Association of the nitric oxide synthase gene polymorphism with an increased risk for progression to diabetic nephropathy in type 2 diabetes.

Neugebauer, Sabine; Baba, T.; Watanabe, Toshiki

doi:10.2337/diabetes.49.3.500

Cited by 118 publications

(77 citation statements)

References 9 publications

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“…There are several reports showing the association of -786T-C polymorphism and diabetic nephropathy [35,36], and there is a report showing the dissociation of Glu298Asp polymorphism and diabetic nephropathy [37]. In this study, there was no difference in the number of patients taking an ACE inhibitor, which has been reported to reduce urinary protein.…”

Section: Discussionsupporting

confidence: 44%

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

et al. 2002

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Aims/hypothesis. Endothelial derived nitric oxide synthase (eNOS) gene polymorphisms affect eNOS activity and are associated with abnormal vasomotility and impaired local blood flow. A decrease in local blood flow has been reported to cause insulin resistance. The aim of this study was to examine a possible association of two eNOS polymorphisms, Glu298Asp (G894T) in exon 7 and -786T-C mutation with insulin resistance. Methods. Genotypes of both Glu298Asp and -786T-C mutation were examined by the PCR-RFLP method. Plasma nitrate and nitrite concentrations were also measured. Results. The allele frequencies of both polymorphisms showed no considerable differences in 233 non-diabetic subjects and 301 patients with Type II (non-insulin-dependent) diabetes mellitus. Non-diabetic subjects with the -786C allele had (p<0.05) higher fasting plasma insulin and homeostasis model assessment of insulin resistance than those with the -786T/ -786T genotype. Diabetic subjects with -786C allele showed higher HbA 1c than those with the -786T/ -786T genotype. A euglycaemic hyperinsulinemic clamp study done on 71 of the 301 patients showed a lower glucose infusion rate in diabetic patients with the -786C allele than those without it. In diabetic patients with the -786C allele, plasma nitrate and nitrite concentrations were lower than in subjects without it (p=0.026). No differences were observed between mutant carriers of Glu298Asp and non-carriers among both nondiabetic subjects and Type II diabetic patients. Conclusions/interpretation. The -786T-C mutation of the eNOS gene is associated with insulin resistance in both Japanese non-diabetic subjects and Type II diabetic patients. [Diabetologia (2002[Diabetologia ( ) 45:1594[Diabetologia ( -1601 Keywords Endothelial nitric oxide synthase, polymorphism, glucose infusion rate, homeostasis model assessment of insulin resistance insulin resistance, intima-media thickness. Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Suita City, Japan a key role in the regulation of vascular tone. Skeletal muscle glucose uptake is enhanced by insulin-mediated vasodilation and the decrease in local blood flow can result in insulin resistance [1][2][3][4][5]. However, several reports deny a major role of endothelial NO production in determining insulin sensitivity [6,7].Recently eNOS knockout mice have been reported to be insulin resistant [8]. These mice have also shown a decrease in whole-body and muscle-glucose uptake as well as the simultaneous decrease in the local blood flow [9]. Two major polymorphisms have been found in the human eNOS gene: Glu298Asp (G894T) in exon 7 and -786T-C mutation in the 5′-flanking region. Glu298Asp causes a structural change of the eNOS Endothelial derived nitric oxide (NO), synthesized from L-arginine by the endothelium isoform of NO synthase (eNOS), mediates local vasodilation and plays

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Section: Discussionsupporting

confidence: 44%

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

et al. 2002

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“…Our results in mice support the finding in human diabetes that a predisposition for development of nephropathy is closely associated with eNOS polymorphisms. 19,55,56 Determination of the molecular pathways through which eNOS deficiency causes glomerular endothelial damage in the setting of diabetes may provide new insights into pathogenesis of diabetic nephropathy and offer better treatment strategies.…”

