Defective nitric oxide synthesis: a link between metabolic insulin resistance, sympathetic overactivity and cardiovascular morbidity

Scherrer, Urs; Sartori, Cláudio

doi:10.1530/eje.0.1420315

Cited by 107 publications

(86 citation statements)

References 118 publications

(47 reference statements)

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“…15,16 We therefore used a transgenic animal model to study the interaction between eNOS and insulin in the regulation of glucose metabolism. We found that eNOS Ϫ/Ϫ mice were insulin resistant, as evidenced by fasting hyperinsulinemia and glucose infusion rates during euglycemic clamp studies that were roughly 40% lower than in wild-type mice.…”

Section: Discussionmentioning

confidence: 99%

Insulin Resistance, Hyperlipidemia, and Hypertension in Mice Lacking Endothelial Nitric Oxide Synthase

et al. 2001

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Background-Insulin resistance and arterial hypertension are related, but the underlying mechanism is unknown.Endothelial nitric oxide synthase (eNOS) is expressed in skeletal muscle, where it may govern metabolic processes, and in the vascular endothelium, where it regulates arterial pressure. Methods and Results-To study the role of eNOS in the control of the metabolic action of insulin, we assessed insulin sensitivity in conscious mice with disruption of the gene encoding for eNOS. eNOS Ϫ/Ϫ mice were hypertensive and had fasting hyperinsulinemia, hyperlipidemia, and a 40% lower insulin-stimulated glucose uptake than control mice. Insulin resistance in eNOS Ϫ/Ϫ mice was related specifically to impaired NO synthesis, because in equally hypertensive 1-kidney/1-clip mice (a model of renovascular hypertension), insulin-stimulated glucose uptake was normal. Conclusions-These

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Section: Discussionmentioning

confidence: 99%

Insulin Resistance, Hyperlipidemia, and Hypertension in Mice Lacking Endothelial Nitric Oxide Synthase

et al. 2001

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“…A more complex interpretation can be derived from the data from another study showing that ligation of the PIA2-genotype integrin could affect outside-in signalling efficacy with the consequence of more intense platelet-platelet interaction, but also increased adherence to immobilized adhesion molecules. Such events might take place not only in the large high flow vessels, but also in the nutritive microcirculation being regulatory part of the skeletal muscle energy metabolism [27,28].…”

Section: Discussionmentioning

confidence: 99%

Genetic variation of the platelet- surface integrin GPIIb-IIIa ( PIA1/A2- SNP) shows a high association with Type 2 diabetes mellitus

et al. 2003

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Aims/hypothesis. The gene encoding the β 3 -subunit (GPIIIa) of the platelet α 2 β 3 -integrin (fibrinogen receptor) shows a polymorphism PlA1/A2 with the A2 allele putatively associated with an increased risk of acute ischaemic events. This study investigated whether Type 2 diabetes as a particular macrovascular risk factor associates with the thrombogenic PIA2 genotype. Methods. The PlA genotype was determined in 112 consecutive Type 2 diabetic patients additionally classified according to the presence of macrovascular disease. Forty-four non-diabetic patients with angiografically documented cardiovascular disease (CAD/ AMI) and a further 59 non-diabetic subjects with no angiografical signs of CAD were investigated as genomic background control (n=103). PIA-genotyping was carried out by standard restriction fragment length analysis (RFLA) of PCR amplified lymphocyte template DNA. Results. The overall allelic PlA2-prevalence accounted to 34.8% (39/112) in diabetic patients as compared to 14.6% (15/103) in non-diabetic patients [OR 3.1 (1.6-6.1), p<0.01].This odds ratio increased to 7.0 (2.5-19.7), (p<0.01) in subjects free of criteria of macrovascular disease. In non-diabetic control subjects without CAD there was an allelic PIA2 frequency of 10.2% (6/59) as compared to 20.5% (9/44) in patients with CAD and a history of AMI being less than either diabetes subgroup. The PIA2 prevalence in the subgroup of diabetes patients with macrovascular complications did not differ from the respective value in patients without macrovascular disease. [29.0% (20/69) vs. 44.2% (19/43)]. Conclusion/interpretation. This study confirms a trendwise association of PlA2 with severe coronary artery disease, but rather suggests an even stronger, highly significant association with the metabolic condition of Type 2 diabetes mellitus. This justifies the speculation that pathways dependent on the platelet α 2 β 3 integrin physiology could be implicated in the pathogenesis of Type 2 diabetes which lends further support to the "common soil" hypothesis of diabetes and vascular disease. [Diabetologia (2003) Abbreviations: AMI, acute myocardial infarction; CAD, coronary artery disease; GPIIIa, β 3 subunit of the platelet surface α 2 β 3 -integrin (GPIIb-IIIa, fibrinogen-receptor); PIA, platelet antigen; RGD, aminoacidsequence Arg-Gly-Asp; SNP, single nucleotide polymorphism. Diabetologia (2003) 46:984-989

