Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inflammation is known to have a pathogenic role in atherosclerosis and the genesis of acute coronary syndromes. The peroxisome proliferator-activated receptor (PPAR)-gamma, which is expressed in many constituent cells of atheromatous plaques, inhibits the activation of several proinflammatory genes responsible for atheromatous plaque development and maturation. Agonists of this receptor, such as rosiglitazone and pioglitazone, are currently available for the treatment of type 2 diabetes mellitus, and several lines of evidence have shown that these drugs have antiatherogenic effects. Insulin resistance is associated with inflammation and has a key role in atherogenesis. The antiatherogenic and insulin sensitizing effects of the thiazolidinediones in patients with type 2 diabetes mellitus may be associated with this action. However, in recent years there has been growing evidence that the antiatherogenic effects of PPAR-gamma agonists are not confined to patients with diabetes mellitus. PPAR-gamma agonists have been shown to downregulate the expression of endothelial activation markers, reduce circulating platelet activity, improve flow-mediated dilatation and attenuate atheromatous plaque progression in patients without diabetes mellitus. These effects of PPAR-gamma agonists appear to result from both insulin sensitization and a direct modulation of transcriptional activity in the vessel wall. This review summarizes the current understanding of the role of PPAR-gamma agonists in atherogenesis and discusses their potential role in the treatment of coronary artery disease in patients with type 2 diabetes mellitus and in nondiabetic patients.
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PMID:Peroxisome proliferator-activated receptor-gamma agonists for management and prevention of vascular disease in patients with and without diabetes mellitus. 1691 24

Increased levels of C-peptide, a cleavage product of proinsulin, circulate in patients with insulin resistance and early type 2 diabetes mellitus. Recent data suggest a potential causal role of C-peptide in atherogenesis by promoting monocyte and T-lymphocyte recruitment into the vessel wall. The present study examined the effect of C-peptide on vascular smooth muscle cells (VSMCs) proliferation and evaluated intracellular signaling pathways involved. In early arteriosclerotic lesions of diabetic subjects, C-peptide colocalized with VSMCs in the media. In vitro, stimulation of human or rat VSMCs with C-peptide induced cell proliferation in a concentration-dependent manner with a maximal 2.6+/-0.8-fold induction at 10 nmol/L human C-peptide (P<0.05 compared with unstimulated cells; n=9) and a 1.8+/-0.2-fold induction at 0.5 nmol/L rat C-peptide (P<0.05 compared with unstimulated cells; n=7), respectively, as shown by [H3]-thymidin incorporation. The proliferative effect of C-peptide on VSMCs was inhibited by Src short interference RNA transfection, PP2, an inhibitor of Src-kinase, LY294002, an inhibitor of PI-3 kinase, and the ERK1/2 inhibitor PD98059. Moreover, C-peptide induced phosphorylation of Src, as well as activation of PI-3 kinase and ERK1/2, suggesting that these signaling molecules are involved in C-peptide-induced VSMC proliferation. Finally, C-peptide induced cyclin D1 expression as well as phosphorylation of Rb in VSMCs. Our results demonstrate that C-peptide induces VSMC proliferation through activation of Src- and PI-3 kinase as well as ERK1/2. These data suggest a novel mechanism how C-peptide may contribute to plaque development and restenosis formation in patients with insulin resistance and early type 2 diabetes mellitus.
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PMID:C-Peptide induces vascular smooth muscle cell proliferation: involvement of SRC-kinase, phosphatidylinositol 3-kinase, and extracellular signal-regulated kinase 1/2. 1712 42

Diabetes incidence is increasing rapidly in the United States. Diabetes increases the risk for cardiovascular disease, the major cause of death in diabetic individuals. The conventional cardiovascular risk factors of hyperlipidemia and hypertension worsen diabetic vascular disease. Treatment targets for low-density lipoprotein cholesterol (LDL-C) and blood pressure in diabetic individuals are being debated. The SANDS is a randomized, open-label, 3-year trial to examine the effects of aggressive LDL-C (goal <70 mg/dL) and blood pressure (BP) (goal <115/75 mm Hg) reduction versus the standard goals of <100 mg/dL for LDL-C and <130/85 mm Hg for BP. Five hundred forty-nine American-Indian men and women >40 years old with type 2 diabetes were randomized to 1 of 2 groups. Lipids and BP are managed using Food and Drug Administration-approved medications in an algorithmic approach. The presence and progression of atherosclerosis are evaluated by carotid ultrasonography; echocardiography assesses cardiac function. The primary end point is the composite outcome of change in carotid artery intimal medial thickness and fatal/nonfatal cardiovascular events. These outcomes are combined by using a ranked analysis for carotid thickness and assigning a "worst rank" for a cardiovascular event. Secondary end points include carotid plaque score, left ventricular geometry and function, serum C-reactive protein, and safety measures. Unique aspects of the study design and analysis plan involve the use of a composite outcome and changes during the trial of LDL-C treatment goals for participants with baseline or incident cardiovascular disease in the conventional group because of changes in the standard of care. Study results will further understanding of the effects of aggressive risk factor reduction on atherosclerosis burden and cardiac function in diabetic individuals in US populations and will help determine optimal LDL-C and BP treatment goals for diabetic patients.
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PMID:Examination of lower targets for low-density lipoprotein cholesterol and blood pressure in diabetes--the Stop Atherosclerosis in Native Diabetics Study (SANDS). 1707 Jan 47

