Abstract
Insulin resistance (IR), a pathological condition of type 2 diabetes mellitus (T2DM) is characterized by an inability of body’s tissue to respond the secreted or administered insulin, a necessary step for cellular glucose transportation. The prevalence of insulin resistance progresses with age, especially in overweight people with central obesity. Insulin receptor substrates (IRS) are important molecular proteins in the insulin signalling pathway, where IRS-1 plays a key function in cells insulin sensitivity. The common mutation (rs1801278; r.2963G > A: Gly972Arg) of the IRS-1 gene occurs when residue glycine changes to arginine at codon 972. The objective of this study was to detect the genetic association of rs1801278 polymorphism of the IRS-1 gene with insulin resistance in type 2 diabetes from the Lahore region of Pakistan. A total of 322 subjects (161 cases and 161 healthy individuals) were included. DNA was isolated for detection of the genotype distribution and allele frequencies by PCR–RFLP. The results showed a significant difference in the genotype distribution and allele frequency between the T2DM cases and controls for single nucleotide polymorphism (SNP) rs1801278 (OR 17.61, 95% CI 8.06–38.4, p < 0.001). In conclusion, association between rs1801278 polymorphism of the IRS-1 gene and insulin resistance in T2DM has been established in a Pakistani population.
Similar content being viewed by others
References
Alharbi KK et al (2014) Association of the genetic variants of insulin receptor substrate 1 (IRS-1) with type 2 diabetes mellitus in a Saudi population. Endocrine 47:472–477
Almind K et al (1996) A common amino acid polymorphism in insulin receptor substrate-1 causes impaired insulin signalling. Evidence from transfection studies. J Clin Invest 97:2569–2575
Alsalman HA, Kaabi YA (2015) Lack of association between the insulin receptor substrates-1 Gly972Arg polymorphism and type-2 diabetes mellitus among Saudis from Eastern Saudi Arabia. Saudi Med J 36:1420–1424
Arikoglu H et al (2014) IRS1 gene polymorphisms Gly972Arg and Ala513Pro are not associated with insulin resistance and type 2 diabetes risk in non-obese Turkish population. Meta Gene 24:579–585
Bodhini D, Radha V, Mohan V (2011) Association study of IRS1 gene polymorphisms with type 2 diabetes in south Indians. Diabetes Technol Ther 13:767–772
Burguete-Garcia AI et al (2010) Association of Gly972Arg polymorphism of IRS1 gene with type 2 diabetes mellitus in lean participants of a national health survey in Mexico: a candidate gene study. Metabolism 59:38–45
Clausen JO et al (1995) Insulin resistance: interactions between obesity and a common variant of insulin receptor substrate-1. Lancet 346:397–402
Dearth RK et al (2007) Oncogenic transformation by the signalling adaptor proteins insulin receptor substrate (IRS)-1 and IRS-2. Cell Cycle 6:705–713
Florez JC et al (2004) Association testing in 9,000 people fails to confirm the association of the insulin receptor substrate-1 G972R polymorphism with type 2 diabetes. Diabetes 53:3313–3318
Gayoso-Diz P et al (2013) Insulin resistance (HOMA-IR) cut-off values and the metabolic syndrome in a general adult population: effect of gender and age: EPIRCE cross-sectional study. BMC Endocr Disord 13:47
Giandalia A et al (2018) Influence of peroxisome proliferator-activated receptor-γ exon 2 and exon 6 and insulin receptor substrate (IRS)-1 Gly972Arg polymorphisms on insulin resistance and beta-cell function in southern mediterranean women with polycystic ovary syndrome. J Clin Transl Endocrinol 13:1–8
Hitman GA et al (1995) Insulin receptor substrate-1 gene mutations in NIDDM; implications for the study of polygenic disease. Diabetologia 38:481–486
Jellema A et al (2003) Gly972Arg variant in the insulin receptor substrate-1 gene and association with Type 2 diabetes: a meta-analysis of 27 studies. Diabetologia 46:990–995
