Skip to main content

Advertisement

SpringerLink
Log in

Serum insulin and C-peptide concentration and breast cancer: a meta-analysis

  • Original Paper
  • Published:
Cancer Causes & Control Aims and scope Submit manuscript

Abstract

Purpose

Chronic hyperinsulinemia may play a role in breast cancer etiology. We performed a meta-analysis examining whether serum concentrations of insulin and C-peptide are associated with increased breast cancer risk.

Methods

We restricted our analyses to prospective studies. After a systematic literature search, we computed summary relative risks (SRRs) and 95 % confidence intervals (95 % CIs) using random effect models applied to the relative risk associated with the highest versus lowest quantile of serum concentrations. We also graphically examined results in order to identify whether dose–response relationships were present.

Results

Six articles including 1,890 cases were retrieved for serum insulin levels and five for serum C-peptide levels including 1,759 cases. SRR and 95 % CI were 1.08 (0.66–1.78) for insulin and 1.04 (0.77–1.41) for C-peptide. Heterogeneity of results between studies was high for insulin and inexistent for C-peptide. Restricting the analysis to women diagnosed with breast cancer before or after menopause did not alter results. In insulin studies, SRR computed from relative risks not adjusted for body mass index (and other risk factors) was 1.22 (0.91–1.63). The SRR fell to 1.02 (0.53–1.97) in studies that adjusted for body mass index and other factors. Similar drops occurred in C-peptide studies, from 1.11 (0.87–1.41) to 1.06 (0.70–1.61). No consistent dose–response relationship was apparent in either pre- or post-menopausal cancers.

Conclusions

Our meta-analysis of observational studies found no evidence of an association between serum insulin or C-peptide concentrations and breast cancer risk. Increased risk found by some studies may have been due to inadequate control for adiposity.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Adami HO, McLaughlin J, Ekbom A, Berne C, Silverman D, Hacker D, Persson I (1991) Cancer risk in patients with diabetes mellitus. Cancer Causes Control 2(5):307–314

    Article  PubMed  CAS  Google Scholar 

  2. Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M (2008) Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet 371(9612):569–578

    Article  PubMed  Google Scholar 

  3. La Vecchia C, Giordano SH, Hortobagyi GN, Chabner B (2011) Overweight, obesity, diabetes, and risk of breast cancer: interlocking pieces of the puzzle. Oncologist 16(6):726–729

    Article  PubMed  Google Scholar 

  4. Belfiore A, Frasca F (2008) IGF and insulin receptor signalling in breast cancer. J Mammary Gland Biol Neoplasia 13(4):381–406

    Article  PubMed  Google Scholar 

  5. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JPA, Mike Clarke M, Devereaux PJ, Kleijnen J, David Moher D (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ 339:b2700

    Article  PubMed  Google Scholar 

  6. van Houwelingen HC, Arends LR, Stijnen T (2002) Advanced methods in meta-analysis: multivariate approach and meta-regression. Stat Med 21(4):589–624

    Article  PubMed  Google Scholar 

  7. R Development Core Team (2011) R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna

    Google Scholar 

  8. Viechtbauer W (2010) Conducting meta-analyses in R with the metafor package. J Stat Softw 36(3):1–48

    Google Scholar 

  9. Begg CB, Mazumdar M (1994) Operating characteristics of a rank correlation test for publication bias. Biometrics 50(4):1088–1101

    Article  PubMed  CAS  Google Scholar 

  10. Egger M, Smith GD, Phillips AN (1997) Meta-analysis: principles and procedures. BMJ 315(7121):1533–1537

    Article  PubMed  CAS  Google Scholar 

  11. Macaskill P, Walter SD, Irwig L (2001) A comparison of methods to detect publication bias in meta-analysis. Stat Med 20(4):641–654

    Article  PubMed  CAS  Google Scholar 

  12. Higgins JP, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21(11):1539–1558

    Article  PubMed  Google Scholar 

  13. Yam D, Fink A, Mashiah A, Ben-Hur E (1996) Hyperinsulinemia in colon, stomach and breast cancer patients. Cancer Lett 104(2):129–132

    Article  PubMed  CAS  Google Scholar 

  14. Del Giudice ME, Fantus IG, Ezzat S, McKeown-Eyssen G, Page D, Goodwin PJ (1998) Insulin and related factors in premenopausal breast cancer risk. Breast Cancer Res Treat 47(2):111–120