Angiotensin II (Ang II) increases adhesion molecules, cytokines and chemokines and exerts a proinflammatory effect on leucocytes, endothelial cells and vascular smooth muscle cells. Acting via the type 1 receptor, Ang II initiates an inflammatory cascade of reduced nicotinamide-adenine dinucleotide phosphate oxidase, reactive oxygen species (ROS) and nuclear factor-kappaB, which mediates transcription and gene expression and increases adhesion molecules and chemokines. An excess of ROS decreases nitric oxide bioavailability, causes endothelial dysfunction, and promotes atherosclerosis. Moreover, Ang II interrupts the anti-inflammatory effects of insulin. Together, these effects promote a prothrombotic state as well as plaque rupture. Ang II receptor blockers suppress mediators of inflammation, including ROS and C-reactive protein, and they increase expression of inhibitory kappaB (an inhibitor of nuclear factor-kappaB). These anti-inflammatory and antioxidative effects, which are probably due in part to unopposed stimulation of the Ang II type 2 receptor, may be beneficial in acute coronary syndromes and may also contribute to the prevention of type II diabetes mellitus, as insulin resistance is mediated by inflammatory processes.
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PMID:Angiotensin II and inflammation: the effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockade. 1709 9

The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand-dependent transcription factor that controls the expression of specific target genes involved in adipogenesis, inflammatory responses, and lipid metabolism. Atherosclerotic plaque progression is influenced by intraplaque inflammation and extracellular matrix deposition. Anti-inflammatory, anti-proliferative and anti-protease activity of PPARgamma may modulate the atherosclerotic process. PPARgamma is expressed in atherosclerotic lesions of human coronary arteries and has direct anti-inflammatory effects in the vascular wall. Thiazolidinediones (TZD) are ligands for PPARgamma used therapeutically to enhance insulin-mediated glucose uptake in persons with type 2 diabetes. These agents may also exert anti-atherogenic effects on cells of the vessel wall including macrophages, vascular endothelium and vascular smooth muscle. This review discusses the impact of PPARgamma and its activators in the numerous processes involved in the formation of atherosclerotic lesions. We provide an overview of in vitro and in vivo data in cell lines, animal models, and humans demonstrating the ways in which PPARgamma activation alters the biology of the arterial wall.
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PMID:PPARgamma activity in the vessel wall: anti-atherogenic properties. 1716 9

We recently developed a novel method for evaluating the elasticity of arterial walls, the phased tracking method. Herein, we evaluated atherosclerosis of the carotid artery with this method in 242 individuals with type 2 diabetes. In multiple regression analysis of subject status, age, systolic blood pressure and hyperlipidemia were found to be independently associated with carotid artery elasticity values. We also measured currently established values for atherosclerosis, carotid artery IMT and baPWV, in these subjects. Carotid artery elasticity correlated with max IMT (r=0.291, p<0.01), plaque score (PS) (r=0.220, p<0.01) and baPWV (r=0.345, p<0.01). Elasticity, max IMT and plaque score, all correlated with the number of risk factors for atherosclerosis, i.e. hypertension, hyperlipidemia and smoking, in addition to diabetes, consistent with the view that these values reflect atherosclerosis. Importantly, however, in subjects with IMT <1.1mm, who are classified as not having atherosclerosis as defined by IMT criteria, only carotid artery elasticity correlated with the number of risk factors (p<0.05). These results suggest that (1) the measured carotid artery elasticity values reflect atherosclerosis and (2) our novel method has potential for detecting atherosclerosis in its early stage.
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PMID:A novel method for evaluating human carotid artery elasticity: possible detection of early stage atherosclerosis in subjects with type 2 diabetes. 1717 21

A model of chronic kidney disease (CKD)-induced vascular calcification (VC) that complicates the metabolic syndrome was produced. In this model, the metabolic syndrome is characterized by severe atherosclerotic plaque formation, hypertension, type 2 diabetes, obesity, and hypercholesterolemia, and CKD stimulates calcification of the neointima and tunica media of the aorta. The CKD in this model is associated the adynamic bone disorder form of renal osteodystrophy. The VC of the model is associated with hyperphosphatemia, and control of the serum phosphorus both in this animal model and in humans has been preventive in the development of VC. This article reports studies that demonstrate reduction of established VC by the addition of sevelamer carbonate to the diets of this murine metabolic syndrome model with CKD. Sevelamer, besides normalizing the serum phosphorus, surprisingly, reversed the CKD-induced trabecular osteopenia. Sevelamer therapy increased osteoblast surfaces in the metaphyseal trabeculae of the tibia and femur. It also increased osteoid surfaces and, importantly, bone formation rates. In addition, sevelamer was found to be effective in decreasing serum cholesterol levels. These results suggest that sevelamer may have important actions in decreasing diabetic and uremic vasculopathy and that sevelamer carbonate may be capable of increasing bone formation rates that are suppressed by diabetic nephropathy.
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PMID:Reversal of the adynamic bone disorder and decreased vascular calcification in chronic kidney disease by sevelamer carbonate therapy. 1718 86

