Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Troglitazone, a thiazolidinedione derivative, overcomes insulin resistance through promoting insulin receptor function. However, the effect of the resultant enhancement of insulin action on the regulation of cellular proliferation remains unknown. We investigated the effect of troglitazone on intimal proliferation after balloon injury in insulin-resistant Zucker fatty rats. Troglitazone markedly decreased blood glucose and triglyceride levels at the therapeutic dosage. The area of neointima significantly decreased in treated animals 2 weeks after operation, as compared with the untreated control animals (0.0526 +/- 0.0292 and 0.115 +/- 0.0354 mm2, respectively). The ratio of neointimal to medial area in treated rats (0.75 +/- 0.26) decreased by as much as 53% compared with untreated rats (1.40 +/- 0.05). We next examined DNA synthesis in cultured smooth muscle cells (SMCs) derived from non-insulin-resistant rats, to assess whether troglitazone suppresses the proliferation of vascular SMCs independent of metabolic effects. The result showed that troglitazone decreased [methyl-3H]thymidine incorporation into DNA. In conclusion, treatment with troglitazone in Zucker fatty rats resulted in a reduction in neointima formation after balloon injury, and also corrected hypertriglyceridemia and hyperglycemia. In addition, in vitro studies revealed that the anti-proliferative effect of troglitazone stems from its direct action on DNA synthesis rather than any accompanying metabolic changes. Therefore, troglitazone seems to be applicable in preventing atherosclerosis in patients with insulin resistance.
Atherosclerosis 1998 Feb
PMID:Troglitazone suppresses intimal formation following balloon injury in insulin-resistant Zucker fatty rats. 954 98

We examined the mechanisms by which insulin may be atherogenic during aging. We postulated that an increase in insulin secretion during aging produces growth factor effects on vascular smooth muscle cells (VSMCs), promoting these cells to synthesize collagen and to migrate. We have previously demonstrated that insulin stimulates collagen synthesis and release in senescent VSMCs that were obtained from a human organism with high levels of insulin secretion. Using the same experimental model, we now study the effects of insulin on VSMC migration. We demonstrate that insulin has a chemoattractant effect on VSMCs which occurs through insulin binding to its own specific receptors as opposed to its effect on collagen production. Blocking the insulin receptor significantly eliminates the insulin effect on cell migration. At the same molarity, the chemotactic effect of insulin is less pronounced than that of insulin-like growth factor-1. In spite of different mechanisms, there is a remarkable correlation between the insulin effects on collagen secretion and cell migration (r2 = 97%, p < 0.0005). Our results indicate that distinct but closely related mechanisms may exist by which insulin becomes atherogenic. Our results also suggest the importance of normal aging processes in the development of atherosclerosis.
 ...
PMID:Phenotypic changes in vascular smooth muscle cells during aging: insulin effect on migration. 959 86

