RESUMO
BACKGROUND: /aim: Abdominal obesity and associated metabolic consequences are a burgeoning problem in Asian Indians and studying their genetic predisposition is important. This study is aimed at assessing variations in Insulin receptor substrate-1 (IRS-1), its expression at regional fat-depots (visceral and subcutaneous) in morbidly obese patients, and correlation with genotype-phenotype traits. METHODS: Gene expression of IRS-1 in paired adipose tissue from 35 morbidly obese subjects (BMI) > 40 kg/m2) with co-morbidities and 15 controls (BMI<25 kg/m2), undergoing bariatric/elective abdominal surgery, respectively was determined by quantitative real time PCR. Genotyping of IRS-1Gly972Arg (n = 436) (rs 1801278) was performed by PCR-RFLP. Metabolic parameters were assessed. Full length sequencing of IRS-1 was performed to identify known/novel variations. RESULTS: A marked reduction in IRS-1 expression was observed in visceral as compared to subcutaneous adipose tissue of morbidly obese subjects (p = 0.02). Homozygous variant of IRS-1 Gly972Arg was absent and there was no association with obesity or insulin resistance. A salient finding of this study was identification of two new variants in IRS-1 gene, representing G > A (codon 1102) encoding Glu > Lys and a deletion of (A) at codon 658 in morbidly obese subjects with insulin resistance. CONCLUSIONS: Observation of a substantially lower expression of IRS-1 for first time in visceral adipose tissue of morbidly obese subjects is suggestive of predictive role of IRS-1 expression in insulin responsiveness of visceral adipose tissue. New variants in IRS-1, a non-synonymous mutation and a deletion should be evaluated further for their role in development of obesity and/orT2DM.
