Pharmacogenetic influence of eNOS gene variant on endothelial and glucose metabolism responses to L-arginine supplementation: Post hoc analysis of the L-arginine trial

Lucilla D. Monti, Elena Galluccio, Barbara Fontana, Serena Spadoni, Mauro Comola, Massimiliano M. Marrocco Trischitta, Roberto Chiesa, Giancarlo Comi, Emanuele Bosi, Piermarco Piatti

Research output: Contribution to journalArticlepeer-review

Abstract

Objective To evaluate whether variants of the eNOS gene are associated with endothelial and metabolic responses to L-arginine (L-arg) supplementation. Material and Methods We examined a single nucleotide polymorphism of the eNOS gene (rs753482-A > C) to investigate the effects of this variant on endothelial function (EF), colony-forming unit-endothelial cell (CFU-EC) number, asymmetric-dimethylarginine (ADMA) level, insulin sensitivity index (ISI), and insulin secretion (IS) in a post hoc analysis of the L-arg trial. The L-arg trial (6.4 g/day for 18 months) was a single-center, randomized, double-blind, parallel-group, placebo-controlled, phase III trial in individuals with impaired glucose tolerance and metabolic syndrome. followed by a 12-month extended follow-up period after termination of the study drug (NCT 00917449). Results At baseline, EF, CFU-EC numbers, ADMA levels, and ISI were impaired in subjects carrying minor allele C (both heterozygotes, AC and homozygotes, CC) as compared to subjects carrying major allele A (homozygotes, AA) (p <0.01). Compared to placebo, L-arg increased EF, CFU-EC numbers, and ISI, and improved ADMA levels and IS (p <0.01). The greatest improvements were found in AA subjects treated with L-arg, while the worst results were found in AC + CC subjects treated with placebo. In the placebo-treated subjects, EF, CFU-EC, ISI, and IS were significantly lower and ADMA was significantly higher in AC + CC subjects than in AA subjects. Conclusions Treatment with L-arg induced similar improvements in EF, CFU-EC numbers, ADMA levels, ISI, and IS in both AA subjects and AC + CC subjects. The presence of minor allele resulted in the worst prognosis in terms of EF, CFU-EC numbers, ADMA levels, ISI, and IS during the 30-month observation period.

Original languageEnglish
Pages (from-to)1582-1591
Number of pages10
JournalMetabolism
Volume64
Issue number11
DOIs
Publication statusPublished - Nov 1 2015

Keywords

  • eNOS polymorphism
  • Insulin Secretion
  • Insulin Sensitivity
  • L-Arginine
  • Pharmacogenetics

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism
  • Medicine(all)

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