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“…6 There is biochemical and physiological evidence suggesting that basal NO production and NO bioavailability are diminished in T2DM. [7][8] In physiological studies where vascular responses are mediated at least in part by NO, for example flow mediated vasodilatation (FMD), impaired responses are observed in subjects with T2DM. [9][10] Decreased NO bioavailability due to increased oxidative stress or quenching of NO by advanced glycation end-products may underlie the impairment in FMD.…”

Section: Introductionmentioning

confidence: 99%

Effect of dietary nitrate on blood pressure, endothelial function, and insulin sensitivity in type 2 diabetes

Gilchrist

Winyard

Aizawa

et al. 2013

Free Radical Biology and Medicine

217

209

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Diets rich in green, leafy vegetables have been shown to lower BP and reduce the risk of cardiovascular disease. Green, leafy vegetables and beetroots are particularly rich in inorganic nitrate. Dietary nitrate supplementation, via sequential reduction to nitrite and NO, has previously been shown to lower BP and improve endothelial function in healthy humans.We sought to determine if supplementing dietary nitrate with beetroot juice, a rich source of nitrate, will lower BP, improve endothelial function and insulin sensitivity in individuals with type 2 diabetes (T2DM). Twenty-seven patients, age 67.2 +/-4.9 years, (18 male) were recruited for a double blind, randomised, placebo-controlled crossover trial. Participants were randomised to begin in either order a 2 week period of supplementation with 250 ml beetroot juice daily (active) or 250 ml nitratedepleted beetroot juice (placebo). At the conclusion of each intervention period 24 hour ambulatory blood pressure monitoring, tests of macro and microvascular endothelial function and a hyperinsulinaemic isoglycaemic clamp were performed. After two weeks administration of beetroot juice mean ambulatory systolic BP was unchanged: 134.6 ± 8.4 mmHg versus 135.1 ± 7.8 mmHg (mean ± SD) placebo vs. active -mean difference of -0.5 mmHg (placebo-active), p=0.737 (95% CI -3.9 to 2.8). There were no changes in macrovascular or microvascular endothelial function or insulin sensitivity. Supplementation of the diet with 7.5 mmoles of nitrate per day for 2 weeks caused an increase in plasma nitrite and nitrate concentration, but did not lower BP, improve endothelial function or insulin sensitivity in individuals with T2DM.3

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Defective nitric oxide synthesis: a link between metabolic insulin resistance, sympathetic overactivity and cardiovascular morbidity

Cited by 107 publications

References 118 publications

Insulin Resistance, Hyperlipidemia, and Hypertension in Mice Lacking Endothelial Nitric Oxide Synthase

Insulin Resistance, Hyperlipidemia, and Hypertension in Mice Lacking Endothelial Nitric Oxide Synthase

Genetic variation of the platelet- surface integrin GPIIb-IIIa ( PIA1/A2- SNP) shows a high association with Type 2 diabetes mellitus

Effect of dietary nitrate on blood pressure, endothelial function, and insulin sensitivity in type 2 diabetes

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