Association of - 786T-C mutation of endothelial nitric oxide synthase gene with insulin resistance

Ohtoshi, Kentaro; Yamasaki, Yoshimitsu; Gorogawa, Shin-ichi; Hayaishi-Okano, Rieko; Node, Koichi; Matsuhisa, Munehide; Kajimoto, Yoshitaka; Hori, Masatsugu

doi:10.1007/s00125-002-0922-6

Cited by 59 publications

(9 citation statements)

References 44 publications

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“…Therefore, a genetic variation that affects NO regulation may contribute to both alteration in vascular tone and to IR. Consistent with this hypothesis, few clinical studies have shown a significant association between that T −786 →C polymorphism in the promoter region of the eNOS gene and IR in both non-diabetic subjects and Type 2 diabetic patients [11,12]. In this framework, our study confirms and extends previous results in patients without known diabetes but with systolic LV dysfunction.…”

Section: Discussionsupporting

confidence: 92%

“…A recent study showed that the T −786 →C promoter polymorphism was specifically associated with a significant reduction in eNOS mRNA expression in myocardial tissue obtained from failing human myocardium, while a different eNOS polymorphism G(894)-->T of exon 7 was not. The authors concluded that the reduced eNOS expression associated with the promoter gene polymorphism might be involved in the pathogenesis of cardiac failure [12]. Our findings did not discover a direct relationship between eNOS polymorphism and the severity of LV dysfunction; however, these conditions were linked by the presence of IR.…”

Section: Discussioncontrasting

confidence: 79%

“…In an experimental study, Duplain et al showed that knockout mice for the endothelial NO synthase (eNOS) gene were insulin-resistant and hypertensive, suggesting that eNOS is important not only for cardiovascular control but also for glucose homeostasis [9]. In humans, a thymidine-to-cytosine (T to C) transition mutation (T −786 →C) in the promoter region of the gene has been associated with reduced eNOS expression [10] and has been linked to IR both in non-diabetic subjects and Type 2 diabetic patients [11,12]. …”

Section: Introductionmentioning

confidence: 99%

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T−786→C polymorphism of the endothelial nitric oxide synthase gene is associated with insulin resistance in patients with ischemic or non ischemic cardiomyopathy

et al. 2012

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BackgroundInsulin resistance (IR) and endothelial dysfunction are frequently associated in cardiac disease. The T−786→C variant in the promoter region of the endothelial nitric oxide synthase (eNOS) gene has been associated with IR in both non-diabetic and diabetic subjects. Aim of the study was to assess the reciprocal relationships between T−786→C eNOS polymorphism and IR in ischemic and non-ischemic cardiomyopathy.MethodA group of 132 patients (108 males, median age 65 years) with global left ventricular (LV) dysfunction secondary to ischemic or non-ischemic heart disease was enrolled. Genotyping of T−786→C eNOS gene promoter, fasting glucose, insulin, and insulin resistance (defined as HOMA-IR index > 2.5) were determined in all patients.ResultsGenotyping analysis yielded 37 patients homozygous for the T allele (TT), 70 heterozygotes (TC) and 25 homozygous for C (CC). Patients with CC genotype had significantly higher systemic arterial pressure, blood glucose, plasma insulin and HOMA index levels than TT. At multivariate logistic analysis, the history of hypertension and the genotype were the only predictors of IR. In particular, CC genotype increased the risk of IR (CI% 1.4-15.0, p < 0.01) 4.5-fold. The only parameter independently associated with the extent of LV dysfunction and the presence of heart failure (HF) was the HOMA index (2.4 CI% 1.1-5.6, p < 0.04).ConclusionsT−786→C eNOS polymorphism was the major independent determinant of IR in a population of patients with ischemic and non-ischemic cardiomyopathy. The results suggest that a condition of primitive eNOS lower expression can predispose to an impairment of glucose homeostasis, which in turn is able to affect the severity of heart disease.

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Section: Discussionsupporting

confidence: 92%

Section: Discussioncontrasting

confidence: 79%

Section: Introductionmentioning

confidence: 99%

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T−786→C polymorphism of the endothelial nitric oxide synthase gene is associated with insulin resistance in patients with ischemic or non ischemic cardiomyopathy

et al. 2012

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“…Most notably, several studies have associated a T(−786)C variant of the NOS3 gene with insulin resistance [318-320]. Several other genetic variants in the NOS3 locus are associated with T2D [321], susceptibility for insulin resistance, hypertriglyceridemia, and low HDL [322], or worsened endothelial function in individuals prone to T2D [323].…”

