3 mg/l denote lower, average, and higher relative risk for future vascular events. Risk-prediction models that incorporate hsCRP, such as the Reynolds Risk Score, have been developed that improve risk classification and the accuracy for global risk prediction, particularly for those deemed at "intermediate risk" by usual algorithms, such as the Framingham Risk Score. With regard to cerebral vessels, increased biomarkers of inflammation, including hsCRP, have been associated with increased stroke risk as well as an increased rate of atherosclerosis progression in the carotid vessels. Although the proportion of variation in hsCRP explained by genetic factors may be as large as 20% to 40%, diet, exercise, and smoking cessation remain critical tools for risk reduction and CRP reduction. Statin therapy reduces hsCRP in a largely low-density lipoprotein (LDL)-independent manner, and the "anti-inflammatory" properties of these agents have been suggested as a potential mechanism beyond LDL reduction for the efficacy of these agents. The ongoing multinational Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial of 17,802 initially healthy men and women with low levels of LDL cholesterol but increased levels of hsCRP will help to define whether vascular protection can be achieved with statin therapy, even in the absence of hyperlipidemia. Targeted anti-inflammatory therapies are being developed that may provide a direct method of translating the biology of inflammation into new clinical treatments across multiple vascular beds. This article summarizes data supporting a role for inflammation in cardiovascular disease and offers the possibility that other disorders characterized by inflammation, such as periodontal disease, may have an indirect role by influencing the risk, manifestation, and progression of vascular events.
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PMID:Inflammation, C-reactive protein, and atherothrombosis. 1867 9

The JUPITER trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) (N Engl J Med 2008; 359:2195-2207) compared rosuvastatin (Crestor) 20 mg daily vs placebo in apparently healthy people who had levels of low-density lipoprotein cholesterol (LDL-C) lower than 130 mg/dL but elevated levels (>or= 2 mg/L) of high-sensitivity C-reactive protein (hs-CRP). Rosuvastatin treatment lowered LDL-C levels by 50% and hs-CRP levels by 37%, accompanied by a 44% relative risk reduction in the composite end point of unstable angina, revascularization, and confirmed death from cardiovascular causes. In absolute terms, 95 people had to be treated over 2 years to prevent one event. There was, however, a higher incidence of diabetes in the rosuvastatin group.
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PMID:Jupiter to earth: a statin helps people with normal LDL-C and high hs-CRP, but what does it mean? 1912 9

High levels of high-sensitivity C-reactive protein (hs-CRP) are an independent cardiovascular marker, which may be reduced by statin therapy. JUPITER is a randomised clinical trial that compares the effects of rosuvastatin 20 mg (n = 8901) and placebo (n = 8901) in apparently healthy individuals, without hyperlipidaemia (LDL < 130 mg/dl; median 108 mg/dl), but with moderately elevated hs-CRP levels (> 2 mg/l; median 4.25 mg/l). Rosuvastatin reduced LDL cholesterol by 50% (to a median of 55 mg/dl) and hs-CRP by 37%. The trial, which should last 5 years, was stopped after a median follow-up of 1.9 years because of an imbalance in favour of the rosuvastatin group. Indeed, when compared to placebo, rosuvastatin was associated with a relative risk reduction in the composite primary end point of 44%, in myocardial infarction of 54%, in stroke of 48%, in revascularization procedures or hospitalisations for unstable angina of 47%, in major cardiovascular events (myocardial infarction, stroke and death) of 47% and in deaths from any cause of 20%. Consistent effects were observed in all subgroups evaluated. The only adverse event was a higher incidence of physician-reported diabetes in the rosuvastatin group compared to the placebo group. This study demonstrates that rosuvastatin 20 mg reduces the incidence of cardiovascular events, including total mortality, in apparently healthy persons without hyperlipidaemia, but with elevated hs-CRP. However, the design of the trial does not allow discriminating which part of the favourable effect results from the drastic reduction in LDL cholesterol and which part results from the reduction in hs-CRP stricto sensu.
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PMID:[JUPITER: reduction by rosuvastatin of cardiovascular events and mortality in healthy subjects without hyperlipidaemia but with elevated C-reactive protein]. 1918 Aug 37

The recent JUPITER (Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin) trial is another study providing evidence about the effectiveness of statin therapy in reducing cardiovascular risk. Yet, in this study significantly higher glycated hemoglobin levels and incidence rates of diabetes were observed in persons treated with rosuvastatin than the placebo group. It should be noted that adverse effects on glucose metabolism have already been reported, albeit rarely, in previous trials with statins. Although the exact mechanisms involved are unknown, it seems that statins may deteriorate glycemic control by decreasing different metabolites, including isoprenoid and ubiquinone, normally produced during the process of cholesterol synthesis. We therefore suggest that, if statins are prescribed, patients should be monitored closely for blood glucose control even though the higher incidence of diabetes by statin therapy may represent a rare finding.
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PMID:Is diabetes the cost to pay for a greater cardiovascular prevention? 1929 38

CRP levels are strong, independent predictors of cardiovascular risk and can enhance risk stratification. Jupiter enrolled 17 802 apparently healthy middle-aged men and women with CRP levels over 2.0 mg/l, and LDL less than 130 mg/dl. They were randomized to receive rosuvastatin 20 mg daily or placebo, and followed for a primary endpoint of nonfatal myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or cardiovascular death for 1.9 years. Rosuvastatin lowered CRP (37%), LDL (50%), nonfatal myocardial infarction (55%), nonfatal stroke (48%), hospitalization and revascularization (47%), all-cause mortality (20%), and benefited women and minority subgroups. Rosuvastatin was tolerated relatively well, with a small rise in physician-reported diabetes. Jupiter data suggest that patients with high levels of CRP should receive statins. Approximately 4.3% of the population satisfies Jupiter inclusion criteria. A review of the assessment of cardiovascular risk is under way at the National Institutes of Health to guide practitioners.
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PMID:The Jupiter study, CRP screening, and aggressive statin therapy-implications for the primary prevention of cardiovascular disease. 1946 Aug 29


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