Skip to main content
SpringerLink
Log in

The p53 codon 72 (Arg72Pro) polymorphism is associated with the degree of insulin resistance in type 2 diabetic subjects: a cross-sectional study

  • Original Article
  • Published:
Acta Diabetologica Aims and scope Submit manuscript

Abstract

Tumor suppressor protein p53 has been demonstrated to regulate genes involved in energy generating metabolic pathways and apoptosis. To date, a new field of research is the involvement of TP53 codon 72 (Arg72Pro) polymorphism in the diabetic disease. The aim of this study was to evaluate whether the genotype and the related genetic models of Arg72Pro polymorphism of TP53 (rs1042522) are associated with insulin resistance and its metabolic parameters in diabetic and non-diabetic subjects. We examined 335 type 2 diabetic patients (65.5 ± 8.4 years) and 367 non-diabetic subjects (60.5 ± 11.7 years). The results were validated in a validation sample consisting of 199 type 2 diabetic (66.2 ± 8.5 years) and 224 non-diabetic subjects (61.2 ± 12.7 years). In the study sample, the analysis of covariance, adjusted for the effects of age, gender and BMI, showed a significant genotype–diabetes effect on insulin resistance evaluated by HOMA-IR (p = 0.038). This result was mediated by variations in fasting plasma insulin (p = 0.027), as no TP53 genotype–diabetes effects were detected for fasting plasma glucose. In particular, in the diabetic subjects, Pro/Pro genotype was associated with lower values of HOMA-IR with respect to Arg/Arg (p = 0.013) and Arg/Pro (p = 0.006) carriers. No difference in HOMA-IR between diabetic and non-diabetic Pro/Pro carriers was found. Significant recessive model–diabetes interaction effects on fasting insulin and HOMA-IR adjusted for age, sex and BMI were found (p = 0.007 and p = 0.029, respectively). Linear regression analyses, based on the assumption of an additive genetic model adjusted for age, sex and BMI, highlight p53 gene–diabetes interaction effects on fasting insulin (β = −1.27; p = 0.001) and HOMA-IR (β = −0.22; p = 0.006). The results of statistical analyses on fasting insulin and HOMA-IR were all confirmed in the validation sample. Furthermore, the logistic regression models confirmed that the effect of HOMA-IR levels on diabetes was moderated by Pro/Pro genotype in both study and validation samples (OR = 0.29, p = 0.034, 95 % CI = 0.09–0.91, OR = 0.37, p = 0.035, 95 % CI = 0.15–0.93, respectively). Our findings suggest that p53 codon 72 (Arg72Pro) polymorphism influences insulin resistance in type 2 diabetic patients independently of body mass.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Green DR, Chipuk JE (2006) p53 and metabolism: inside the TIGAR. Cell 126:30–32

    Article  PubMed  CAS  Google Scholar 

  2. Bensaad K, Tsuruta A, Selak MA, Vidal MN, Nakano K et al (2006) TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell 126:107–120

    Article  PubMed  CAS  Google Scholar 

  3. Matoba S, Kang JG, Patino WD, Wragg A, Boehm M et al (2006) p53 regulates mitochondrial respiration. Science 312:1650–1653

    Article  PubMed  CAS  Google Scholar 

  4. Crighton D, Wilkinson S, O’Prey J, Syed N, Smith P et al (2006) DRAM, a p53-induced modulator of autophagy, is critical for apoptosis. Cell 126:121–134

    Article  PubMed  CAS  Google Scholar 

  5. Vousden KH, Ryan KM (2009) p53 and metabolism. Nat Rev Cancer 9:691–700

    Article  PubMed  CAS  Google Scholar 

  6. Minamino T, Orimo M, Shimizu I, Kunieda T, Yokoyama M et al (2009) A crucial role for adipose tissue p53 in the regulation of insulin resistance. Nat Med 15:1082–1087

    Article  PubMed  CAS  Google Scholar 

  7. Thomas M, Kalita A, Labrecque S, Pim D, Ban L (1999) Two polymorphic variants of wild-type p53 differ biochemically and biologically. Mol Cell Biol 19:1092–1100

    PubMed  CAS  Google Scholar 

  8. Bonafé M, Salvioli S, Barbi C, Trapassi C, Tocco F et al (2004) The different apoptotic potential of the p53 codon 72 alleles increases with age and modulates in vivo ischemia-induced cell death. Cell Death Differ 11:962–973

    Article  PubMed  Google Scholar 

  9. Bergamaschi D, Samuels Y, Sullivan A, Zvelebil M, Breyssens H et al (2006) iASPP preferentially binds p53 proline-rich region and modulates apoptotic function of codon 72-polymorphic p53. Nat Genet 38:1133–1141

    Article  PubMed  CAS  Google Scholar 

  10. Jeong BS, Hu W, Belyi V, Rabadan R, Levine AJ (2010) Differential levels of transcription of p53-regulated genes by the arginine/proline polymorphism: p53 with arginine at codon 72 favors apoptosis. FASEB J 24:1347–1353

    Article  PubMed  CAS  Google Scholar 

  11. Molina V, Papiol S, Sanz J, Rosa A, Arias B et al (2011) Convergent evidence of the contribution of TP53 genetic variation (Pro72Arg) to metabolic activity and white matter volume in the frontal lobe in schizophrenia patients. Neuroimage 56:45–51

