Endothelial Nitric Oxide Synthase Polymorphisms Are Associated With Type 2 Diabetes and the Insulin Resistance Syndrome

Monti, Lucilla D.; Barlassina, Cristina; Citterio, Lorena; Galluccio, Elena; Berzuini, Carlo; Setola, Emanuela; Valsecchi, G.; Lucotti, Pietro; Pozza, G.; Bernardinelli, Luisa; Casari, Giorgio; Piatti, PierMarco

doi:10.2337/diabetes.52.5.1270

Cited by 183 publications

(149 citation statements)

References 32 publications

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“…This implies that eNOS gene may also indicate susceptibility to diabetes. It has been shown that eNOS polymorphisms are implicated in insulin resistance and T2DM 75,76 ; however, replication studies providing strong evidence of this association do not exist.…”

Section: Discussionmentioning

confidence: 98%

Endothelial nitric oxide synthase gene polymorphisms and diabetic nephropathy: A HuGE review and meta-analysis

Ζιντζαράς

Papathanasiou

Stefanidis

2009

Genetics in Medicine

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Candidate-gene association studies that examined the association between polymorphisms of endothelial nitric oxide synthase (NOS3) gene (G894T, 4b/a, and T786C) and diabetic nephropathy or diabetes leading to severe nephropathy produced inconclusive results. Thus, a meta-analysis of all candidate-gene association studies with endothelial nitric oxide synthase genotyping (7401 cases and 8046 controls) was conducted. Other study designs, such as family-based association studies and genome-wide linkage and association studies were also reviewed for supportive evidence of implication of endothelial nitric oxide synthase gene in diabetic nephropathy. The meta-analysis showed that G894T is significantly associated with diabetic nephropathy and diabetes leading to severe nephropathy in type 2 diabetics and in East Asians, respectively. Concerning the 4b/a polymorphism and its relationship to diabetes leading to severe nephropathy, a significant association was shown for East Asians. Heterogeneity between studies was in general high. There was no differential magnitude of effect in large versus small studies. One genome-wide linkage scan provided evidence of linkage nearby the endothelial nitric oxide synthase locus. Studies exploring gene and environment interactions with endothelial nitric oxide synthase polymorphisms may help understand better the genetics of diabetic nephropathy. Genet Key Words: eNOS, NOS3, G894T, 4b/a, T786C, diabetic nephropathy, diabetes, polymorphism, meta-analysis, genetic epidemiology Gene and gene variantsVascular endothelial nitric oxide (NO) regulates endothelial function and precipitates vasodilatory effects in multiple organs, including the kidney. 1 NO is produced by the oxidation of L-arginine to L-citrulline by NO synthase (NOS). There are three isoforms of NOS: endothelial NOS (eNOS), neuronal NOS, and inducible NOS. 2,3 Each isoform is coded by separate genes with a different pattern of expression. 4 The eNOS gene (NOS3) is located on chromosome 7q35-36, and it comprises 26 exons and 25 introns, with an entire length of 21kb. 4 Variants of eNOS gene contribute to endothelial dysfunction and attenuate the NO production. 5 Dysfunctional eNOS may play a critical role in the pathogenetic pathway, leading to diabetic vascular complications including diabetic nephropathy (DN). 6 Several polymorphisms of the eNOS gene have been identified, and their association with various diseases has been investigated, including coronary artery disease, myocardial infarction, coronary spasm, hypertension, end-stage renal disease (ESRD), and DN. 4,[7][8][9][10] The most clinically relevant polymorphisms that have been described in the eNOS gene 11 are the following: (i) a G894T substitution in exon 7 that results in a Glu to Asp substitution at codon 298, 7 (ii) an insertion-deletion in intron 4 consisting of two alleles (the a-deletion has 4 tandem 27-bp repeats, and the b-insertion has 5 repeats), 12 and (iii) a T786C substitution in the promoter region, which is strongly linked to 4b/a....

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Section: Discussionmentioning

confidence: 98%

Endothelial nitric oxide synthase gene polymorphisms and diabetic nephropathy: A HuGE review and meta-analysis

Ζιντζαράς

Papathanasiou

Stefanidis

2009

Genetics in Medicine

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“…The increase in fasting NOx levels has been already reported in insulin-resistant subjects, 14 -16 and recently our group demonstrated that not only type 2 diabetic patients but also control subjects carrying 2 single nucleotide variants of endothelial NO synthase gene (E298D and IVS18ϩ27A/C) had increased fasting NOx levels in the presence of IR, suggesting a common trait unifying IR syndrome and cardiovascular disease. 17 The impairment of NOx release during OGTT in patients with restenosis was never, to our knowledge, previously demonstrated. This finding supports previous data in which restenosis was related to impaired NO production by the damaged endothelium.…”