The resistance to insulin (insulin resistance, IR) is a common feature and a possible link between such frequent disorders as non-insulin dependent diabetes mellitus (NIDDM), hypertension and obesity. Pharmacological amelioration of IR and understanding its pathophysiology are therefore essential for successful management of these disorders. In this review, we will discuss the mechanisms of action of thiazolidinediones (TDs), a new family of insulin-sensitizing agents. Experimental studies of various models of IR and an increasing number of clinical studies have shown that TDs normalize a wide range of metabolic abnormalities associated with IR. By improving insulin sensitivity in skeletal muscles, the adipose tissue and hepatocytes, TDs reduce fasting hyperglycaemia and insulinaemia. Furthermore, TDs markedly influence lipid metabolism--they decrease plasma triglyceride, free fatty acid and LDL-cholesterol levels, and increase plasma HDL-cholesterol concentrations. Although TDs do not stimulate insulin secretion, they improve the secretory response of beta cells to insulin secretagogues. TDs act at various levels of glucose and lipid metabolism--ameliorate some defects in the signalling cascade distal to the insulin receptor and improve glucose uptake in insulin-resistant tissues via increased expression of glucose transporters GLUT1 and GLUT4. TDs also activate glycolysis in hepatocytes, oppose intracellular actions of cyclic AMP, and increase intracellular magnesium levels. TDs bind to peroxisome proliferator activating receptors gamma (PPAR gamma), members of the steroid/thyroid hormone nuclear receptor superfamily of transcription factors involved in adipocyte differentiation and glucose and lipid homeostasis. Activation of PPAR gamma results in the expression of adipocyte-specific genes and differentiation of various cell types in mature adipocytes capable of active glucose uptake and energy storage in the form of lipids. Furthermore, TDs inhibit the pathophysiological effects exerted by tumour-necrosis factor (TNF alpha), a cytokine involved in the pathogenesis of IR. These effects are most likely also mediated by stimulation of PPAR gamma. In mature adipocytes, PPAR gamma stimulation inhibits stearoyl-CoA desaturase 1 (SCD1) enzyme activity resulting in a change of cell membrane fatty acid composition. Apart from their metabolic actions, TDs modulate cardiovascular function and morphology independently of the insulin-sensitizing effects. TDs decrease blood pressure in various models of hypertension as well as in hypertensive insulin-resistant patients, and inhibit proliferation, hypertrophy and migration of vascular smooth muscle cells (VSMC) induced by growth factors. These processes are considered to be crucial in the development of vascular remodelling, atherosclerosis and diabetic organ complications. TDs induce vasodilation by blockade of Ca2+ mobilisation from intracellular stores and by inhibition of extracellular calcium uptake via L-channels. Furthermore, TDs interfere with pressor systems (catecholamines, renin-angiotensin system) and enhance endothelium-dependent vasodilation. A key role of TDs effects in vascular remodelling is played by inhibition of the mitogen-activated protein (MAP) kinase pathway. This signalling pathway is important for VSMC growth and migration in response to stimulation with tyrosine-kinase dependent growth factors. In addition to the vasoprotective mechanisms mentioned above, troglitazone, the latest representative of this pharmacological group, possesses antioxidant actions comparable to vitamin E. In summary, TDs have the unique ability to attack mechanisms responsible for metabolic alterations as well as for vascular abnormalities characteristic for IR. Therefore, TDs represent a powerful research tool in attempts to find a common denominator underlying the pathophysiology of the metabolic syndrome X. A recently reported link between MAP kinase signalling pathway and PPAR gamma
 ...
PMID:Thiazolidinediones--tools for the research of metabolic syndrome X. 980 67

There is accumulating evidence for the importance of small, dense low-density lipoprotein (LDL), the defining feature of the atherogenic lipoprotein phenotype, as a risk factor for coronary heart disease. Although both family studies and twin studies have demonstrated genetic influences on this phenotype, the specific gene(s) involved remain to be identified. The purpose of this study was to determine whether there was evidence for genetic linkage between small, dense LDL (LDL subclass phenotype B), as determined by gradient gel electrophoresis, and selected candidate genes known to be involved in lipid metabolism. The linkage analyses were based on a sample of 19 families, including 142 individual family members, using a lod score linkage analysis approach. Nine candidate genes were examined, including loci for manganese superoxide dismutase (Mn SOD2), apolipoproteins CIII, AII, and apo CII, lipoprotein lipase, hepatic lipase, microsomal triglyceride transport protein, the insulin receptor and the LDL receptor. The analyses did not provide significant evidence for genetic linkage between markers for any of these genes and LDL subclass phenotype B, nor did it confirm previous reports of linkage between the LDL receptor gene and LDL subclass phenotype B. Using three closely linked markers for the Mn SOD2 locus excluded close linkage between this candidate gene region and LDL subclass phenotype B. These findings demonstrate the complexity of genetically mapping risk factor phenotypes, and emphasize the necessity of identifying new genetic loci, other than known candidate genes, involved in susceptibility to atherosclerosis.
Atherosclerosis 1999 Jan
PMID:Linkage analysis of candidate genes and the small, dense low-density lipoprotein phenotype. 992 May 8

Cholesteryl ester transfer protein (CETP) is a plasma enzyme involved in cholesterol metabolism. As a potential target in the treatment of atherosclerosis, a number of studies have focused how this enzyme is regulated. It has been postulated that insulin may regulate CETP gene expression, and these effects may be mediated through CCAAT/enhancer binding protein alpha (C/EBPalpha). The present study examines the effects of insulin on the activity of the CETP promoter in rat fibroblasts expressing the human insulin receptor (HIRc). HIRc cells were stably transfected with a chimeric construct containing 3.2 kb of the CETP promoter attached to the bacterial chloramphenicol acyltransferase gene (pCETP-CAT) without significantly affecting the expression of the insulin receptor. CAT activity was 8-fold higher in cultured HIRc/pCETP-CAT in the presence of 100 mg/dL LDL cholesterol, than those cultured without cholesterol (p < 0.05). However, culturing these cells in the presence of 100 nM insulin did not result in any change in CAT activity when compared to control cells. In HIRc/pCETP-CAT cells transiently transfected with a construct that constitutively expressed C/EBPalpha protein, a 3-fold increase in CAT activity was observed when compared to cells transiently transfected with non-specific DNA (p < 0.05). However, no observable effect on the CETP promoter was observed in the presence of insulin. Thus, in HIRc/pCETP-CAT cells, we were unable to substantiate the hypothesis that insulin regulates CETP gene transcription. These results suggest that the effects of insulin on CETP expression regulation may be downstream of transcription.
 ...
PMID:Insulin does not regulate the promoter of cholesteryl ester transfer protein (CETP) in HIRc/pCETP-CAT cells. 1105 41

