Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

The G1057D polymorphism of IRS-2 gene and its relationship with obesity in conferring susceptibility to type 2 diabetes in Asian Indians

International Journal of Obesity volume 31, pages 97–102 (2007)Cite this article

Abstract

Objective:

To investigate the association of insulin receptor substrate-2 (IRS-2) G1057D polymorphism with type 2 diabetes and obesity in Asian Indians.

Methods:

The study comprised of 1193 normal glucose tolerant (NGT) subjects and 1018 subjects with type 2 diabetes, aged ⩾20 years with an average body mass index of 23.7±4.6 and 25.3±4.2 kg/m2, respectively. The subjects were unrelated and randomly selected from the Chennai Urban Rural Epidemiology Study (CURES), a population-based study in Chennai in southern India. The G1057D polymorphism of the IRS-2 gene was genotyped using PCR-RFLP assay.

Results:

The genotype frequency of the IRS-2 G1057D polymorphism was significantly different between the NGT and type 2 diabetic groups (P=0.0007) in the total study subjects and among the obese subjects (P=0.00007). Logistic regression analysis showed that the DD genotype showed an increased susceptibility to diabetes with an odds ratio (adjusted for age and sex) of 2.19 (95% CI: 1.34–3.57, P=0.002) when compared to the GG+GD genotype, among the obese subjects, but not in non obese subjects. In order to explore possible interaction with obesity, logistic regression analysis was performed and the coefficient corresponding to the interaction parameter (genotype × obesity) was significant (P=0.0001).

Conclusion:

In Asian Indians, the DD genotype increases susceptibility to type 2 diabetes by interacting with obesity.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

Abbreviations

IRS-2:

insulin receptor substrate-2

CURES:

Chennai Urban Rural Epidemiology Study

NGT:

normal glucose tolerance

OR:

odds ratio.

References

  1. Sun XJ, Wang L-M, Zhang Y, Yenush L, Myers Jr MG, Glasheen E et al. Role of IRS-2 in insulin and cytokine signalling. Nature 1995; 377: 173–177.

    Article  CAS  Google Scholar 

  2. Withers DJ, Gutierrez JS, Towery H, Burks DJ, Ren JM, Previs S et al. Disruption of IRS-2 causes type 2 diabetes in mice. Nature 1998; 391: 900–904.

    Article  CAS  Google Scholar 

  3. Withers DJ, Burks DJ, Towery HH, Altamuro SL, Flint CL, White MF . IRS-2 coordinates Igf-1 receptor-mediated beta-cell development and peripheral insulin signalling. Nat Genet 1999; 23: 32–40.

    Article  CAS  Google Scholar 

  4. Bernal D, Almind K, Yenush L, Ayoub M, Zhang Y, Rosshani L et al. Insulin receptor substrate-2 amino acid polymorphisms are not associated with random type 2 diabetes among Caucasians. Diabetes 1998; 47: 976–979.

    Article  CAS  Google Scholar 

  5. Almind K, Frederiksen SK, Bernal D, Hansen T, Ambye L, Urhammer S et al. Search for variants of the gene-promoter and the potential phosphotyrosine encoding sequence of the insulin receptor substrate-2 gene: evaluation of their relation with alterations in insulin secretion and insulin sensitivity. Diabetologia 1999; 42: 1244–1249.

    Article  CAS  Google Scholar 

  6. Wang H, Rissanen J, Miettinen R, Karkkainen P, Kekalainen P, Kuusisto J et al. New amino acid substitutions in the IRS-2 gene in Finnish and Chinese subjects with late-onset type 2 diabetes. Diabetes 2001; 50: 1949–1951.

    Article  CAS  Google Scholar 

  7. Fritsche A, Madaus A, Renn W, Tschritter O, Teigeler A, Weisser M et al. The prevalent Gly1057Asp polymorphism in the insulin receptor substrate-2 gene is not associated with impaired insulin secretion. J Clin Endocrinol Metab 2001; 86: 4822–4825.

