Relationship between Gly972Arg Variant of Insulin Receptor Substrate-1 Gene and Endothelial Dysfunction Measured by Flow Mediated Dilation

Author : P. Wulandari, R. Sukmawan, I. Sunu, S.F. Supari
Upload Date : 19-04-2018

Background: Insulin receptor substrate-1 (IRS-1) functions as one of the key downstream signaling molecules in the insulin receptor signaling pathways. Insulin has multiple physiological effects on the vascular tissues including regulation of the expression of endothelial nitric oxide synthase (eNOS). This regulatory effect of insulin on endothelial function is mediated via the activation of the signaling pathway involving the insulin receptor/ IRS-1 / phosphoinositide-3 kinase (PI3K). Recent studies found that human endothelial cells obtained from carriers of the Gly972Arg variant of IRS-1 gene exhibited reduced eNOS expression in response to chronic exposure to insulin. A reduction in eNOS expression would be expected to be associated with impaired endothelium-dependent vasodilation. However, little is known about the relationship between Gly972Arg variant of IRS-1 gene and endothelial dysfunction in vivo.

Objective: To investigate the relationship between genetic polymorphism and endothelial dysfunction in vivo, measured by flow mediated dilation (FMD).

Methods: 81 subjects were genotyped for the Gly972Arg IRS-1 polymorphism using Taq-Man method. Flow mediated vasodilation examination in the brachial artery was performed using Aloka Prosound at the Vascular clinic.

Results: 81 subjects were clustered into three groups according to IRS-1 genotype (CC 17,3%, CT 64,2% and TT 18,5%). There were significant relationship between Gly972Arg variant of  IRS-1 gene and endothelial dysfunction measured by FMD amongst those groups (p=0.019). There was also an increased risk of endothelial dysfunction between heterozygous and homozygous group (OR 12,8; 95% CI 1,5 to 106; p 0,018 in CT group and OR 18; 95% CI 1,8 to 183,3; p 0,015 in TT group).

Conclusion: Gly972Arg variant of IRS-1 gene may be a significant genetic determinant for endothelial dysfunction in vivo, measured by FMD.

KEYWORDS : Insulin receptor substrate-1, polymorphism, Gly972Arg variant, endothelial dysfunction, flow mediated dilation

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