Lack of association between endothelial nitric oxide synthase glu298Asp variation, visceral obesity and insulin related phenotypes in Turkish type 2 diabetic patients
Keywords:
Glu298Asp polymorphism, Type 2 diabetes, eNOS, Hepatic insulin sensitivity, β-cell indexAbstract
Nitric oxide (NO) is an endothelium derived relaxing factor(EDRF) important in regulating heart-vessel physiology. Theobjective of this study was to investigate whether the eNOSgene Glu298Asp variation influenced the lipid parameters,visceral obesity, insulin related phenotypes and type 2 diabetesmellitus (T2DM) development, for the first time in a Turkishstudy group. We analyzed the the eNOS gene Glu298Aspgenotype frequencies in 115 type 2 diabetic and 68 healthycontrol subjects. Serum lipids and insulin-related phenotypeswere also analyzed. No significant difference for genotypicfrequencies was observed for the Ban II (Eco241) restrictionsite in T2DM patients as compared to controls. eNOSGlu298Asp polymorphism was not found to affect visceralobesity and insulin related phenotypes. However, T2DM patientswith Asp/Asp genotype were found to have lower hepaticinsulin sensitivity (HIS) in comparison to Glu/Glu. Inhealthy controls, the insulin and HOMA levels were foundto be lower in Glu/Asp genotype with respect to Glu/Glugenotype carriers (p>0.05). In T2DM patients, visceral obesitywas observed in higher frequencies with Asp/Asp genotype,in comparison to Glu/Glu genotype. eNOS Glu298Asppolymorphism was not found to affect serum lipid levels inthe T2DM group. However in the control group, lower serumapoB levels were observed in Asp/Asp genotype carriers incomparison to Glu/Glu genotype (p ≤ 0.05). The eNOS geneGlu298Asp polymorphism was not found to be associatedwith T2DM in the present study group. Although not significant,since the eNOS Glu298Asp genotypes were found tobe related to HIS, insulin, HOMA and visceral obesity in thepresent study, further studies on larger samples are needed toexplore the exact role of eNOS Glu298Asp polymorphism ininsulin related phenotypes and visceral obesity.Downloads
References
Tilburg J, Haeften TW, Pearson P, Wijmenga C. Defining the genetic contribution of type 2 diabetes mellitus. J Med Genet. 2001;38(9):569-78.
Morton NE, Lio P. Oligogenic linkage and map integration. In: Pawlowitzki H, Edwards JH, Thompson EA (Eds). Genetic Mapping of Disease Genes, first ed. Academic Press, San Diego, CA 1997. pp 17-21.
Marsden P, Heng H, Scherer S, Stewart R, Hall AV, Shi XM, et al. Structure and chromosomal localization of the human constitutive endothelial nitric oxide synthase gene. J Biol Chem. 1993;268(23):17478-88.
Hayden MR, Tyagi SC. Is type 2 diabetes mellitus a vascular disease (atheroscleropathy) with hyperglycemia a late manifestation? The role of NOS, NO, and redox stres. Cardiovasc Diabetol. 2003;2:2.
Monti LD, Barlassina C, Citterio L, Galluccio E, Berzuini C, Setola E, et al. Endothelial nitric oxide synthase polymorphisms are associated with type 2 diabetes and the insulin resistance syndrome. Diabetes. 2003;52(5):1270-5.
McNamara DM, Holubkov R, Postava L, Ramani R, Janosko K, Mathier M, et al. Effect of the Asp298 variant of endothelial nitric oxide synthase on survival for patients with congestive heart failure. Circulation. 2003;107(12):1598-602.
Lüscher T, Noll G. Is it all in genes…? Nitric oxide synthase and coronary vasospasm. Circulation. 1999;99(22):2855-7.
Paradossi U, Ciofini E, Clerico A, Botto N, Biagini A, Colombo MG. Endothelial function and carotid intima-media thickness in young healthy subjects among endothelial nitric oxide synthase Glu298 → Asp and T–786 → C polymorphisms. Stroke. 2004;35(6):1305-9.
Yoshimura T, Hisatomi A, Kajihara S, Yasutake T, Ogawa Y, Mizuta T, et al. The relationship between insulin resistance and polymorphisms of the endothelial nitric oxide synthase gene in patients with coronary artery disease. J Atheroscler Thromb. 2003;10(1):43-7.
Barroso I, Luan J, Middelberg RPS, Harding AH, Franks PW, Jakes RW, et al. Candidate gene association study in type 2 diabetes indicates a role for genes involved in β-cell function as well as insulin action. PLoS Biol. 2003;1(3):445.