    Article  PubMed  Google Scholar 

  15. Jernström H, Barrett-Connor E (1999) Obesity, weight change, fasting insulin, proinsulin, C-peptide, and insulin-like growth factor-1 levels in women with and without breast cancer: the Rancho Bernardo Study. J Womens Health Gend Based Med 8(10):1265–1272

    Article  PubMed  Google Scholar 

  16. Hirose K, Toyama T, Iwata H, Takezaki T, Hamajima N, Tajima K (2003) Insulin, insulin-like growth factor-I and breast cancer risk in Japanese women. Asian Pac J Cancer Prev 4(3):239–246

    PubMed  Google Scholar 

  17. Lawlor DA, Smith GD, Ebrahim S (2004) Hyperinsulinaemia and increased risk of breast cancer: findings from the British Women’s Heart and Health Study. Cancer Causes Control 15(3):267–275

    Article  PubMed  Google Scholar 

  18. Han C, Zhang HT, Du L, Liu X, Jing J, Zhao X, Yang X, Tian B (2005) Serum levels of leptin, insulin, and lipids in relation to breast cancer in China. Endocrine 26(1):19–24

    Article  PubMed  CAS  Google Scholar 

  19. Gonullu G, Ersoy C, Ersoy A, Evrensel T, Basturk B, Kurt E, Oral B, Gokgoz S, Manavoglu O (2005) Relation between insulin resistance and serum concentrations of IL-6 and TNF-alpha in overweight or obese women with early stage breast cancer. Cytokine 31(4):264–269

    Article  PubMed  CAS  Google Scholar 

  20. Garmendia ML, Pereira A, Alvarado ME, Atalah E (2007) Relation between insulin resistance and breast cancer among Chilean women. Ann Epidemiol 17(6):403–409

    Article  PubMed  Google Scholar 

  21. Abbasi M, Tarafdari A, Esteghamati A, Vejdani K, Nakhjavani M (2010) Insulin resistance and breast carcinogenesis: a cross-sectional study among Iranian women with breast mass. Metab Syndr Relat Disord 8(5):411–416

    Article  PubMed  CAS  Google Scholar 

  22. Muti P, Quattrin T, Grant BJ, Krogh V, Micheli A, Schünemann HJ, Ram M, Freudenheim JL, Sieri S, Trevisan M, Berrino F (2002) Fasting glucose is a risk factor for breast cancer: a prospective study. Cancer Epidemiol Biomarkers Prev 11(11):1361–1368

    PubMed  CAS  Google Scholar 

  23. Sieri S, Muti P, Agnoli C, Berrino F, Pala V, Grioni S, Abagnato CA, Blandino G, Contiero P, Schunemann HJ, Krogh V (2012) Prospective study on the role of glucose metabolism in breast cancer occurrence. Int J Cancer 130(4):921–92924

    Article  PubMed  CAS  Google Scholar 

  24. Al-Delaimy WK, Flatt SW, Natarajan L, Laughlin GA, Rock CL, Gold EB, Caan BJ, Parker BA, Pierce JP (2011) IGF1 and risk of additional breast cancer in the WHEL study. Endocr Relat Cancer 18(2):235–244

    PubMed  Google Scholar 

  25. Eliassen AH, Tworoger SS, Mantzoros CS, Pollak MN, Hankinson SE (2007) Circulating insulin and c-peptide levels and risk of breast cancer among predominately premenopausal women. Cancer Epidemiol Biomarkers Prev 16(1):161–164

    Article  PubMed  CAS  Google Scholar 

  26. Mink PJ, Shahar E, Rosamond WD, Alberg AJ, Folsom AR (2002) Serum insulin and glucose levels and breast cancer incidence: the atherosclerosis risk in communities study. Am J Epidemiol 156(4):349–352

    Article  PubMed  Google Scholar 

  27. Kaaks R, Lundin E, Rinaldi S, Manjer J, Biessy C, Söderberg S, Lenner P, Janzon L, Riboli E, Berglund G, Hallmans G (2002) Prospective study of IGF-I, IGF-binding proteins, and breast cancer risk, in Northern and Southern Sweden. Cancer Causes Control 13(4):307–316

    Article  PubMed  Google Scholar 

  28. Gunter MJ, Hoover DR, Yu H, Wassertheil-Smoller S, Rohan TE, Manson JE, Li J, Ho GY, Xue X, Anderson GL, Kaplan RC, Harris TG, Howard BV, Wylie-Rosett J, Burk RD, Strickler HD (2009) Insulin, insulin-like growth factor-I, and risk of breast cancer in postmenopausal women. J Natl Cancer Inst 101(1):48–60

