Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0948265 (metabolic syndrome)
 24,271 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Insulin has a major anabolic function leading to storage of lipidic and glucidic substrates. All its effects result from insulin binding to a specific membrane receptor which is expressed at a high level on the 3 insulin target tissues: liver, adipose tissue and muscles. The insulin receptor exhibits a tyrosine-kinase activity which leads, first, to receptor autophosphorylation and then to tyrosine phosphorylation of substrates proteins, IRS proteins in priority. This leads to the formation of macromolecular complexes close to the receptor. The two main transduction pathways are the phosphatidylinositol 3 kinase pathway activating protein kinase B which is involved in priority in metabolic effects, and the MAP kinase pathway involved in nuclear effects, proliferation and differentiation. However, in most cases, a specific effect of insulin requires the participation of the two pathways in a complex interplay which could explain the pleiotropy and the specificity of the insulin signal. The negative control of the insulin signal can result from hormone degradation or receptor dephosphorylation. However, the major negative control results from phosphorylation of serine/threonine residues on the receptor and/or IRS proteins. This phosphorylation is activated in response to different signals involved in insulin resistance, hyperinsulinism, TNFalpha or increased free fatty acids from adipose tissue, which are transformed inside the cell in acyl-CoA. A deleterious role for molecules issued from the adipose tissue is postulated in the resistance to insulin of the liver and muscles present in type 2 diabetes, obesity and metabolic syndrome.
 ...
PMID:[Insulin signaling: mechanisms altered in insulin resistance]. 1659 3

Insulin-resistance is a major problem associated with diabetes and that is increasing rapidly worldwide. Insulin is a peptide hormone secreted by the beta-cells of the pancreatic islets of Langerhans in response to increased circulating levels of glucose and amino acids and it is essential for appropriate tissue development, growth, and maintenance of whole-body glucose homeostasis by regulating carbohydrate, lipid and protein metabolism. Insulin resistance is a defect in signal transduction. The signaling mechanisms involved in the various biologic responses to insulin remain somewhat elusive. This review focuses on the structure and activity of insulin receptor, inheritance of insulin resistance, insulin receptor and alleles, enzyme activity in insulin resistance, insulin receptor in phosphorylation and relating substrate. We have discussed insulin receptor substrate-family (IRS) related to insulin resistance, detail downstream signaling effects, GLUT4 vesicle translocation and related events, cytokine-mediated insulin resistance, and feedback control mechanisms. This review also focuses on insulin resistance in obesity-linked metabolic syndrome, insulin resistance related to plasma membrane disturbances and insulin resistance for exercise and cellular integrity. Finally, we can conclude that insulin resistance is really a complex phenomenon in which several genetic defects combine with environmental stresses.
 ...
PMID:Biochemical and molecular basis of insulin resistance. 1661 Nov 37

Insulin resistance has been described in several diseases that increase cardiovascular risk and mortality, such as diabetes, obesity, hypertension, metabolic syndrome, and heart failure. Abnormalities of insulin signaling account for insulin resistance. Insulin mediates its action on target organs through phosphorylation of a transmembrane-spanning tyrosine kinase receptor, the insulin receptor (IR). Several mechanisms have been described as responsible for the inhibition of insulin-stimulated tyrosine phosphorylation of IR and the IR substrate (IRS) proteins, including proteasome-mediated degradation, phosphatase-mediated dephosphorylation, and kinase-mediated serine/threonine phosphorylation. In particular, phosphorylation of IRS-1 on serine Ser612 causes dissociation of the p85 subunit of phosphatidylinositol 3-kinase, inhibiting further signaling. On the other hand, phosphorylation of IRS-1 on Ser307 results in its dissociation from the IR and triggers proteasome-dependent degradation. Dysregulation of sympathetic nervous and renin-angiotensin systems resulting in enhanced stimulation of both adrenergic and angiotensin II receptors is a typical feature of several cardiovascular diseases and, at the same time, is involved in the pathogenesis of insulin resistance. The characterization of molecular mechanisms involved in the pathogenesis of insulin resistance may help to design efficacious pharmacologic molecules to treat endothelial and metabolic dysfunction associated with insulin resistance states to reduce the cardiovascular risk and to ameliorate the prognosis of patients with cardiovascular diseases.
 ...
PMID:Insulin resistance and cardiovascular risk: New insights from molecular and cellular biology. 1683 60

