Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Here we investigated the biological functions of adiponectin, a fat-derived hormone, by disrupting the gene encodes it in mice. Adiponectin knockout mice (KO) exhibited severe diet-induced insulin resistance with reduced IRS-1-associated P13-kinase activity in muscle. KO also revealed severe neo-intimal thickening in response to vascular-injury and hypertension induced by salt diet. Carbon-tetrachloride induced severe liver fibrosis in KO with the elevated gene expression of growth factors. These phenotypes in KO were reversed by viral-mediated production of adiponectin. Our results indicate that adiponectin should be one of key molecule of the metabolic syndrome and may be a new therapeutic target for the metabolic syndrome.
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PMID:[Adiponectin knockout mice]. 1520 43

Some cardiovascular risk factors, such as hypertension and insulin resistance, are associated with endothelial dysfunction. Insulin regulates both in vitro and in vivo expression of endothelial nitric oxide synthase (eNOS) via a pathway involving insulin receptor substrate-1 (IRS-1) and phosphatidylinositol-3 kinase. Recently, we found that human endothelial cells obtained from carriers of the Arg(972) IRS-1 polymorphism exhibited reduced eNOS expression in response to chronic exposure to insulin. A reduction in eNOS expression would be expected to be associated with impaired endothelium-dependent vasodilation. To investigate a possible relationship between Arg(972) IRS-1 polymorphism and endothelial dysfunction in vivo, we enrolled a cohort of 100 never-treated hypertensive subjects. Endothelium-dependent and endothelium-independent vasodilation were assessed by increasing doses of acetylcholine and sodium nitroprusside. IRS-1 polymorphism was detected by PCR. The allelic frequency of the Arg(972) IRS-1 variant was 8.0%. Stratifying subjects according to IRS-1 genotype, we observed that acetylcholine-stimulated forearm blood flow was significantly (P < 0.0001) lower in Gly/Arg heterozygous carriers than in Gly/Gly carriers (11.3 +/- 4.4 vs. 14.7 +/- 5.9 ml/100 ml(-1) of tissue per min(-1)). Sodium nitroprusside caused comparable increments in forearm blood flow in both groups (12.9 +/- 2.4 vs. 13.3 +/- 3.5 ml/100 ml(-1) of tissue per min(-1)). Our data strongly suggest that, by inducing endothelial dysfunction, the Arg(972) IRS-1 polymorphism may contribute to the genetic predisposition to develop cardiovascular disease.
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PMID:Impaired endothelial function in never-treated hypertensive subjects carrying the Arg972 polymorphism in the insulin receptor substrate-1 gene. 1524 Jun 53

Insulin resistance is associated with cardiovascular disease. Impaired insulin receptor substrate (IRS)-mediated signal transduction is a major contributor to insulin resistance. Recently, IRS-1 phosphorylation at serine 307 by stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) has been highlighted as a molecular event that causes insulin resistance. We investigated IRS-1-mediated insulin signaling, IRS-1 phosphorylation at serine 307, and SAPK/JNK activation status in the aorta of spontaneously hypertensive rats (SHR) by immunoprecipitation and immunoblotting. Insulin-stimulated tyrosine phosphorylation of insulin receptor and IRS-1 in SHR was decreased to 55% (P<0.01) and 40% (P<0.01) of the levels in Wistar-Kyoto rats (WKY), respectively. Insulin-stimulated IRS-1-associated phosphatidylinositol 3-kinase activation in SHR was reduced to 28% of the level in WKY (P<0.0001). Immunoblot analysis revealed that phosphorylated IRS-1 at serine 307 in SHR was increased to 261% (P<0.001) of the level in WKY. Phosphorylated (activated) SAPK/JNK in SHR was increased to 223% of the level in WKY (P<0.01). Serine-phosphorylated IRS-1 that was immunoprecipitated from the aorta of SHR was capable of inhibiting in vitro tyrosine phosphorylation by recombinant insulin receptor compared with WKY-derived IRS-1. These findings demonstrate that insulin resistance in the aorta of SHR was associated with elevated IRS-1 phosphorylation at serine 307 and increased SAPK/JNK activation. The present study suggests that increased SAPK/JNK activation may play an important role in the pathogenesis of vascular insulin resistance via inhibitory serine phosphorylation of IRS-1.
Hypertension 2004 Oct
PMID:Increased insulin receptor substrate 1 serine phosphorylation and stress-activated protein kinase/c-Jun N-terminal kinase activation associated with vascular insulin resistance in spontaneously hypertensive rats. 1530 44