    Article  CAS  Google Scholar 

  8. Mammarella S, Romano F, Di Valerio A, Creati B, Esposito DL, Palmirotta R et al. Interaction between the G1057D variant of IRS-2 and overweight in the pathogenesis of type 2 diabetes. Hum Mol Genet 2000; 9: 2517–2521.

    Article  CAS  Google Scholar 

  9. Stefan N, Kovacs P, Stumvoll M, Hanson RL, Lehn-Stefan A, Permana PA et al. Metabolic effects of the Gly1057Asp polymorphism in IRS-2 and interactions with obesity. Diabetes 2003; 52: 1544–1550.

    Article  CAS  Google Scholar 

  10. Wild S, Roglic G, Green A, Sicree R, King H . Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabet Care 2004; 27: 1047–1053.

    Article  Google Scholar 

  11. Mohan V, Sharp PS, Cloke HR, Burrin JM, Schumer B, Kohner EM . Serum immunoreactive insulin responses to a glucose load in Asian Indian and European type 2 (non-insulin-dependent) diabetic patients and control subjects. Diabetologia 1986; 29: 235–237.

    Article  CAS  Google Scholar 

  12. Sharp PS, Mohan V, Levy JC, Mather HM, Kohner EM . Insulin resistance in patients of Asian Indian and European origin with non-insulin dependent diabetes. Horm Metab Res 1987; 19: 84–85.

    Article  CAS  Google Scholar 

  13. McKeigue PM, Pierpoint T, Ferrie JE, Marmot MG . Relationship of glucose intolerance and hyperinsulinaemia to body fat pattern in south Asians and Europeans. Diabetologia 1992; 35: 785–791.

    CAS  Google Scholar 

  14. Simmons D, Powell MJ . Metabolic and clinical characteristics of south Asians and Europeans in Coventry. Diabet Med 1993; 10: 751–758.

    Article  CAS  Google Scholar 

  15. Misra A, Vikram NK . Insulin resistance syndrome (metabolic syndrome) and Asian Indians. Curr Sci 2002; 83: 1483–1496.

    CAS  Google Scholar 

  16. Ramachandran A, Snehalatha C, Viswanathan V, Viswanathan M, Haffner SM . Risk of noninsulin dependent diabetes mellitus conferred by obesity and central adiposity in different ethnic groups: a comparative analysis between Asian Indians, Mexican Americans and Whites. Diabet Res Clin Pract 1997; 36: 121–125.

    Article  CAS  Google Scholar 

  17. Joshi SR . Metabolic syndrome – emerging clusters of the Indian phenotype. J Assoc Phys India 2003; 51: 445–446.

    Google Scholar 

  18. Chandalia M, Abate N, Garg A, Stray-Gundersen J, Grundy SM . Relationship between generalized and upper body obesity to insulin resistance in Asian Indian men. J Clin Endocrinol Metab 1999; 84: 2329–2335.

    CAS  Google Scholar 

  19. Deepa M, Pradeepa R, Rema M, Anjana M, Deepa R, Shanthirani S et al. The Chennai Urban Rural Epidemiology Study (CURES) – study design and methodology (urban component) (CURES – 1). J Assoc Phys India 2003; 51: 863–870.

    CAS  Google Scholar 

  20. Alberti KG, Zimmet PZ . Definition diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus, provisional report of a WHO consultation. Diabet Med 1998; 15: 539–553.

    Article  CAS  Google Scholar 

  21. The Asia Pacific perspective: Redefining obesity and its treatment. Regional office for the western Pacific of the World Health Organization. World Health Organization, International association for the study of Obesity and International Obesity Task force. Health Communications Australia Pvt Limited. 22–29 2000.

  22. Friedewald WT, Levy RI, Fredrickson DS . Estimation of low density lipoprotein cholesterol without the use of the preparative ultracentrifuge. Clin Chem 1972; 18: 499–502.

    CAS  Google Scholar 

  23. Stefan N, Fritsche A, Machicao F, Tschritter O, Haring HU, Stumvogel M . The Gly1057Asp polymorphism in IRS-2 interacts with obesity to affect beta cell function. Diabetologia 2004; 47: 759–761.