Ghrelin is an orexigenic peptide hormone secreted by the stomach. In patients with metabolic syndrome and low ghrelin levels, intra-arterial ghrelin administration acutely improves their endothelial dysfunction. Therefore, we hypothesized that ghrelin activates endothelial nitric oxide synthase (eNOS) in vascular endothelium, resulting in increased production of nitric oxide (NO) using signaling pathways shared in common with the insulin receptor. Similar to insulin, ghrelin acutely stimulated increased production of NO in bovine aortic endothelial cells (BAEC) in primary culture (assessed using NO-specific fluorescent dye 4,5-diaminofluorescein) in a time- and dose-dependent manner. Production of NO in response to ghrelin (100 nM, 10 min) in human aortic endothelial cells was blocked by pretreatment of cells with NG-nitro-L-arginine methyl ester (nitric oxide synthase inhibitor), wortmannin [phosphatidylinositol (PI) 3-kinase inhibitor], or (D-Lys3)-GHRP-6 (selective antagonist of ghrelin receptor GHSR-1a), as well as by knockdown of GHSR-1a using small-interfering (si) RNA (but not by mitogen/extracellular signal-regulated kinase inhibitor PD-98059). Moreover, ghrelin stimulated increased phosphorylation of Akt (Ser473) and eNOS (Akt phosphorylation site Ser1179) that was inhibitable by knockdown of GHSR-1a using siRNA or by pretreatment of cells with wortmannin but not with PD-98059. Ghrelin also stimulated phosphorylation of mitogen-activated protein (MAP) kinase in BAEC. However, unlike insulin, ghrelin did not stimulate MAP kinase-dependent secretion of the vasoconstrictor endothelin-1 from BAEC. We conclude that ghrelin has novel vascular actions to acutely stimulate production of NO in endothelium using a signaling pathway that involves GHSR-1a, PI 3-kinase, Akt, and eNOS. Our findings may be relevant to developing novel therapeutic strategies to treat diabetes and related diseases characterized by reciprocal relationships between endothelial dysfunction and insulin resistance.
 ...
PMID:Ghrelin has novel vascular actions that mimic PI 3-kinase-dependent actions of insulin to stimulate production of NO from endothelial cells. 1710 60

This research work focuses on an important topic--the study of cause and effect links between partial androgen deficiency of ageing men (PADAM) and an increased expression of genes of a series of factors that make proliferate activity. The results of this research show that an increased expression of genes of several proliferation factors, and a decreased expression of the gene of the insulin receptor among men of older age groups are all connected to PADAM. The given changes are directed at compensation for testicular inadequacy, and are a particular expression of metabolic syndrome (X-syndrome); their effect can be inversed however by androgen-replacement therapy.
 ...
PMID:[Testosterone's role in regulating expression of genes of several proliferation factors]. 1716 44

Insulin resistance is a pathophysiological link of obesity to type 2 diabetes. The initial cause of insulin resistance is critical for prevention and treatment of type 2 diabetes. Lipotoxicity is a well-known concept in the explanation of initiation of insulin resistance. Although there are several prevailing hypotheses about the cellular/molecular mechanisms of lipotoxicity, such as inflammation, oxidative stress, hyperinsulinemia, and ER stress, the relative importance of these hypothesized events remains to be determined. The role of hyperinsulinemia is relatively under documented in the literature for the initiation of insulin resistance. In this review, an interaction of fatty acid and beta-cells, and a synergy between free fatty acids (FFAs) and insulin are emphasized for the role of hyperinsulinemia. This article presents the evidence about FFA-induced insulin secretion in vitro and in vivo, recent advances in the molecular mechanism of FFA action in beta-cells, a role of GPR40 in the development of insulin resistance, and the negative feedback loop of the insulin receptor signal pathway. The negative feedback loop is discussed in detail with a focus on IRS-1 serine kinases. This article provides a substantial support for the role of insulin in the early stages of FFA-associated insulin resistance. The hypothesis of insulin's role in lipotoxicity is referred to as the "insulin hypothesis" in this review. According to this hypothesis, prevention of increased beta-cell response to glucose may be a potential approach for early intervention of metabolic syndrome.
 ...
PMID:Role of insulin in the pathogenesis of free fatty acid-induced insulin resistance in skeletal muscle. 1734 4