Section: Regulation Of Obesity and Insulin Resistance By Nomentioning

confidence: 99%

Regulation of obesity and insulin resistance by nitric oxide

Sansbury

Hill

2014

Free Radical Biology and Medicine

220

193

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Obesity is a risk factor for developing type 2 diabetes and cardiovascular disease and has quickly become a world-wide pandemic with few tangible and safe treatment options. While it is generally accepted that the primary cause of obesity is energy imbalance, i.e., the calories consumed are greater than are utilized, understanding how caloric balance is regulated has proven a challenge. Many “distal” causes of obesity, such as the structural environment, occupation, and social influences, are exceedingly difficult to change or manipulate. Hence, molecular processes and pathways more proximal to the origins of obesity—those that directly regulate energy metabolism or caloric intake—appear to be more feasible targets for therapy. In particular, nitric oxide (NO) is emerging as a central regulator of energy metabolism and body composition. NO bioavailability is decreased in animal models of diet-induced obesity and in obese and insulin resistant patients, and increasing NO output has remarkable effects on obesity and insulin resistance. This review discusses the role of NO in regulating adiposity and insulin sensitivity and places its modes of action into context with the known causes and consequences of metabolic disease.

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“…Correlations with anthropometric parameters also revealed that carriers of the bb genotype had significantly higher BMI compared to those homozygous for the (a) allele [231]. Although this VNTR has not been reported to be associated with T2D, other eNOS SNPs are associated with T2D [231] and insulin resistance [232–234]. eNOS SNPs also appear to increase susceptibility for hypertriglyceridemia and low HDL [235] and worsen endothelial function in individuals prone to T2D [236].…”

Section: Main Textmentioning

confidence: 99%

The association of insertions/deletions (INDELs) and variable number tandem repeats (VNTRs) with obesity and its related traits and complications

Say

2017

J Physiol Anthropol

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BackgroundDespite the fact that insertions/deletions (INDELs) are the second most common type of genetic variations and variable number tandem repeats (VNTRs) represent a large portion of the human genome, they have received far less attention than single nucleotide polymorphisms (SNPs) and larger forms of structural variation like copy number variations (CNVs), especially in genome-wide association studies (GWAS) of complex diseases like polygenic obesity. This is exemplified by the vast amount of review papers on the role of SNPs and CNVs in obesity, its related traits (like anthropometric measurements, biochemical variables, and eating behavior), and its related complications (like hypertension, hypertriglyceridemia, hypercholesterolemia, and insulin resistance—collectively known as metabolic syndrome). Hence, this paper reviews the types of INDELs and VNTRs that have been studied for association with obesity and its related traits and complications.Main body of the abstractThese INDELs and VNTRs could be found in the obesity loci or genes from the earliest GWAS and candidate gene association studies, like FTO, genes in the leptin–proopiomelanocortin pathway, and UCP2/3. Given the important role of the brain serotonergic and dopaminergic reward system in obesity susceptibility, the association of INDELs and VNTRs in these neurotransmitters’ metabolism and transport genes with obesity is also reviewed. Next, the role of INS VNTR in obesity and its related traits is questionable, since recent large-scale studies failed to replicate the earlier positive associations. As obesity results in chronic low-grade inflammation of the adipose tissue, the proinflammatory cytokine gene IL1RA and anti-inflammatory cytokine gene IL4 have VNTRs that are implicated in obesity. A systemic proinflammatory state in combination with activation of the renin–angiotensin system and decreased nitric oxide bioavailability as found in obesity leads to endothelial dysfunction. This explains why VNTR and INDEL in eNOS and ACE, respectively, could be predisposing factors of obesity. Finally, two novel genes, DOCK5 and PER3, which are involved in the regulation of the Akt/MAPK pathway and circadian rhythm, respectively, have VNTRs and INDEL that might be associated with obesity.Short conclusionIn conclusion, INDELs and VNTRs could have important functional consequences in the pathophysiology of obesity, and research on them should be continued to facilitate obesity prediction, prevention, and treatment.

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Association of - 786T-C mutation of endothelial nitric oxide synthase gene with insulin resistance

Cited by 59 publications

References 44 publications

T−786→C polymorphism of the endothelial nitric oxide synthase gene is associated with insulin resistance in patients with ischemic or non ischemic cardiomyopathy

T−786→C polymorphism of the endothelial nitric oxide synthase gene is associated with insulin resistance in patients with ischemic or non ischemic cardiomyopathy

Regulation of obesity and insulin resistance by nitric oxide

The association of insertions/deletions (INDELs) and variable number tandem repeats (VNTRs) with obesity and its related traits and complications

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