Abstract 9939: Insulin Receptor Substrate-2 Genetic Variants Interact with Plasma Monounsaturated and n-3 PUFA Fatty Acid Levels to Influence Insulin Resistance: From the LIPGENE Study

Abstract

Background: The insulin receptor substrate-2 (IRS-2) is a major insulin signalling molecule. IRS-2 regulates body weight control and glucose homeostasis. Several IRS-2 polymorphic sites have been studied for their potential use as risk markers for obesity and type 2 diabetes mellitus. Fatty acids are key metabolic regulators which may interact with genetic factors and influence glucose metabolism. Objective: To examine whether the genetic variability at the IRS-2 gene locus was associated with the degree of insulin resistance and plasma fatty acid levels in subjects with metabolic syndrome (MetS). Design: Intravenous glucose tolerance tests (IVGTT) and HOMA indices were used to estimate insulin sensitivity (insulin sensitivity index, HOMA-IR), insulin secretion (first phase insulin secretion (AIRg), disposition index, HOMA-B) and glucose effectiveness. Plasma fatty acid composition and three IRS-2 single nucleotide polymorphisms (SNPs) were also determined in a cross-sectional analysis of 452 subjects with MetS participating in the LIPGENE dietary intervention cohort ( NCT00429195 ). Results: The rs2289046 SNP interacted with plasma monounsaturated (MUFA) and omega-3 polyunsaturated fatty acids (n-3 PUFA) levels which were significantly associated with insulin resistance. Among subjects with the lowest level of MUFA (below the median) the A/A genotype was associated with lower glucose effectiveness (P<0.03), higher fasting insulin concentrations (P<0.02) and higher HOMA-IR (P<0.03) compared to subjects carrying the minor G-allele (A/G and G/G). In contrast, among subjects with the highest level of MUFA (above the median), the A/A genotype was associated with lower fasting insulin concentrations and HOMA-IR. Whereas, individuals carrying the G allele and with the highest level of n-3 PUFA (above the median) showed lower fasting insulin (P<0.01) and HOMA-IR (P<0.02) compared with A/A subjects. Conclusions: The rs2289046 polymorphism at the IRS-2 gene locus may influence insulin resistance and glucose effectiveness by interacting with plasma fatty acid composition in subjects with the MetS. Further studies are needed to confirm whether targeted dietary recommendations can prevent MetS in genetically susceptible individuals.