Ukkola O, Erkkila PH, Savolainen MJ, Kesaniemi YA. Lack of association between polymorphism of catalase, copper-zinc superoxide dismutase (SOD), extracellular SOD and endothelial nitric oxide synthase genes and macroangiopathy in patients with type 2 diabetes mellitus. J Int Med. 2001;249(5):451-9.
Colombo MG, Paradossi U, Andreassi MG, Botto N, Manfredi S, Masetti S, et al. Endothelial nitric oxide synthase gene polymorphisms and risk of coronary artery disease. Clin Chem. 2003;49(3):389-95.
World Health Organization. Definition, Diagnosis and Classification of Diabetes Mellitus and Its Complications. Geneva, World Health Organization, 1999.
Arroyo P, Pardio J, Fernandez V, Vargas-Ancona L, Canul G, Loria A. Obesity and cultural environment in the Yucatan region. Nutr Rev. 1999;57(5 Pt 2):S78-82.
Hosker JP, Matthews DR, Rudenski AS, Burnett MA, Darling P, Bown EG, et al. Continuous infusion of glucose with model assessment: measurement of insulin and β-cell function in man. Diabetologia. 1985;28(7):401-11.
Matsuda M, DeFronzo RA. Insulin sensitivity indices obtained from oral glucose tolerance testing. Diabetes Care. 1999;22(9):1462-70.
Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from nucleated cells. Nucleic Acids Res. 1988;16(3):1215.
Saiki RK, Gelfand DH, Stoffel S, Scharf SJ, Higuchi R, Horn GT, et al. Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science.1988; 239(4839):487-91.
Kahn C. Insulin action, diabetogenes, and the cause of type II diabetes. Diabetes. 1994; 43(8):1066-84.
Yki-Järvinen H. Role of insulin resistance in the pathogenesis of NIDDM. Diabetologia. 1995; 38(12):1378-88.
Hales C, Barker D. Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis. Diabetologia. 1992;3(7):595-601.
Veldman BA, Spiering W, Doevendans PA, Ver-Voort G, Kroon AA, de Leeuw PW, et al. The Glu298Asp polymorphism of the NOS 3 gene as a determinant of the baseline production of nitric oxide. J Hypertens. 2002; 20(10):2023-7.
Hayden MR, Tyagi SC. Islet redox stress: the manifold toxicities of insulin resistance, metabolic syndrome and amylin derived islet amyloid in type 2 diabetes mellitus. JOP. 2002;3(4):86-108.
Hayden MR, Tyagi SC. Intimal Redox Stress: Accelerated atherosclerosis in metabolic syndrome and type 2 diabetes mellitus. Atheroscleropathy. Cardiovasc Diabetol. 2002;1:3.
Thameem F, Puppala S, Arar NH, Stern MP, Blangero J, Duggirala R, et al. Endothelial nitric oxide synthase (eNOS) gene polymorphisms and their association with type 2 diabetes-related traits in Mexican Americans. Diab Vasc Dis Res. 2008;5(2):109-13.
Srivastava K, Biswas UK, Narang R, Varghese JJ, Das N. Prevalence of eNOS Glu298Asp Polymorphism in Healthy Volunteers from a Region of Northern India. Community Genet. 2005;8(3):180-3.
Yoshimura T, Hisatomi A, Kajihara S, Yasutake T, Ogawa Y, Mizuta T, et al. The relationship between insulin resistance and polymorphisms of the endothelial nitric oxide synthase gene in patients with coronary artery disease. J Atheroscler Thromb. 2003;10(1):43-7.
Roy D, Perreault M, Marette A. Insulin stimulation of glucose uptake in skeletal muscles and adipose tissues in vivo is NO dependent. AJP-Endocrinology and Metabolism. 1998;274(4 Pt 1): E692-E699.
Kapur S, Bedard S, Marcotte B, Cote CH, Marette A. Expression of nitric oxide synthase in skeletal muscle: a novel role for nitric oxide as a modulator of insulin action. Diabetes. 1997;46(11):1691-700.
Shiuchi T, Cui TX, Wu L, Nakagami H, Takeda- Matsubara Y, Iwai M, et al. ACE inhibitor improves insulin resistance in diabetic mouse via bradykinin and NO. Hypertension. 2002;40(3):329-34.
Paradossi U, Ciofini E, Clerico A, Botto N, Biagini A, Colombo MG. Endothelial function and carotid intima-media thickness in young healthy subjects among endothelial nitric oxide synthase Glu298 → Asp and T–786 → C polymorphisms. Stroke. 2004;35(6):1305-9.