Type 2 diabetes mellitus is a complex metabolic disorder resulting from the action and interaction of many genetic and environmental factors. It has been reported that polymorphisms in genes involved in the metabolism of glucose are associated with the susceptibility to develop type 2 diabetes mellitus. Although the risk of developing type 2 diabetes mellitus increases with age, as well as with obesity and hypertension, its prevalence and incidence are different among geographical regions and ethnic groups. In Mexico, a higher prevalence and incidence has been described in the south of the country, and differences between urban and rural communities have been observed. We studied 73 individuals from Santiago Jamiltepec, a small indigenous community from Oaxaca State, Mexico. This population has shown a high prevalence of type 2 diabetes mellitus, and the aim of this study was to analyze the relationship between the Pst I (insulin gene), Nsi I (insulin receptor gene) and Gly972Arg (insulin receptor substrate 1 gene) polymorphisms and type 2 diabetes mellitus, obesity and hypertension in this population. Clinical evaluation consisted of BMI and blood pressure measurements, and biochemical assays consisted of determination of fasting plasma insulin and glucose levels. PCR and restriction enzyme digestion analysis were applied to genomic DNA to identify the three polymorphisms. From statistical analysis carried out here, individually, the Pst I, Nsi I and Gly972Arg polymorphisms were not associated with the type 2 diabetes, obese or hypertensive phenotypes in this population. Nevertheless, there was an association between the Nsi I and Pst I polymorphisms and increased serum insulin levels.
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PMID:DNA polymorphism analysis of candidate genes for type 2 diabetes mellitus in a Mexican ethnic group. 1558 31

The so-called essential hypertension is not a single entity but a mixed bag with several polygenic quantitative traits acting in concert in different combinations in different individuals. This review collates all published information from different centres using different approaches to identify candidate genes in human hypertension. 1) gene targeting approach in animal models of HT (Smithies and Maeda, 1995); 2) identification of 874 candidate SNPs in 75 candidate genes for human HT (Halushka et al, 1999); 3) comparative genomic approach translating QTLs between rat and human HT, to identify 26 chromosome regions on 16 autosomes (Stoll M et al, 2000); 4) Ten centimorgan genome-wide scan done on 2010 affected sibling pairs drawn from 1599 severely hypertensive families (Caulfield et al, 2003). The molecular mechanisms of various molecules involved in the homeostasis of blood pressure are discussed. NO, O2, PG12, EDHF, endothelin, IL-6, selectin, phospholipase A2G1B, BH4, SOD, IRS-1, adrenomedullin, PAMP, CGRP, ANP, bradykinin and bombesin; adducin alpha, beta, gamma, SAH, renin, angiotensinogen. angiotensin II, aldosterone CYP11B1, mineralocorticoid receptors, 11betaHSD, DBH, PNMT, beta2adrenoreceptors, and genes related to ion transport-sodium-lithium cotransporters, ENaC, NaCl cotransporters NKCC2, KCNJ and NaKATPase. Altered gene expression in fetus due to maternal malnutrition also "programmes" for adult hypertension.
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PMID:Hypertension: molecular approach. 1563 21