In order to define the role of the ubiquitin-proteasome system in atherosclerotic plaque rupture in patients with type 2 diabetes mellitus (T2DM), we evaluated the amount of this system, of the main inflammatory cells, of the collagen content and some indexes indicative of oxidative stress in the carotid plaques of both diabetic and non-diabetic asymptomatic patients. Plaques were obtained from 31 type 2 diabetic and 27 non-diabetic patients undergoing endoterectomy. Both were examined for macrophages, T-lymphocytes, ubiquitin/proteasome 20S activity, NFkB, IkB-b, nitrotyrosine, matrix metalloproteinase-9 (MMP-9) and collagen. Diabetic plaques had more macrophages,T-lymphocytes, inflammatory cells (HLA-DR), ubiquitin/proteasome, NFkB, nitrotyrosine, MMP-9 and lower collagen content and IkB-b levels, in comparison with non-diabetic plaques. These findings indicate that in diabetic patients, ubiquitin/proteasome overactivity is associated with enhanced inflammatory activity induced by diabetic oxidative stress. This induces the NFkB release into the nucleus which, in turn, is responsible for the expression of inflammatory cytokines causing plaque rupture.
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PMID:Role of the ubiquitin-proteasome system in carotid plaque instability in diabetic patients. 1720 20

Little has been known about the role of tumor necrosis factor-alpha (TNF-alpha) gene polymorphisms in metabolic syndrome and atherosclerosis in type 2 diabetes, although TNF-alpha was reported to be involved in these conditions. We examined the association of TNF-alpha gene promoter polymorphisms, G-238A, G-308A, C-857T, C-863A, and T-1031C, with metabolic syndrome and surrogate markers of atherosclerosis in Japanese patients with type 2 diabetes. DNA was obtained from 162 patients and TNF-alpha gene promoter polymorphisms determined by direct sequencing. Allelic frequency of -238A, -308A, -857T, -863A, and -1031C was 0.6%, 2.2%, 11.1%, 16.7%, and 15.7%, respectively. Association of the gene polymorphisms with a number of variables, because of their high frequency, was analyzed in the latter 3 polymorphisms. There were no significant differences in components of metabolic syndrome and variables affecting atherosclerosis, except in case of serum low-density-lipoprotein cholesterol (LDL-C) (111+/-33 vs 125+/-39 mg/dl, p<0.05) between -857C/C and -857(C/T+T/T). In contrast, no significant differences were found in these markers between -863C/C and -863(C/A+A/A) and between -1031T/T and -1031(T/C+C/C). Furthermore, 87% of the patients with -857(C/T+T/T) and 64% with -857C/C had carotid plaques (p<0.05). There was no difference in proportion of patients treated with medications such as statins, fibrates, oral hypoglycemic agents, insulin, or antihypertensive drugs between -857C/C and -857(C/T+T/T). These data imply that TNF-alpha gene polymorphism (C-857T) is likely associated with higher serum LDL-C levels and carotid plaque formation in Japanese patients with type 2 diabetes.
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PMID:Association of TNF-alpha gene promoter C-857T polymorphism with higher serum LDL cholesterol levels and carotid plaque formation in Japanese patients with type 2 diabetes. 1734 50

The aim of the study was to evaluate the prevalence of carotid artery disease in type 2 diabetes patients with coronary artery disease, and to establish the influence of metabolic factors on its occurrence. In all, 145 patients (aged 59.85+/-8.43 years, diabetes duration 8.89+/-6.29 years) were randomly selected in a cross-sectional study. Carotid ultrasound was used for evaluation of the presence of carotid plaque (CP) and stenosis (CS). A logistic regression model was constructed to define the influence of risk factors-- arterial hypertension, systolic blood pressure, weight, waist to hip ratio, high blood glucose and plasma lipid levels. Carotid artery disease was present in these patients with a prevalence of 81.9% for CP, 25.2% for unilateral CS and 13.5% for bilateral CS. The low-density lipoprotein (LDL) cholesterol level was an independent predictor for CS (OR 1.936; 95% CI 1.2413.026). Non-high density lipoprotein (HDL) cholesterol (OR 1.374; 95% CI 1.0351.825) and glycaemia (OR 1.214; 95% CI 1.0221.442) were predictors for carotid plaque.
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PMID:Influence of metabolic risk factors on the presence of carotid artery disease in patients with type 2 diabetes and coronary artery disease. 1746 44


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