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)

Flavonoids have been identified as the antidiabetic components in a number of traditional ethnic remedies. However, the mechanisms whereby these compounds exert their hypoglycemic and hypolipidemic action in type-2 diabetes have rarely been investigated. Therefore, this study investigated the effect of the flavonoids hesperidin and naringin on glucose and lipid regulation in C57BL/KsJ-db/db mice. Hesperidin and naringin both significantly increased the glucokinase mRNA level, while naringin also lowered the mRNA expression of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase in the liver. In addition, the hepatic glucose transporter 2 protein expression was significantly reduced, while the expression of adipocyte glucose transporter 4 and hepatic and adipocyte peroxisome proliferator-activated receptor gamma were elevated in the hesperidin and naringin groups when compared with the control group. Furthermore, hesperidin and naringin effectively lowered the plasma free fatty acid and plasma and hepatic triglyceride levels, and simultaneously reduced the hepatic fatty acid oxidation and carnitine palmitoyl transferase activity. These changes were seemingly attributable to a suppression of the hepatic fatty acid synthase, glucose-6-phosphate dehydrogenase, and phosphatidate phosphohydrolase activities and an increase in the fecal triglycerides. The two flavonoids also led to a decrease in the plasma and hepatic cholesterol levels that may have been partly due to the decreased hepatic 3-hydroxy-3-methylglutaryl-coenzyme (HMG-CoA) reductase and acyl CoA: cholesterol acyltransferase (ACAT) activities and increased fecal cholesterol. Consequently, the current results suggest that hesperidin and naringin are beneficial for improving hyperlipidemia and hyperglycemia in type-2 diabetic animals by partly regulating the fatty acid and cholesterol metabolism and affecting the gene expression of glucose-regulating enzymes.
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PMID:Effect of citrus flavonoids on lipid metabolism and glucose-regulating enzyme mRNA levels in type-2 diabetic mice. 1642 99

The prevalence of diabetes mellitus (DM), particularly Type 2 DM, has rapidly increased in industrialized and many developing countries. The predominant cause of death in diabetic patients is vascular complications. Dyslipidemia and hypercholesterolemia are common in diabetic patients. 3-Hydroxy-3-methylglutaryl-CoA reductase inhibitors (statins) were designed for lowering cholesterol synthesis. Landmark clinical trials indicated that statins effectively reduced cardiac death and events in patients with coronary artery disease or DM. The benefits of statins on the prevention of vascular events were independent from age, sex or baseline lipid levels in diabetic patients. Statins not only prevent atherosclerotic macrovascular complications, but also postpone the development of microvascular complications of DM, such as nephropathy and retinopathy. The non-cholesterol lowering or pleiotropic effects of statins have attracted vast attention. Results from experimental and clinical studies suggest that statins may attenuate inflammation, oxidative stress, coagulation, platelet aggregation, and improve insulin resistance, fibrinolysis and endothelial functions and help to prevent thrombosis, restenosis or organ transplantation rejection. Statins may affect the intracellular prenylation of proteins, which modulate the activity of small-GTP binding proteins. This may be an underlying mechanism for some pleiotropic effects of statins. Statins have an excellent safety profile and seldom cause adverse effects. Increasing evidence suggests that statins are the current treatment of choice to prevent vascular complications in diabetic patients with hypercholesterolemia.
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PMID:Statins for diabetic cardiovascular complications. 1684 42

Numerous reports on the molecular mechanism of atherogenesis indicate an increase in oxidative stress, formation of advanced glycoxidation end products (AGEs), chronic inflammation, and activated cellular response particularly in diabetic patients. To elucidate the initiating and early accelerating events this review will focus on the molecular causes of the induction of these stress factors, their interactions, and their contribution to atherogenesis. Metabolic factors such as elevated free fatty acids, high glucose levels or AGEs induce reactive oxygen species (ROS) in vascular cells leading to ongoing AGE formation and to gene induction of proinflammatory cytokines. Vice versa, numerous cytokines found elevated in obesity and diabetes may also induce oxidative stress thus a circulus vitious may be initiated and accelerated. Increased production of ROS, mainly from mitochondria and NAD(P)H oxidase, stimulates signaling cascades including protein kinase C and mitogen-activated protein kinase pathway leading to nuclear translocation of transcription factors such as nuclear factor-kappaB (NF-kappaB), activator protein 1, and specificity protein 1. Subsequently, the expression of numerous genes including cytokines is rapidly induced, which, in turn, may act on vascular cells promoting the deleterious effects. From animal models of accelerated atherosclerosis a causal role of NAD(P)H oxidase and the AGE/RAGE/NF-kappaB axis to atherogenesis is suggested. Because all factors involved form a highly interwoven network of interactions, the blockade of ROS or AGE formation at different sites may interrupt the vicious cycle. Promising candidate agents are, currently on trial. Most important to clinical practice, a number of drugs commonly used in the treatment of diabetes, hypertension, or cardiovascular disease, such as angiotensin-converting enzyme inhibitors, AT(1) receptor blockers, 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors (statins), and thiazolidindiones have shown promising 'preventive' intracellular antioxidant activity in addition to their primary pharmacological actions.
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PMID:Oxidative stress, AGE, and atherosclerosis. 1765 6

