title: Insulin-mediated venodilation is impaired in young, healthy carriers of the 825T allele of the G-protein beta3 subunit gene (GNB3).
abstract: OBJECTIVE
  A C825T polymorphism has been identified for the gene encoding the G-protein beta 3 subunit ( GNB3 ). The 825T allele is associated with hypertension and obesity, which in turn are closely linked with resistance to the metabolic and vascular effects of insulin. We hypothesized that venodilation in response to insulin would be impaired in GNB3 825T-allele carriers. Because vasodilatory properties of insulin are mainly mediated by nitric oxide, we also investigated the influence of the T-786C polymorphism of the gene for endothelial nitric oxide synthase ( NOS3 ) on insulin-mediated venous responses.
  
  
  METHODS
  We used the linear variable transducer technique to compare dorsal hand vein compliance in 31 young, healthy men ( GNB3 C825T: 15 CC, 14 CT, and 2 TT; NOS3 T-786C: 14 TT, 13 TC, and 4 CC). Individual dose-response curves to phenylephrine (3.2-10,000 ng/min) were established, and veins were preconstricted by a constant infusion of phenylephrine at the individual dose needed to procure 70% of maximal constriction. Then insulin was infused (50-250,000 microU/min), and the changes in venous diameter were recorded.
  
  
  RESULTS
  Venous response to insulin was biphasic, with venoconstriction at low doses being followed by venodilation at higher doses. Insulin dose-response curves of GNB3 825T-allele carriers were significantly shifted to the right (ANOVA, P < .001, versus CC). NOS3 T-786C-allele carrier status had no influence on insulin-induced vascular responses ( P = .60 for TC/CC versus TT).
  
  
  CONCLUSIONS
  This study is the first to show the influence of a genetic polymorphism on insulin-mediated venodilation in men in vivo. Further studies are needed to determine whether these results translate to other vascular beds, and possible gender-specific differences remain to be investigated.
authors.affiliation: Department of Nephrology and Hypertension, Institute of Pharmacology, University of Duisburg-Essen Medical School, Essen.
authors.forename: Anna
authors.initials: A
authors.lastname: Mitchell
authors.forename: Mutlu
authors.initials: M
authors.lastname: Pace
authors.forename: Jens
authors.initials: J
authors.lastname: Nürnberger
authors.forename: René R
authors.initials: RR
authors.lastname: Wenzel
authors.forename: Winfried
authors.initials: W
authors.lastname: Siffert
authors.forename: Thomas
authors.initials: T
authors.lastname: Philipp
authors.forename: Rafael F
authors.initials: RF
authors.lastname: Schäfers
mesh_terms: D000328:Adult; D000483:Alleles; D020962:Heterotrimeric GTP-Binding Proteins / Q000235:genetics*; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000494:pharmacology*; D008297:Male; D019001:Nitric Oxide Synthase / Q000235:genetics*; D052250:Nitric Oxide Synthase Type III; D011110:Polymorphism, Genetic; D014664:Vasodilation / Q000187:drug effects* / Q000235:genetics
chemical_list: C454420:G-protein beta3 subunit; D007328:Insulin; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D020962:Heterotrimeric GTP-Binding Proteins