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(Hypertension. 2003;41:124.)
© 2003 American Heart Association, Inc.

Scientific Contributions

G Protein ß3 Gene Variant, Vascular Function, and Insulin Sensitivity in Type 2 Diabetes

José Manuel Fernández-Real; Georgina Peñarroja; Cristóbal Richart; Antoni Castro; Joan Vendrell; Montserrat Broch; Abel López-Bermejo; Wifredo Ricart

From Unitat de Diabetologia, Endocrinologia i Nutricio (J.M.F.-R., A.L.-B., W.R.) and Servei de Medicina Interna (G.P., A.C.), University Hospital of Girona "Dr Josep Trueta," Girona; and Unitat de Endocrinologia i Nutricio (C.R., J.V., M.B.), University Hospital of Tarragona "Joan XXIII," Institut d’Estudis Avançats, Tarragona, Spain.

Correspondence to J.M. Fernández-Real, MD, PhD, Unit of Diabetes, Endocrinology and Nutrition, Hospital de Girona "Dr Josep Trueta," Ctra. França s/n, 17007 Girona, Spain. E-mail endocrino{at}htrueta.scs.es

A common polymorphism (825 C/T) in exon 10 of the GNB3 gene, that encodes for the ß-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.

Key Words: G protein • endothelium • vascular resistance • nitric oxide • polymorphism • insulin • diabetes mellitus

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