Section: Discussionmentioning

confidence: 99%

Deficiency of Endothelial Nitric-Oxide Synthase Confers Susceptibility to Diabetic Nephropathy in Nephropathy-Resistant Inbred Mice

Kanetsuna

Takahashi

Nagata

et al. 2007

The American Journal of Pathology

166

150

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Recent studies have implicated dysfunctional endothelial nitric-oxide synthase (eNOS) as a common pathogenic pathway in diabetic vascular complications. However, functional consequences are still incompletely understood. To determine the role of eNOS-derived nitric oxide (NO) in diabetic nephropathy, we induced diabetes in eNOS knockout (KO) and wild-type (WT) mice on the C57BL6 background, using low-dose streptozotocin injection, and we investigated their glomerular phenotype at up to 20 weeks of diabetes. Although the severity of hyperglycemia in diabetic eNOS KO mice was similar to diabetic WT mice, diabetic eNOS KO mice developed overt albuminuria, hypertension, and glomerular mesangiolysis, whereas diabetic WT and nondiabetic control mice did not. Glomerular hyperfiltration was also significantly reduced in diabetic eNOS KO mice. Electron micrographs from diabetic eNOS KO mice revealed an injured endothelial morphology, thickened glomerular basement membrane, and focal foot process effacement. Furthermore, the anionic sites at glomeru- Nitric oxide (NO) is a free radical that mediates diverse functions in a range of biological systems.1 NO is produced by a family of nitric-oxide synthase (NOS) enzymes to catalyze the stoichiometric five-electron oxidation of the terminal quanidino group of L-arginine to produce NO and L-citrulline. Three NOS isoforms have been distinguished in mammalian species: neuronal NOS, inducible NOS, which is expressed in a variety of activated tissues, and endothelial NOS (eNOS).1 In the vasculature, NO is mostly generated by eNOS, and the generated NO plays a crucial role in maintaining vascular homeostasis, including vascular tone, leukocyte adhesion to endothelium, proliferation of vascular smooth muscle cells, and platelet aggregation and adhesion to the vessel wall.

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“…In surveying a recent 2-year period (July 1999 to July 2001), we found wide variability with respect to the quality of duration data, the analytic approaches to handle duration data, and the discussion of how duration characteristics of the study population may have influenced results (15)(16)(17)(18)(19)(20).…”

Section: Treatment Of Duration In Recent Diabetes Articlesmentioning

confidence: 99%

Genetic Studies of Late Diabetic Complications

2002

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Genes play a role in many processes underlying late diabetic complications, but efforts to identify genetic variants have produced disappointing and contradictory results. Here, we evaluate whether the study designs and analytic methods commonly being used are optimal for finding susceptibility genes for diabetic complications. We do so by generating plausible genetic models and assessing the performance of case-control and family-based trio study designs. What emerges as a key determinant of success is duration of diabetes. This perspective focuses on duration of diabetes before complication onset and its influence on the ability to detect major and minor gene effects. It does not delve into the distinct effect of duration after complication onset, which can enrich case subjects with genotypes conferring survival advantage. We use clinically diagnosed nephropathy in type 1 diabetes to show how ignoring duration can result in considerable power loss in both case-control and family-based trio designs. We further show how, under certain circumstances, disregard for duration information can paradoxically lead to implicating nonrisk alleles as causative. Our results indicate that problems can be minimized by selecting case subjects with short diabetes duration and, to a lesser extent, control subjects with long duration or, perhaps, by adjusting for duration during analysis. Diabetes 51: [1655][1656][1657][1658][1659][1660][1661][1662] 2002

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Association of the nitric oxide synthase gene polymorphism with an increased risk for progression to diabetic nephropathy in type 2 diabetes.

Cited by 118 publications

References 9 publications

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

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

Deficiency of Endothelial Nitric-Oxide Synthase Confers Susceptibility to Diabetic Nephropathy in Nephropathy-Resistant Inbred Mice

Genetic Studies of Late Diabetic Complications

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