Several association studies have indicated the insulin receptor substrate-1 (IRS-1) gene G972R variant as a genetic risk factor for insulin resistance, particularly in presence of obesity. A few studies have also suggested a possible effect of the G972R variant on insulin secretion. The aim of this study was to evaluate the role of the IRS-1 gene G972R variant in 61 subjects with "uncomplicated" obesity [i.e. without diabetes, hypertension, dyslipidemia, coronary artery disease (CAD)], studied by hyperinsulinemic-euglycemic clamp. The presence of the G972R variant, detected in real-time with LightCycler hybridisation probes, was related to the indexes of insulin sensitivity. Furthermore, the possible role of this variant on insulin secretion was studied by means of insulin release indexes derived from oral tolerance test (OGTT). Twenty-four point five percent (24.5%) (no.=15) of the obese subjects proved to be carriers of the G972R variant. M index (p<0.05), non-oxidative glucose (p<0.01), insulin clearance (p<0.03) and insulin sensitivity index (ISI) (p<0.005) were all significantly reduced in G972R carriers compared to non-carriers, indicating a significant reduction in insulin sensitivity in carriers of the variant. A logistic regression analysis confirmed the independent association between the G972R variant and reduced insulin sensitivity (p<0.03). The interaction between obesity and the G972R variant was also independently associated with a reduced insulin sensitivity (p<0.005), suggesting that obesity and G972R variant were more than additive in predicting insulin resistance. The analysis of insulin release indexes did not show any significant differences. Our results demonstrate the association of the G972R variant of the IRS-1 gene with reduced insulin sensitivity in obese subjects, and indicate a possible interaction between the IRS-1 variant and obesity in worsening of insulin sensitivity.
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PMID:The G972R variant of the insulin receptor substrate-1 (IRS-1) gene is associated with insulin resistance in "uncomplicated" obese subjects evaluated by hyperinsulinemic-euglycemic clamp. 1563 29

Essential hypertension is frequently associated with insulin resistance of skeletal muscle glucose transport, with a potential role of angiotensin II in the pathogenesis of both conditions. The male heterozygous TG(mREN2)27 rat harbors the mouse transgene for renin, exhibits local elevations in angiotensin II, and is an excellent model of both hypertension and insulin resistance. The present study was designed to investigate the potential cellular mechanisms for insulin resistance in this hypertensive animal model, including an assessment of elements of the insulin-signaling pathway. Compared with nontransgenic, normotensive Sprague-Dawley control rats, male heterozygous TG(mREN2)27 rats displayed elevated (P < 0.05) fasting plasma insulin (74%), an exaggerated insulin response (108%) during an oral glucose tolerance test, and reduced whole body insulin sensitivity. TG(mREN2)27 rats also exhibited decreased insulin-mediated glucose transport and glycogen synthase activation in both the type IIb epitrochlearis (30 and 46%) and type I soleus (22 and 64%) muscles. Importantly, there were significant reductions (approximately 30-50%) in insulin stimulation of tyrosine phosphorylation of the insulin receptor beta-subunit and insulin receptor substrate-1 (IRS-1), IRS-1 associated with the p85 subunit of phosphatidylinositol 3-kinase, Akt Ser473 phosphorylation, and Ser9 phosphorylation of glycogen synthase kinase-3beta in epitrochlearis and soleus muscles of TG(mREN2)27 rats. Soleus muscle triglyceride concentration was 25% greater in the transgenic group compared with nontransgenic animals. Collectively, these data provide the first evidence that the insulin resistance of the hypertensive male heterozygous TG(mREN2)27 rat can be attributed to specific defects in the insulin-signaling pathway in skeletal muscle.
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PMID:Defective insulin signaling in skeletal muscle of the hypertensive TG(mREN2)27 rat. 1565 91