Patients with hypertension have a high prevalence of concurrent metabolic abnormalities (eg, obesity, dyslipidemia, and hyperglycemia). Clustering of these risk factors, defined as the metabolic syndrome, is associated with a high cardiovascular risk profile. This review summarizes current knowledge about the prevalence and characteristics of the metabolic syndrome in primary aldosteronism, and discusses the possible pathophysiological link between aldosterone and individual components of the metabolic syndrome, other than hypertension. Impaired glucose metabolism due to insulin resistance appears to be the major contributor to metabolic dysfunction in primary aldosteronism. Experimental observations support the possibility that aldosterone could act directly on insulin receptor function. The potential proadipogenic role of aldosterone and its negative effect on insulin sensitivity through production of cytokines remains to be investigated. Higher rates of cardiovascular events reported in primary aldosteronism could be due in part to the increased prevalence of the metabolic syndrome in this disorder.
 ...
PMID:The metabolic syndrome in primary aldosteronism. 1744 20

The insulin resistance syndrome, also referred to as the metabolic syndrome or syndrome X, is associated with a primary cellular defect in insulin action (insulin resistance) and a compensatory increase in insulin secretion. The combination of insulin resistance and subsequent hyperinsulinaemia causes a number of metabolic and cardiovascular changes that result in a syndrome typically characterised by type 2 diabetes, obesity, dyslipidaemia, coronary artery disease and hypertension. Moreover, disturbances in sleep (sleep apnoea) and ovarian dysfunction are also characterised by insulin resistance. The pathophysiological basis for these disturbances reflects the impact of variable genetic and environmental influences. At a molecular level, insulin resistance involves defects of insulin signalling such as reduced insulin receptor tyrosine kinase activity and reduced post-receptor phosphorylation steps that impinge on metabolic and vascular effects of insulin.
 ...
PMID:The insulin resistance syndrome: physiological considerations. 1746 39

Insulin resistance plays a central role in the development of the metabolic syndrome, but how it relates to cardiovascular disease remains controversial. Liver insulin receptor knockout (LIRKO) mice have pure hepatic insulin resistance. On a standard chow diet, LIRKO mice have a proatherogenic lipoprotein profile with reduced high-density lipoprotein (HDL) cholesterol and very low-density lipoprotein (VLDL) particles that are markedly enriched in cholesterol. This is due to increased secretion and decreased clearance of apolipoprotein B-containing lipoproteins, coupled with decreased triglyceride secretion secondary to increased expression of Pgc-1 beta (Ppargc-1b), which promotes VLDL secretion, but decreased expression of Srebp-1c (Srebf1), Srebp-2 (Srebf2), and their targets, the lipogenic enzymes and the LDL receptor. Within 12 weeks on an atherogenic diet, LIRKO mice show marked hypercholesterolemia, and 100% of LIRKO mice, but 0% of controls, develop severe atherosclerosis. Thus, insulin resistance at the level of the liver is sufficient to produce the dyslipidemia and increased risk of atherosclerosis associated with the metabolic syndrome.
 ...
PMID:Hepatic insulin resistance is sufficient to produce dyslipidemia and susceptibility to atherosclerosis. 1824 66

Patients with hypertension have a high prevalence of concurrent metabolic abnormalities (eg, obesity, dyslipidemia, and hyperglycemia). Clustering of these risk factors, defined as the metabolic syndrome, is associated with a high cardiovascular risk profile. This review summarizes current knowledge about the prevalence and characteristics of the metabolic syndrome in primary aldosteronism, and discusses the possible pathophysiological link between aldosterone and individual components of the metabolic syndrome, other than hypertension. Impaired glucose metabolism due to insulin resistance appears to be the major contributor to metabolic dysfunction in primary aldosteronism. Experimental observations support the possibility that aldosterone could act directly on insulin receptor function. The potential proadipogenic role of aldosterone and its negative effect on insulin sensitivity through production of cytokines remains to be investigated. Higher rates of cardiovascular events reported in primary aldosteronism could be due in part to the increased prevalence of the metabolic syndrome in this disorder.
 ...
PMID:The metabolic syndrome in primary aldosteronism. 1836 98


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>