    Article  CAS  Google Scholar 

  24. D’Alfonso R, Marini MA, Frittita L, Sorge R, Frontoni S, Porzio O et al. Polymorphisms of the IRS-2 in patients with type 2 diabetes. J Clin Endocrinol Metab 2003; 88: 317–322.

    Article  Google Scholar 

  25. Okazawa K, Yoshimasa Y, Miyamoto Y, Takahashi-Yasuno A, Miyawaki T, Masuzaki H et al. The haplotypes of the IRS-2 gene affect insulin sensitivity in Japanese patients with type 2 diabetes. Diabet Res Clin Prac 2005; 68: 39–48.

    Article  CAS  Google Scholar 

  26. Lin X, Taguchi A, Park S, Kushner JA, Li F, Li Y et al. Dysregulation of insulin receptor substrate 2 in β cells and brain causes obesity and diabetes. J Clin Invest 2004; 114: 908–916.

    Article  CAS  Google Scholar 

  27. Kubota N, Terauchi Y, Tobe K, Yano W, Suzuki R, Ueki K et al. Insulin receptor substrate 2 plays a crucial role in β cells and hypothalamus. J Clin Invest 2004; 114: 917–927.

    Article  CAS  Google Scholar 

  28. Lautier C, Mkadem SAE, Renard E, Brun JF, Gris JC, Bringer J et al. Complex haplotypes of IRS 2 gene are associated with severe obesity and reveal heterogeneity in the effect of Gly1057Asp mutation. Hum Genet 2003; 113: 34–43.

    CAS  PubMed  Google Scholar 

  29. Ehrmann DA, Tang X, Yoshiuchi I, Cox NJ, Bell GI . Relationship of insulin receptor substrate-1 and –2 genotypes to phenotypic features of polycystic ovary syndrome. J Clin Endocrinol Metab 2002; 87: 4297–4300.

    Article  CAS  Google Scholar 

  30. Comings DE, MacMurray JP . Molecular heterosis: a review. Molec Genet Metab 2000; 71: 19–31.

    Article  CAS  Google Scholar 

  31. Basu A, Mukherjee N, Roy S, Sengupta S, Banerjee S, Chakraborty M et al. Ethnic India: a genomic view, with special reference to peopling and structure. Genome Res 2003; 13: 2277–2290.

    Article  CAS  Google Scholar 

  32. Devlin B, Roeder K, Wasserman L . Genomic control, a new approach to genetic-based association studies. Theor Popul Biol 2001; 60: 155–166.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The financial support offered by the Department of Biotechnology (DBT), Government of India and the help of Dr Reddy's Laboratories Limited, Hyderabad, India, to set up the genetics lab at our centre are gratefully acknowledged. We also thank the Chennai Wellingdon Corporate Foundation, Chennai, for their financial support for the CURES field study. This is the 19th publication from the CURES study (CURES 19).

Author information

Authors and Affiliations

  1. Madras Diabetes Research Foundation and Dr Mohan's Diabetes Specialities Centre, Gopalapuram, Chennai, India

    D Bodhini, V Radha, R Deepa & V Mohan

  2. Human Genetics Unit, Indian Statistical Institute, Kolkata, India

    S Ghosh & P P Majumder

  3. Department of Biochemistry, Indian Institute of Science, Bangalore, India

    M R S Rao

  4. Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, India

    M R S Rao

Authors
  1. D Bodhini
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. V Radha
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R Deepa
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S Ghosh
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. P P Majumder
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M R S Rao
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. V Mohan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to V Radha.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bodhini, D., Radha, V., Deepa, R. et al. The G1057D polymorphism of IRS-2 gene and its relationship with obesity in conferring susceptibility to type 2 diabetes in Asian Indians. Int J Obes 31, 97–102 (2007). https://doi.org/10.1038/sj.ijo.0803356

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.ijo.0803356

Keywords

This article is cited by

Search

Advanced search

Quick links