Mukti Sharma1, Sandeep Aggarwal2, Umakant Nayar2, Naval Kishore Vikram3, Anoop Misra4, Kalpana Luthra5. 1. Department of Biochemistry, All India Institute of Medical Sciences, Delhi, India. 2. Department of Surgery, All India Institute of Medical Sciences, Delhi, India. 3. Department of Medicine, All India Institute of Medical Sciences, Delhi, India. 4. Diabetic Foundation, National Diabetes Obesity and Cholesterol Foundation (N-DOC), New Delhi, India; Fortis C-DOC Center of Excellence for Diabetes, Metabolic Diseases, and Endocrinology, B 16, Chirag Enclave, New Delhi, India. 5. Department of Biochemistry, All India Institute of Medical Sciences, Delhi, India. Electronic address: kalpanaluthra@gmail.com.
Abstract
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.
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.