Insulin resistance contributes to a number of metabolic disorders, including type II diabetes, hypertension, and atherosclerosis. Cytokines, such as tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-6, and hormones, such as growth hormone, are known to cause insulin resistance, but the mechanisms by which they inhibit the cellular response to insulin have not been elucidated. One mechanism by which these agents could cause insulin resistance is by inducing the expression of cellular proteins that inhibit insulin receptor (IR) signaling. Suppressors of cytokine signaling (SOCS) proteins are negative regulators of cytokine signaling pathways, the expression of which is regulated by certain cytokines. SOCS proteins are therefore attractive candidates as mediators of cytokine-induced insulin resistance. We have found that SOCS-1 and SOCS-6 interact with the IR when expressed in human hepatoma cells (HepG2) or in rat hepatoma cells overexpressing the human IR. In SOCS-1-expressing cells, insulin treatment increases the extent of interaction with the IR, whereas in SOCS-6-expressing cells the association with the IR appears to require insulin treatment. SOCS-1 and SOCS-6 do not inhibit insulin-dependent IR autophosphorylation, but both proteins inhibit insulin-dependent activation of ERK1/2 and protein kinase B in vivo and IR-directed phosphorylation of IRS-1 in vitro. These results suggest that SOCS proteins may be inhibitors of IR signaling and could mediate cytokine-induced insulin resistance and contribute to the pathogenesis of type II diabetes.
 ...
PMID:Suppressors of cytokine signaling-1 and -6 associate with and inhibit the insulin receptor. A potential mechanism for cytokine-mediated insulin resistance. 1134 31

The epidemic of type 2 diabetes and impaired glucose tolerance is one of the main causes of morbidity and mortality worldwide. In both disorders, tissues such as muscle, fat and liver become less responsive or resistant to insulin. This state is also linked to other common health problems, such as obesity, polycystic ovarian disease, hyperlipidaemia, hypertension and atherosclerosis. The pathophysiology of insulin resistance involves a complex network of signalling pathways, activated by the insulin receptor, which regulates intermediary metabolism and its organization in cells. But recent studies have shown that numerous other hormones and signalling events attenuate insulin action, and are important in type 2 diabetes.
 ...
PMID:Insulin signalling and the regulation of glucose and lipid metabolism. 1174 12

There are several potential cellular and molecular pathways whereby cardiovascular risk factors act through very specific signal transduction pathways in the formation of atherosclerosis, as seen often in the metabolic syndrome. Many examples point to multiple postreceptor defects in the insulin signaling pathway in vascular tissue, however, there are differences in the insulin receptor pathway in vascular tissue compared with skeletal muscle or fat. In addition to insulin receptors, insulin may affect atherosclerotic changes in the vascular cells via stimulation of insulin-like growth factor-1 receptors and their signaling pathway. Insulin also causes activation of the vascular renin-angiotensin system in both vascular smooth muscle cells and endothelial cells. Insulin-activated tissue renin-angiotensin system leads to increased cell growth and contributes to the cause of atherosclerosis. The fact that agents that inhibit the renin-angiotensin system also block insulin-mediated renin-angiotensin system expression and cell growth reinforces the potential implication of a vascular insulin-renin-angiotensin system pathway. Finally, novel substances such as the adipokines, factors produced from fat cells, reveal new risk factors in the metabolic syndrome and offer further evidence for a link between insulin resistance and accelerated atherosclerosis.
 ...
PMID:Vascular signaling pathways in the metabolic syndrome. 1188 65