Mahmutovic L et al (2019) Association of IRS1 genetic variants with glucose control and insulin resistance in type 2 diabetic patients from Bosnia and Herzegovina. Drug Metab Pers Ther. https://doi.org/10.1515/dmpt-2018-0031
Marín C et al (2011) The insulin sensitivity response is determined by the interaction between the G972R polymorphism of the insulin receptor substrate 1 gene and dietary fat. Mol Nutr Food Res 55:328–335
Martínez-Gómez LE et al (2011) A replication study of the IRS1, CAPN10, TCF7L2, and PPARG gene polymorphisms associated with type 2 diabetes in two different populations of Mexico. Ann Hum Genet 75:612–620
Matthews DR et al (1985) Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28:412–419
Morini E et al (2009) IRS1 G972R polymorphism and type 2 diabetes: a paradigm for the difficult ascertainment of the contribution to disease susceptibility of ‘low-frequency-low-risk’ variants. Diabetologia 52:1852–1857
Mousavinasab F et al (2005) Common polymorphisms in the PPARgamma2 and IRS-1 genes and their interaction influence serum adiponectin concentration in young Finnish men. Mol Genet Metab 84:344–348
Suer FEO, Mergen H, Bolu E, Ozata M (2005) Molecular scanning for mutations in the insulin receptor substrate-1 (IRS-1) gene in Turkish with type 2 diabetes mellitus. Endocr J 52:593–598
Owen K, Ayres S, Corbett S, Hattersley A (2002) Increased risk of diabetes in first-degree relatives of young-onset type 2 diabetic patients compared with relatives of those diagnosed later. Diabetes Care 25:636–637
Pappalardo MA et al (2010) Very high frequency of the polymorphism for the insulin receptor substrate 1 (IRS-1) at codon 972 (glycine972arginine) in Southern Italian women with polycystic ovary syndrome. Horm Metab Res 42:575–584
Radha V, Mohan V (2007) Genetic predisposition to type 2 diabetes among Asian Indians. Indian J Med Res 125:259–274
Roberts CK, Hevener AL, Barnard RJ (2013) Metabolic syndrome and insulin resistance: underlying causes and modification by exercise training. Compr Physiol 3:1–58
Sesti G et al (2001) Defects of the insulin receptor substrate (IRS) system in human metabolic disorders. FASEB J 15:2099–2111
Yamauchi T et al (1996) Insulin signalling and insulin actions in the muscles and livers of insulin-resistant, insulin receptor substrate 1-deficient mice. Mol Cell Biol 16:3074–3084
Yousef AA et al (2018) IRS-1 genetic polymorphism (r.2963G > A) in type 2 diabetes mellitus patients associated with insulin resistance. Dovepress 11:99–106
Huri HZ et al (2012) Optimisation of glycaemic control during episodes of severe/acute hyperglycaemia in patients with type 2 diabetes mellitus. Int J Clin Pharm 34:863–870
Zeggini E et al (2004) Association studies of insulin receptor substrate 1 gene (IRS1) variants in type 2 diabetes samples enriched for family history and early age of onset. Diabetes 53:3319–3322
Acknowledgements
We would like to thank Mr. Ali Amar Research fellow and Miss. Osheen Sajjad Lecturer of Department of Human Genetics for their assistance. We wish to thank Mrs. Amara Lab Manager of the department of Pharmacology for continuous support.
Author information
Authors and Affiliations
Contributions
MS and SM: conceived and designed the study: AAA: collected the samples from subjects and performed laboratory experiments, AAA, MIU and MR: data integration and statistical analyses and its interpretation; AAA and MIU: draft the manuscript, MS, SM and MR: edit and approve the manuscript.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no competing interests.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Albegali, A.A., Shahzad, M., Mahmood, S. et al. Genetic association of insulin receptor substrate-1 (IRS-1, rs1801278) gene with insulin resistant of type 2 diabetes mellitus in a Pakistani population. Mol Biol Rep 46, 6065–6070 (2019). https://doi.org/10.1007/s11033-019-05041-w
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11033-019-05041-w