    Article  PubMed  CAS  Google Scholar 

  29. Kabat GC, Kim M, Caan BJ, Chlebowski RT, Gunter MJ, Ho GY, Rodriguez BL, Shikany JM, Strickler HD, Vitolins MZ, Rohan TE (2009) Repeated measures of serum glucose and insulin in relation to postmenopausal breast cancer. Int J Cancer 125(11):2704–2710

    Article  PubMed  CAS  Google Scholar 

  30. Capasso I, Esposito E, Pentimalli F, Crispo A, Montella M, Grimaldi M, De Marco M, Cavalcanti E, D’Aiuto M, Fucito A, Frasci G, Maurea N, Esposito G, Pedicini T, Vecchione A, D’Aiuto G, Giordano A (2011) Metabolic syndrome affects breast cancer risk in postmenopausal women: National Cancer Institute of Naples experience. Cancer Biol Ther 10(12):1240–1243

    Google Scholar 

  31. Bruning PF, Bonfrèr JM, van Noord PA, Hart AA, de Jong-Bakker M, Nooijen WJ (1992) Insulin resistance and breast-cancer risk. Int J Cancer 52(4):511–516

    Article  PubMed  CAS  Google Scholar 

  32. Yang G, Lu G, Jin F, Dai Q, Best R, Shu XO, Chen JR, Pan XY, Shrubsole M, Zheng W (2001) Population-based, case-control study of blood C-peptide level and breast cancer risk. Cancer Epidemiol Biomarkers Prev 10(11):1207–1211

    PubMed  CAS  Google Scholar 

  33. Malin A, Dai Q, Yu H, Shu XO, Jin F, Gao YT, Zheng W (2004) Evaluation of the synergistic effect of insulin resistance and insulin-like growth factors on the risk of breast carcinoma. Cancer 100(4):694–700

    Article  PubMed  CAS  Google Scholar 

  34. Schairer C, Hill D, Sturgeon SR, Fears T, Pollak M, Mies C, Ziegler RG, Hoover RN, Sherman ME (2004) Serum concentrations of IGF-I, IGFBP-3 and c-peptide and risk of hyperplasia and cancer of the breast in postmenopausal women. Int J Cancer 108(5):773–779

    Article  PubMed  CAS  Google Scholar 

  35. Falk RT, Brinton LA, Madigan MP, Potischman N, Sturgeon SR, Malone KE, Daling JR (2006) Interrelationships between serum leptin, IGF-1, IGFBP3, C-peptide and prolactin and breast cancer risk in young women. Breast Cancer Res Treat 98(2):157–165

    Article  PubMed  CAS  Google Scholar 

  36. Fair AM, Montgomery K (2009) Energy balance, physical activity, and cancer risk. In: Verma M (ed) Methods of molecular biology, cancer epidemiology, vol 472. Humana Press, Totowa

    Google Scholar 

  37. Keinan-Boker L, Bueno De Mesquita HB, Kaaks R, Van Gils CH, Van Noord PA, Rinaldi S, Riboli E, Seidell JC, Grobbee DE, Peeters PH (2003) Circulating levels of insulin-like growth factor I, its binding proteins-1,-2,-3, C-peptide and risk of postmenopausal breast cancer. Int J Cancer 106(1):90–95

    Article  PubMed  CAS  Google Scholar 

  38. Verheus M, Peeters PH, Rinaldi S, Dossus L, Biessy C, Olsen A, Tjønneland A, Overvad K, Jeppesen M, Clavel-Chapelon F, Téhard B, Nagel G, Linseisen J, Boeing H, Lahmann PH, Arvaniti A, Psaltopoulou T, Trichopoulou A, Palli D, Tumino R, Panico S, Sacerdote C, Sieri S, van Gils CH, Bueno-de-Mesquita BH, González CA, Ardanaz E, Larranaga N, Garcia CM, Navarro C, Quirós JR, Key T, Allen N, Bingham S, Khaw KT, Slimani N, Riboli E, Kaaks R (2006) Serum C-peptide levels and breast cancer risk: results from the European Prospective Investigation into Cancer and Nutrition (EPIC). Int J Cancer 119(3):659–667