Metabolic Syndrome X defined by Reaven is caused by peripheral insuline receptor resistance, leads to hyperinsulinemia regarded as a cause of secondary dyslipidemia, hypertension, hemostatic disturbances, atherosclerosis and insulin as a growth factor takes part in carcinogenesis. Depending on a contribution of the primary risk factors of type 2 Diabetes Mellitus (2-DM) mainly genetic factors and obesity--an independent cause of insulin receptor resistance--glucose intolerance and 2-DM may overlap the Syndrome X. The aims of these studies were to determine in cross-sectional investigation a plasma insulin concentration in subjects aged over 35 years and to assess the clinical usefulness of insulinemia in early diagnosis of diabetes type 2. Investigations were carried out in Krakow town's district with 200,000 inhabitants, out of those 3060 randomly selected subjects (1720 females and 1340 males aged over 35 years) took part in the Polish Multicenter Study on Diabetes Epidemiology (PMSDE) with protocol and methods previously presented. Glucose concentration was determine by enzymatic method, insuline in plasma by IRMA method using ready kits produced by the Swierk-Poland. Logistic multiple regression model was used to estimate the effect of risk factors on the development of glucose intolerance, Chi square test, Fisher test and Mann-Whitney test were used for statistical analysis by means of statistical package BMPD. Fasting insulinemia in persons with normal glucose tolerance and body weight (BMI < 25 and glycemia < 6.1 mmol/l) in subpopulation aged over 35 years was 5.73 (SD = 3.99) in men and 7.05 (SD = 4.67) microU/ml in women. These values were positively correlated with BMI and at the range 25-30 and > 30 increased by 50 and 100% responsively and in 2-nd h in OGTT by five-times. In the persons with glucose intolerance and new-diagnosed 2-DM insulinemia increased 2-3 fold depending on BMI, and gender. In the subgroup with 2-DM and BMI > 30, insulinemia in 2 h-OGTT treated values 152 (SD = 90) in women and 112 (SD = 83.4) microU/ml in men. Obesity and insulinemia in 2 h-OGTT in multiple analysis have been identified as a strong predictors and risk factors of impaired glucose intolerance (IGT) 2-DM fasting insulinemia may be useful as an indicator of the peripheric insulin receptor resistance. The results lead to the conclusions that determination of the plasma insulin concentration may be useful in early diagnosis of IGT and diabetes type 2, and should be monitored in the course of non-pharmacological and pharmacological treatment 2-DM. One of the main goals in the course of treatment of obesity and early phases of the 2-DM should be normalization or at least reduction of hyperinsulinemia. Insulinemia may be regarded also as an important criterion for selection of the oral antidiabetic drugs.
 ...
PMID:[Insulinemia--a marker of early diagnosis and control of efficacy of treatment of type II diabetes]. 1192 88

The relation between insulin resistance/hyperinsulinemia and cardiovascular diseases has attracted much attention. Insulin affects not only glucose metabolism, but also protein synthesis and cell growth. Insulin stimulates both the phosphatidylinositol 3-kinase (PI3-K) and mitogen-activated protein kinase (MAPK) pathways, but the relationship between cardiovascular disease and selective insulin signal pathways is unclear. We investigated the tissue specificity and intracellular signal transduction selectivity of insulin resistance in the vasculature and skeletal muscle of fructose-fed rats (FFR). Sprague-Dawley rats were fed either normal rat chow (control rats) or fructose-rich chow. Normal saline with or without 1,000 (microg/kg) insulin was injected, and then the thoracic aorta or soleus muscle was removed under anesthetization. Insulin-induced tyrosine phosphorylation of insulin receptor beta subunit (IRbeta) and insulin receptor substrate-1 (IRS-1) and tyrosine/threonine phosphorylation of p44/42 MAPK (ERK-1/2) were evaluated. There were no significant differences in the degree of phosphorylation of IRbeta or ERK-1/2 in the thoracic aorta or in the soleus muscle between FFR and controls. However, tyrosine phosphorylation of IRS-1 in the soleus muscle of FFR was significantly reduced to 80% (p<0.001) of that in controls. The results suggest that PI3-K pathway in skeletal muscle is selectively impaired in FFR, and this impairment may induce hyperinsulinemia, which in turn may stimulate the MAPK pathway and lead to atherosclerosis. Thus PI3-K pathway may be one of the factors underlying the onset of cardiovascular disease in patients with insulin resistance.
 ...
PMID:Tissue-specific impairment of insulin signaling in vasculature and skeletal muscle of fructose-fed rats. 1262 78


<< Previous 1 2 3 4 5 6 7 Next >>