title: G protein beta3 gene variant, vascular function, and insulin sensitivity in type 2 diabetes.
abstract: A common polymorphism (825 C/T) in exon 10 of the GNB3 gene, that encodes for the beta-3 subunit, has been associated with different degrees of activation of heterotrimeric guanine nucleotide binding proteins (G proteins). Many hormones and neurotransmitters use specific receptors that interact noncovalently with G proteins in the transmembrane signaling process. Among them, insulin uses an inhibitory G protein-sensitive mechanism that is involved in metabolic and vascular events, leading to enhanced glucose transport and vasodilation. We hypothesized differences in peripheral and vascular insulin sensitivity according to GNB3 gene polymorphism in type 2 diabetic patients. To address this issue, we used an intervention-optimization protocol to examine whether diabetic patients with the variant show a different response in terms of insulin-sensitivity. Interindividual differences in baseline insulin sensitivity and vascular dysfunction (vasodilatory response to glyceryl trinitrate) were not attributable to this polymorphism of the GNB3 gene. However, in contrast to normal homozygotes, insulin sensitivity (S(I)) significantly improved (P=0.01) in carriers of the 825T variant. Parallel to these findings, stimulated C-peptide tended to decrease, and the response to glyceryl trinitrate significantly improved (P=0.004) among 825T carriers. Body mass index, systolic and diastolic blood pressure, heart rate, or serum lipid levels did not significantly change in either group. Our findings suggest an effect of GNB3 gene polymorphism on important phenotypic variations in type 2 diabetes mellitus. The GNB3 gene polymorphism might be an example of pharmacogenetics, with the underlying etiological genetic defect altering the response to treatment.
authors.affiliation: Unitat de Diabetologia, Endocrinologia i Nutricio, University Hospital of Girona Dr Josep Trueta, Girona, Spain. endocrino@htrueta.scs.es
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Fernández-Real
authors.forename: Georgina
authors.initials: G
authors.lastname: Peñarroja
authors.forename: Cristóbal
authors.initials: C
authors.lastname: Richart
authors.forename: Antoni
authors.initials: A
authors.lastname: Castro
authors.forename: Joan
authors.initials: J
authors.lastname: Vendrell
authors.forename: Montserrat
authors.initials: M
authors.lastname: Broch
authors.forename: Abel
authors.initials: A
authors.lastname: López-Bermejo
authors.forename: Wifredo
authors.initials: W
authors.lastname: Ricart
mesh_terms: D000328:Adult; D000368:Aged; D001786:Blood Glucose / Q000032:analysis; D001916:Brachial Artery / Q000000981:diagnostic imaging / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D020962:Heterotrimeric GTP-Binding Proteins / Q000235:genetics*; D006801:Humans; D007328:Insulin / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D005996:Nitroglycerin / Q000494:pharmacology; D011110:Polymorphism, Genetic; D014463:Ultrasonography; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D001786:Blood Glucose; C454420:G-protein beta3 subunit; D007328:Insulin; D014665:Vasodilator Agents; D020962:Heterotrimeric GTP-Binding Proteins; D005996:Nitroglycerin