    Article  PubMed  CAS  Google Scholar 

  39. Toniolo P, Bruning PF, Akhmedkhanov A, Bonfrer JM, Koenig KL, Lukanova A, Shore RE, Zeleniuch-Jacquotte A (2000) Serum insulin-like growth factor-I and breast cancer. Int J Cancer 88(5):828–832

    Article  PubMed  CAS  Google Scholar 

  40. Cust AE, Stocks T, Lukanova A, Lundin E, Hallmans G, Kaaks R, Jonsson H, Stattin P (2009) The influence of overweight and insulin resistance on breast cancer risk and tumour stage at diagnosis: a prospective study. Breast Cancer Res Treat 113(3):567–576

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was part of the research activities of the International Prevention Research Institute (iPRI) Research Group on Diabetes, Metabolic Disorders and Cancer, whose members are: P. Autier, A. Koechlin, M. Boniol, P. Mullie, P. Boyle, F. Valentini, K. Coppens, L.-L. Fairley, M. Boniol, M. Pasterk, M. Smans, M.-P. Curado, M. Bota (iPRI, Lyon, France); S. Gandini (European Institute of Oncology, Milan, Italy); Chris Robertson (Department of Mathematics and Statistics, University of Strathclyde, Glasgow, Scotland); Tongzhang Zheng, Yawei Zhang (Yale University School of Public Health, New Haven, Connecticut, United States of America); Geremia Bolli (Department of Internal Medicine and Oncology, S.M. Misericordia Hospital, University of Perugia, Perugia, Italy); J. Rosenstock (Dallas Diabetes and Endocrine Center, Dallas, United States of America). This study was part of works associated with an unrestricted research grant from Sanofi. None of the authors has received an honorarium for this work and no author has a conflict of interest to declare in relation to the study presented in this article. The corresponding author, Philippe Autier, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Conflict of interest

None.

Author information

Authors and Affiliations

  1. International Prevention Research Institute, 95 cours Lafayette, 69006, Lyon, France

    Philippe Autier, Alice Koechlin, Mathieu Boniol, Patrick Mullie & Peter Boyle

  2. Department of Medicine, S.M. della Misericordia Hospital, University of Perugia, Perugia, Italy

    Geremia Bolli

  3. Dallas Diabetes and Endocrine Center at Medical City, Dallas, TX, USA

    Julio Rosenstock

Authors
  1. Philippe Autier
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alice Koechlin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mathieu Boniol
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Patrick Mullie
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Geremia Bolli
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Julio Rosenstock
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Peter Boyle
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Philippe Autier.

Electronic supplementary material

Below is the link to the electronic supplementary material.

10552_2013_164_MOESM1_ESM.ppt

Online Resource 1: Prisma flowchart for literature search on a) insulin and breast cancer, b) c-peptide and breast cancer (PPT 143 kb)

Appendix: Algorithms for literature search

Appendix: Algorithms for literature search

For insulin and breast cancer

“insulin” AND “breast neoplasms”

(“endogenous” AND “insulin”) OR “insulin”[MeSH] OR “endogenous insulin” OR (“insulin”[Mesh] AND “endogenous”) OR (“serum”[Mesh] AND “insulin”[Mesh]) OR (“serum” AND “insulin”) OR “serum insulin” OR (“insulin” AND “index”) OR (“Hyperinsulinism”[Mesh] OR “hyperinsulinaemia” OR “hyperinsulinism” OR “hyperinsulinemia” OR “insulin resistance”[MeSH] OR (“insulin” AND “resistance”) OR “insulin resistance”

“breast neoplasms”[Mesh] OR “breast neoplasms” OR “breast cancer” OR (“breast” AND “neoplasms”) OR (“breast” AND “cancer”)

For C-peptide and breast cancer

“C-peptide” AND “breast neoplasms”

“breast neoplasms”[Mesh] OR “breast neoplasms” OR “breast cancer” OR (“breast” AND “neoplasms”) OR (“breast” AND “cancer”)

“c-peptide”[Mesh] OR “c-peptide” OR”c peptide”

Rights and permissions

Reprints and permissions

About this article

Cite this article

Autier, P., Koechlin, A., Boniol, M. et al. Serum insulin and C-peptide concentration and breast cancer: a meta-analysis. Cancer Causes Control 24, 873–883 (2013). https://doi.org/10.1007/s10552-013-0164-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10552-013-0164-6

Keywords

Search

Navigation