    Article  PubMed  CAS  Google Scholar 

  12. Gomez-Sanchez JC, Delgado-Esteban M, Rodriguez-Hernandez I, Sobrino T, Perez de la Ossa N et al (2011) The human Tp53 Arg72Pro polymorphism explains different functional prognosis in stroke. J Exp Med 208:429–437

    Article  PubMed  CAS  Google Scholar 

  13. Gaulton KJ, Willer CJ, Li Y, Scott LJ, Conneely KN et al (2008) Comprehensive association study of type 2 diabetes and related quantitative traits with 222 candidate genes. Diabetes 57:3136–3144

    Article  PubMed  CAS  Google Scholar 

  14. Burgdorf KS, Grarup N, Justesen JM, Harder MN, Witte DR et al (2011) Studies of the association of Arg72Pro of tumor suppressor protein p53 with type 2 diabetes in a combined analysis of 55, 521 Europeans. PLoS One 6:e15813

    Article  PubMed  CAS  Google Scholar 

  15. American Diabetes Association (2011) Diagnosis and classification of diabetes mellitus. Diabetes Care 34(Suppl 1):S62–S69

    Article  Google Scholar 

  16. Bonafè M, Olivieri F, Mari D, Baggio G, Mattace R et al (1999) p53 codon 72 polymorphism and longevity: additional data on centenarians from continental Italy and Sardinia. Am J Hum Genet 65:1782–1785

    Article  PubMed  Google Scholar 

  17. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF 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

    Article  PubMed  CAS  Google Scholar 

  18. Wallace TM, Levy JC, Matthews DR (2004) Use and abuse of HOMA modelling. Diabetes Care 27:1487–1495

    Article  PubMed  Google Scholar 

  19. Gallwitz B, Kazda C, Kraus P, Nicolay C, Schernthaner G, Acta Diabetol (2011) Contribution of insulin deficiency and insulin resistance to the development of type 2 diabetes: nature of early stage diabetes. Acta Diabetol. doi:10.1007/s00592-011-0319-4

  20. Oda E (2012) Metabolic syndrome: its history, mechanisms, and limitations. Acta Diabetol 49:89–95

    Article  PubMed  CAS  Google Scholar 

  21. Kanat M, Norton L, Winnier D, Jenkinson C, DeFronzo RA et al (2011) Impaired early- but not late-phase insulin secretion in subjects with impaired fasting glucose. Acta Diabetol 48:209–217

    Article  PubMed  CAS  Google Scholar 

  22. Qu L, He B, Pan Y, Xu Y, Zhu C et al (2011) Association between polymorphisms in RAPGEF1, TP53, NRF1 and type 2 diabetes in Chinese Han population. Diabetes Res Clin Pract 91:171–176

    Article  PubMed  CAS  Google Scholar 

  23. Bojesen SE, Nordestgaard BG (2008) The common germline Arg72Pro polymorphism of p53 and increased longevity in humans. Cell Cycle 15:158–163

    Article  Google Scholar 

  24. van Heemst D, Mooijaart SP, Beekman M, Schreuder J, de Craen AJ et al (2005) Variation in the human TP53 gene affects old age survival and cancer mortality. Exp Gerontol 40:11–15

    Article  PubMed  Google Scholar 

  25. Paolisso G, Barbieri M, Rizzo MR, Carella C, Rotondi M et al (2001) Low insulin resistance and preserved beta-cell function contribute to human longevity but are not associated with TH-INS genes. Exp Gerontol 37:149–156

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Metabolic Diseases and Diabetology Unit, National Institute of Health and Science on Aging (INRCA), Via della Montagnola 81, 60131, Ancona, Italy

    Anna Rita Bonfigli, Michela Cucchi, Gabriele Brandoni, Massimo Boemi & Maurizio Marra

  2. Biostatistical Centre, National Institute of Health and Science on Aging (INRCA), Ancona, Italy

    Cristina Sirolla & Liana Spazzafumo

  3. Experimental Models in Clinical Pathology, National Institute of Health and Science on Aging (INRCA), Ancona, Italy

    Roberto Testa

  4. Department of Experimental Pathology, University of Bologna, Bologna, Italy

    Stefano Salvioli & Claudio Franceschi

  5. Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain

    Antonio Ceriello

  6. Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain

    Antonio Ceriello

  7. Dipartimento di Scienze Cliniche e Molecolari, Università Politecnica delle Marche, Ancona, Italy

    Fabiola Olivieri, Roberto Festa & Antonio Domenico Procopio

  8. Centre of Clinical Pathology and Innovative Therapy, National Institute of Health and Science on Aging (INRCA), Ancona, Italy

    Fabiola Olivieri & Antonio Domenico Procopio

Authors
  1. Anna Rita Bonfigli
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cristina Sirolla
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Roberto Testa
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Michela Cucchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Liana Spazzafumo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Stefano Salvioli
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Antonio Ceriello
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Fabiola Olivieri
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Roberto Festa
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Antonio Domenico Procopio
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Gabriele Brandoni
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Massimo Boemi
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Maurizio Marra
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Claudio Franceschi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anna Rita Bonfigli.

Additional information

Communicated by Massimo Federici.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bonfigli, A.R., Sirolla, C., Testa, R. et al. The p53 codon 72 (Arg72Pro) polymorphism is associated with the degree of insulin resistance in type 2 diabetic subjects: a cross-sectional study. Acta Diabetol 50, 429–436 (2013). https://doi.org/10.1007/s00592-012-0450-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00592-012-0450-x

Keywords

Search

Navigation