Male heterozygous TG(mREN2)27 rats (TGR) overexpress a murine renin transgene, display marked hypertension, and have insulin resistance of skeletal muscle glucose transport and insulin signaling. We have shown previously that voluntary exercise training by TGR improves insulin-mediated skeletal muscle glucose transport (Kinnick TR, Youngblood EB, O'Keefe MP, Saengsirisuwan V, Teachey MK, and Henriksen EJ. J Appl Physiol 93: 805-812, 2002). The present study evaluated whether this training-induced enhancement of muscle glucose transport is associated with upregulation of critical insulin signaling elements, including insulin receptor substrate-1 (IRS-1), phosphatidylinositol 3-kinase, Akt, and glycogen synthase kinase-3. TGR remained sedentary or ran spontaneously in activity wheels for 6 wk, averaging 7.1 +/- 0.8 km/day by the end of week 3 and 4.3 +/- 0.5 km/day over the final week of training. Exercise training reduced total abdominal fat by 20% (P < 0.05) in TGR runners (2.64 +/- 0.01% of body weight) compared with sedentary TGR controls (3.28 +/- 0.01%). Insulin-stimulated (2 mU/ml) glucose transport activity in soleus muscle was 36% greater in TGR runners compared with sedentary TGR controls. However, the protein expression and functionality of tyrosine phosphorylation of insulin receptor and IRS-1, IRS-1 associated with the p85 regulatory subunit of phosphatidylinositol 3-kinase, and Ser473 phosphorylation of Akt were not altered by exercise training. Only insulin-stimulated glycogen synthase kinase-3beta Ser9 phosphorylation was increased (22%) by exercise training. These results indicate that voluntary exercise training in TGR can enhance insulin-mediated glucose transport in skeletal muscle, as well as reduce total abdominal fat mass. However, this adaptive response in muscle occurs independently of modifications in the proximal elements of the insulin signaling cascade.
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PMID:Voluntary exercise training enhances glucose transport but not insulin signaling capacity in muscle of hypertensive TG(mREN2)27 rats. 1571 10

Insulin resistance is a major player in the pathogenesis of the metabolic syndrome and type 2 diabetes, and yet, the mechanisms responsible for it remain poorly understood. Magnetic resonance spectroscopy studies in humans suggest that a defect in insulin-stimulated glucose transport in skeletal muscle is the primary metabolic abnormality in insulin-resistant type 2 diabetics. Fatty acids appear to cause this defect in glucose transport by inhibiting insulin-stimulated tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-1 associated phosphatidylinositol 3-kinase activity. A number of different metabolic abnormalities may increase intramyocellular/intrahepatic fatty acid metabolites; these include increased fat delivery to muscle/liver as a consequence of either excess energy intake or defects in adipocyte fat metabolism and acquired or inherited defects in mitochondrial fatty acid oxidation. Understanding the molecular/biochemical defects responsible for insulin resistance is beginning to unveil novel therapeutic targets for treatment of the metabolic syndrome and type 2 diabetes.
Hypertension 2005 May
PMID:Mechanisms of insulin resistance in humans and possible links with inflammation. 1582 95

Clinical evidence suggests a relationship between hypertension and insulin resistance, and cross-talk between angiotensin II (Ang II) and insulin signaling pathways may take place. We now report the effect of Ang II on insulin-induced glucose uptake and its intracellular mechanisms in vascular smooth muscle cells (VSMC). We examined the translocation of glucose transporter-4 (GLUT-4) and glucose uptake in rat aortic smooth muscle cells (RASMC). Mitogen-activated protein (MAP) kinases and Akt activities, and phosphorylation of insulin receptor substrate-1 (IRS-1) at the serine and tyrosine residues were measured by immunoprecipitation and immunoblotting. As a result, Ang II inhibited insulin-induced GLUT-4 translocation from cytoplasm to the plasma membrane in RASMC. Ang II induced extracellular signal-regulated kinase (ERK) 1/2 and c-Jun N-terminal kinase (JNK) activation and IRS-1 phosphorylation at Ser307 and Ser616. Ang II-induced Ser307 and Ser616 phophorylation of IRS-1 was inhibited by a MEK inhibitor, PD98059, and a JNK inhibitor, SP600125. Ang II inhibition of insulin-stimulated IRS-1 tyrosyl phophorylation and Akt activation were reversed by PD98059 but not by SP600125. Ang II inhibited insulin-induced glucose uptake, which was also reversed by PD98059 but not by SP600125. It is shown that Ang II-induced ERK1/2 activation inhibits insulin-dependent glucose uptake through serine phophorylation of IRS-1 in RASMC.
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PMID:ERK1/2 activation by angiotensin II inhibits insulin-induced glucose uptake in vascular smooth muscle cells. 1592 82


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