title: Endothelial nitric oxide synthase polymorphisms are associated with type 2 diabetes and the insulin resistance syndrome.
abstract: Endothelial nitric oxide synthase (eNOS) variants were previously demonstrated in cardiovascular disease. To evaluate whether eNOS gene variants are associated with insulin resistance and type 2 diabetes, we evaluated polymorphisms in Exon7 (E298D), intron 18 (IVS18 + 27A-->C), and intron 23 (IVS23 + 10G-->T) in 159 type 2 diabetic patients without macrovascular complications and in 207 healthy control subjects. Samples for all hormonal and metabolic variables were obtained after an overnight fast. The D298 and IVS18 + 27C alleles, but not the IVS23 + 10G-->T variant, were significantly more frequent in type 2 diabetic patients than in control subjects. The two- and three-loci haplotype analysis showed that there is a statistically significant association between the eNOS variants and type 2 diabetes. No significant differences were observed in the clinical characteristics of type 2 diabetic patients according to genotypes (except for visceral obesity [waist-to-hip ratio], which was significantly more present in D298 homozygotes). Healthy control subjects homozygous for both D298 and IVS18 + 27C presented higher insulin, C-peptide, and nitric oxide levels, as well as higher HOMA (homeostasis model assessment) values than the double wild-type homozygotes, with values superimposable on those found in type 2 diabetic patients. In conclusion, we described a significant association between eNOS gene polymorphisms and type 2 diabetes, suggesting a new genetic susceptibility factor for hyperinsulinemia, insulin resistance, and type 2 diabetes.
authors.affiliation: Diabetology, Endocrinology and Metabolic Disease Unit, Medicine Division, San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy. lucilla.monti@hsr.it
authors.forename: Lucilla D
authors.initials: LD
authors.lastname: Monti
authors.forename: Cristina
authors.initials: C
authors.lastname: Barlassina
authors.forename: Lorena
authors.initials: L
authors.lastname: Citterio
authors.forename: Elena
authors.initials: E
authors.lastname: Galluccio
authors.forename: Carlo
authors.initials: C
authors.lastname: Berzuini
authors.forename: Emanuela
authors.initials: E
authors.lastname: Setola
authors.forename: Gianpietro
authors.initials: G
authors.lastname: Valsecchi
authors.forename: Pietro
authors.initials: P
authors.lastname: Lucotti
authors.forename: Guido
authors.initials: G
authors.lastname: Pozza
authors.forename: Luisa
authors.initials: L
authors.lastname: Bernardinelli
authors.forename: Giorgio
authors.initials: G
authors.lastname: Casari
authors.forename: PierMarco
authors.initials: P
authors.lastname: Piatti
mesh_terms: D002318:Cardiovascular Diseases / Q000201:enzymology / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology / Q000235:genetics*; D003925:Diabetic Angiopathies / Q000201:enzymology / Q000235:genetics; D005091:Exons; D014644:Genetic Variation; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics*; D007438:Introns; D019001:Nitric Oxide Synthase / Q000235:genetics*; D052250:Nitric Oxide Synthase Type III; D011110:Polymorphism, Genetic; D012016:Reference Values
chemical_list: C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III