It has been shown that HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors (statins) lower the incidence of a first stroke in patients with coronary heart disease, diabetes, or risk factors for cardiovascular disease. However, it is unknown whether statin therapy could reduce the incidence of a second stroke in patients without evidence of heart disease. This article reviews the results of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels trial, a prospective, randomized, multicentered, double-blind, placebo-controlled, international trial designed to examine the effect of high-dose atorvastatin on secondary stroke prevention. Trial participants (4,731) had experienced a stroke or transient ischemic attack within 1 to 6 months before randomization into the study. Over the 5-year follow-up period, incidence of second stroke or transient ischemic attack was significantly reduced in the atorvastatin treatment group compared with the placebo group. In addition, high-dose atorvastatin therapy significantly decreased major coronary artery and other negative cardiovascular events. The reduction in incidence of secondary stroke was specific to ischemic stroke as opposed to hemorrhagic stroke. Results of the trial are clinically significant and support extension of the latest secondary stroke prevention guidelines to include statin therapy for those patients without coronary heart disease.
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PMID:High-dose statin therapy for secondary prevention of stroke: stroke prevention by aggressive reduction in cholesterol levels study review. 1815

The indication for HMG-CoA-reductase-inhibitors (CSE inhibitors, "statins") for primary prevention of atherosclerosis requires a careful risk/benefit calculation. For this, the PROCAM and SCORE risk scores offer validated, hands on decision support tools. In patients with manifest atherosclerosis and diabetes mellitus statins are indicated regardless of the serum cholesterol level.
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PMID:[To give or not to give? Towards the indication of CSE inhibitors ("statins")]. 1855 75

Antiplatelet resistance has been proposed as a possible mechanism to explain recurrent cardiovascular events in patients who have coronary artery disease and who are undergoing dual antiplatelet therapy. A comprehensive search on PubMed was conducted for literature that was printed in the English language between January 1996 and November 2007 on aspirin and clopidogrel resistance. Significant traits for aspirin hyporesponsiveness were female sex, older age, and lower levels of hemoglobin. Diabetes mellitus and elevated body mass index showed trends toward a higher incidence of resistance in some aspirin trials but did not reach statistical significance. Clopidogrel studies suggested that patients with type-2 diabetes mellitus are more likely to manifest inadequate response to the medication. Although 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors were initially suspected to decrease response to clopidogrel, later studies refuted this possibility. Patients with a suboptimal response to aspirin or clopidogrel seem to be at increased risk of recurrent cardiovascular events. Large clinical trials with standardized laboratory methods and well-defined protocols are needed to determine whether common features exist in patients with suspected hyporesponsiveness to antiplatelet therapy, and to validate the clinical relevance of response variability. A concise nonarbitrary definition of physiologic "resistance" is needed, and investigators should identify patients as having a variable response to antiplatelet therapy.
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PMID:Aspirin and clopidogrel response variability: review of the published literature. 1894 11

In this study, we investigated the effect of different antihypertensive agents on pulse pressure (PP). The study was designed in a prospective manner and patients were sequentially allocated to one of the seven different therapy groups, according to the order of enrollment (every first patient to group I, every second patient to group II, and etc). Patients in group I received 10 mg of lisinopril, in group II 10/6.25 mg of lisinopril/hydrochlorothiazide, in group III 80 mg of valsartan, in group IV 80/6.25 mg of valsartan/hydrochlorothiazide, in group V 5 mg of amlodipine, in group VI 1.25 mg of indapamide, and finally those in group VII received 50 mg of atenolol. The reduction in PP was more significant in patients receiving lisinopril, lisinopril hydrochlorothiazide, valsartan, and valsartan hydrochlorothiazide, when compared with patients receiving indapamide, atenolol, and amlodipine (P < 0.05 for each group). Factors such as age, gender, and body mass index were not found to significantly influence the effectiveness of antihypertensive agents on PP. The reduction in PP was more apparent with lisinopril, lisinopril hydrochlorothiazide, valsartan, and valsartan hydrochlorothiazide in diabetic patients, when compared with those without diabetes (P < 0.001, P < 0.05). And also patients on therapy with 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitors had a greater reduction in PP with lisinopril, lisinopril hydrochlorothiazide, valsartan, and valsartan hydrochlorothiazide (P < 0.001, P < 0.05).
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PMID:Effect of seven different modalities of antihypertensive therapy on pulse pressure in patients with newly diagnosed stage I hypertension. 1920 74