Section: Piatti Et Al New Predictors Of In-stent Restenosis 2077mentioning

confidence: 97%

Association of insulin resistance, hyperleptinemia, and impaired nitric oxide release with in-stent restenosis in patients undergoing coronary stenting

Piatti¹,

Mario²,

Monti³

2004

ACC Current Journal Review

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Background-Previously undiagnosed diabetes, impaired glucose tolerance, and insulin resistance are common in patients with acute myocardial infarction and coronary heart disease (CHD) and might be involved in early restenosis after stent implantation. To evaluate whether markers of insulin resistance syndrome, including leptin, and endothelial dysfunction are related to increased rate of early restenosis, we studied nondiabetic patients with CHD after successful coronary stenting. Methods and Results-Both patients with CHD undergoing coronary stenting (120 patients) and control subjects (58 patients) were submitted to an oral glucose tolerance test (OGTT). Fasting leptin levels and fasting and postglucose load insulin sensitivity were assessed. Endothelial function was measured by nitrite and nitrate release (NOx) during OGTT. More than 50% of patients treated with stent implantation presented impaired glucose tolerance or type 2 diabetes, which was previously undiagnosed. These patients also had higher glucose, insulin, and leptin levels than control subjects. Among the stented patients, insulin and leptin levels were higher in patients with restenosis than in patients without restenosis. A significant increase in NOx levels was found during OGTT both in patients without restenosis and in control subjects. On the contrary, NOx profiles were blunted in patients with restenosis. At multiple regression analysis, only ⌬AUC-NOx areas and insulin sensitivity index showed an independent correlation with the minimal lumen diameter at follow-up. Conclusions-We demonstrated that insulin resistance and endothelial dysfunction are independent predictors of early restenosis after coronary stenting.

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“…One such candidate mechanism, linking metabolic and cardiovascular disease in humans, is a defect in endogenous synthesis and bioavailability of nitric oxide (NO). Indeed, polymorphism in the endothelial NO synthase (eNOS) gene is associated with metabolic syndrome in humans (2,3), and eNOS-deficient mice display many of its defining features, including hypertension, dyslipidemia, insulin resistance, and increased weight gain (4)(5)(6)(7).…”

mentioning

confidence: 99%

Dietary inorganic nitrate reverses features of metabolic syndrome in endothelial nitric oxide synthase-deficient mice

Carlström

Larsen

Nyström

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

321

246

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The metabolic syndrome is a clustering of risk factors of metabolic origin that increase the risk for cardiovascular disease and type 2 diabetes. A proposed central event in metabolic syndrome is a decrease in the amount of bioavailable nitric oxide (NO) from endothelial NO synthase (eNOS). Recently, an alternative pathway for NO formation in mammals was described where inorganic nitrate, a supposedly inert NO oxidation product and unwanted dietary constituent, is serially reduced to nitrite and then NO and other bioactive nitrogen oxides. Here we show that several features of metabolic syndrome that develop in eNOS-deficient mice can be reversed by dietary supplementation with sodium nitrate, in amounts similar to those derived from eNOS under normal conditions. In humans, this dose corresponds to a rich intake of vegetables, the dominant dietary nitrate source. Nitrate administration increased tissue and plasma levels of bioactive nitrogen oxides. Moreover, chronic nitrate treatment reduced visceral fat accumulation and circulating levels of triglycerides and reversed the prediabetic phenotype in these animals. In rats, chronic nitrate treatment reduced blood pressure and this effect was also present during NOS inhibition. Our results show that dietary nitrate fuels a nitratenitrite-NO pathway that can partly compensate for disturbances in endogenous NO generation from eNOS. These findings may have implications for novel nutrition-based preventive and therapeutic strategies against cardiovascular disease and type 2 diabetes.glucose | insulin | s-nitrosothiol | obesity | bacteria

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Endothelial Nitric Oxide Synthase Polymorphisms Are Associated With Type 2 Diabetes and the Insulin Resistance Syndrome

Cited by 183 publications

References 32 publications

Endothelial nitric oxide synthase gene polymorphisms and diabetic nephropathy: A HuGE review and meta-analysis

Endothelial nitric oxide synthase gene polymorphisms and diabetic nephropathy: A HuGE review and meta-analysis

Association of insulin resistance, hyperleptinemia, and impaired nitric oxide release with in-stent restenosis in patients undergoing coronary stenting

Dietary inorganic nitrate reverses features of metabolic syndrome in endothelial nitric oxide synthase-deficient mice

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