Bone marrow (BM)-derived endothelial progenitor cells (EPC) contribute to vascular maintenance by participating in angiogenesis, re-endothelialization, and remodeling. Myeloid progenitor cells in the BM are functionally and quantitatively an important precursor pool for cells that contribute to these processes. However, these precursor pools in the BM also give rise to important effector cells of the innate immune system, such as macrophages and dendritic cells. We hypothesized that the disturbed repair responses that are being observed in diabetes mellitus are also related to an effect on functional and differentiation characteristics at the level of this bone marrow precursor pool. Indeed, we observed that bone marrow differentiation cultures for EPC, macrophages (Mph), or dendritic cells (DC) from hyperglycemic BM yielded 40% fewer EPC and 50% more Mph compared with control BM. These changes were directly related to the hemoglobin A(1C) levels of the donor mice. BM-derived DC numbers were not affected by hyperglycemia. The composition of the BM was not altered; in particular, the numbers of CD31+/Ly6C+ cells, which serve as common progenitors for EPC, Mph, and DC, were unaffected. In addition, BM-derived EPC from hyperglycemic mice were less angiogenic and more proinflammatory in regards to endocytosis, T-cell activation, and interleukin 12 production. HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibition by statin supplementation of the culture medium counteracted these hyperglycemia-induced changes. Our study results show that hyperglycemia alters the differentiation fate of BM precursor cells, reducing the potential to generate vascular regenerative cells and favoring the development of proinflammatory cells.
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PMID:Differentiation of bone marrow-derived endothelial progenitor cells is shifted into a proinflammatory phenotype by hyperglycemia. 1929 18

For years, statins have been used to lower elevated total and low-density lipoprotein cholesterol levels while raising high-density lipoprotein cholesterol levels. Statins work by inhibiting HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase, thus stopping the conversion of HMG-CoA to mevalonate, which is found in the cholesterol synthesis cascade. Unfortunately, several studies have shown increased diagnosis and lack of glycemic control of diabetes mellitus when patients are taking high and/or long-term doses of statins, and several mechanisms have been identified that may help explain this side effect.
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PMID:Association of statins and diabetes mellitus. 2001 85

The combination of diabetes and hyperlipidemia promotes the development of atherosclerosis. Therefore, it is important for diabetic patients to control blood fat. 3-Hydroxy-3-methylglutaryl enzyme A (HMG-CoA) reductase inhibitors (statins), like pravastatin, are frequently administered to diabetic patients for this purpose. Although the alterations of metabolic enzymes and transporters in the diabetic liver maybe change the disposition of pravastatin, the effect has not been fully investigated. In the present study, we investigated the disposition of pravastatin and the mRNA expression of transporters in the liver. Pravastatin (5 mg.kg(-1) body weight) was administered intravenously to diabetic rats, and the pravastatin concentrations in the plasma, urine, and bile were measured by high-performance liquid chromatography. Changes in the mRNA expressions of multidrug resistance-associated protein 2 (MRP2) and organic anion transporting polypeptide 2 (OATP2) in the liver were also estimated using reverse transcriptase-polymerase chain reaction (RT-PCR). We found that the plasma pravastatin concentration was lower in the diabetic rat because the transportation of pravastatin into hepatocytes was promoted along with increased expression of OATP2. The biliary excretion ratio of pravastatin was significantly lower in the diabetic rat because the pravastatin transportation into bile was reduced along with the decreased expression of MRP2. To clarify these phenomena, the analysis of mRNA expression using real-time PCR and the measurement of the amount and the activity of proteins are necessary in future study.
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PMID:The disposition of pravastatin in a rat model of streptozotocin-induced diabetes and organic anion transporting polypeptide 2 and multidrug resistance-associated protein 2 expression in the liver. 2004 56


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