Skip to main content
Log in

Circulating insulin-like peptide 5 levels and its association with metabolic and hormonal parameters in women with polycystic ovary syndrome

  • Original Article
  • Published:
Journal of Endocrinological Investigation Aims and scope Submit manuscript

Abstract

Purpose

Insulin-like peptide 5 (INSL5) is a gut peptide hormone that is a member of relaxin/insulin superfamily. Growing evidence implicates the crucial role of the peptide in some metabolisms including food intake, glucose homeostasis and reproductive system. Polycystic ovary syndrome (PCOS) is involved in both reproductive and metabolic issues. The aim of the study was determination of circulating levels of INSL5 alteration in women with PCOS and evaluation of the relationship between INSL5 and hormonal-metabolic parameters as well as carotid intima media thickness (cIMT).

Methods

A total of 164 subjects were recruited in this cross-sectional study (82 women with PCOS and 82 age- and BMI-matched controls). Circulating INSL5 levels were assessed via ELISA method. High-resolution B-mode ultrasound was used to measure cIMT. The hormonal and metabolic parameters of the recruited subjects were determined.

Results

Circulating INSL5 levels were significantly elevated in women with PCOS compared to controls (27.63 ± 7.74 vs. 19.90 ± 5.85 ng/ml, P < 0.001). The mean values of INSL5 were significantly higher in overweight subjects compared to lean weight subjects in both groups. The women with PCOS having insulin resistance have increased INSL5 compared to those of PCOS subjects without insulin resistance. INSL5 is associated with insulin resistance, BMI, luteinizing hormone and free androgen index. Multivariate logistic regression analyses revealed that the odds ratio for having PCOS in the highest tertile of INSL5 was higher than in the lowest tertile.

Conclusions

PCOS subjects exhibited an elevation in circulating INSL5 levels along with a link between INSL5 level induction and metabolic-hormonal parameters.

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

Access this article

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Abbreviations

BMI:

Body mass index

CI:

Confidence interval

cIMT:

Carotid intima media thickness

CV:

Coefficient of variability

DBP:

Diastolic blood pressure

DHEA-S:

Dehydroepiandrosterone sulfate

FAI:

Free androgen index

FBG:

Fasting blood glucose

FG:

Ferriman–Gallwey

GLP-1:

Glucagon-like peptide-1

HDL-C:

High-density lipoprotein cholesterol

HOMA-IR:

Homeostasis model assessment of insulin resistance

Hs-CRP:

High-sensitivity C-reactive protein

INSL-5:

Insulin-like peptide 5

LDL-C:

Low-density lipoprotein cholesterol

OGTT:

Oral glucose tolerance test

OR:

Odds ratio

PCOS:

Polycystic ovary syndrome

ROC:

Receiver operating characteristic

SBP:

Systolic blood pressure

VIF:

Variance inflation factor

References

  1. Ehrmann DA (2005) Polycystic ovary syndrome. N Engl J Med 352:1223–1236. https://doi.org/10.1056/NEJMra041536

    Article  PubMed  CAS  Google Scholar 

  2. Azziz R, Woods KS, Reyna R, Key TJ, Knochenhauer ES, Yildiz BO (2004) The prevalence and features of the polycystic ovary syndrome in an unselected population. J Clin Endocrinol Metab 89:2745–2749. https://doi.org/10.1210/jc.2003-032046

    Article  PubMed  CAS  Google Scholar 

  3. March WA, Moore VM, Willson KJ, Phillips DIW, Norman RJ, Davies MJ (2010) The prevalence of polycystic ovary syndrome in a community sample assessed under contrasting diagnostic criteria. Hum Reprod 25:544–551. https://doi.org/10.1093/humrep/dep399

    Article  PubMed  Google Scholar 

  4. Stepto NK, Cassar S, Joham AE, Hutchison SK, Harrison CL, Goldstein RF et al (2013) Women with polycystic ovary syndrome have intrinsic insulin resistance on euglycaemic-hyperinsulaemic clamp. Hum Reprod 28:777–784. https://doi.org/10.1093/humrep/des463

    Article  PubMed  CAS  Google Scholar 

  5. Christian RC, Dumesic DA, Behrenbeck T, Oberg AL, Sheedy PF, Fitzpatrick LA (2003) Prevalence and predictors of coronary artery calcification in women with polycystic ovary syndrome. J Clin Endocrinol Metab 88:2562–2568

    Article  PubMed  CAS  Google Scholar 

  6. Orio F, Palomba S, Spinelli L, Cascella T, Tauchmanovà L, Zullo F et al (2004) The cardiovascular risk of young women with polycystic ovary syndrome: an observational, analytical, prospective case-control study. J Clin Endocrinol Metab 89:3696–3701. https://doi.org/10.1210/jc.2003-032049

    Article  PubMed  CAS  Google Scholar 

  7. Conklin D, Lofton-Day CE, Haldeman BA, Ching A, Whitmore TE, Lok S et al (1999) Identification of INSL5, a New Member of the insulin superfamily. Genomics 60:50–56. https://doi.org/10.1006/geno.1999.5899

    Article  PubMed  CAS  Google Scholar 

  8. Dun SL, Brailoiu E, Wang Y, Brailoiu GC, Liu-Chen L-Y, Yang J et al (2006) Insulin-like peptide 5: expression in the mouse brain and mobilization of calcium. Endocrinology 147:3243–3248. https://doi.org/10.1210/en.2006-0237

    Article  PubMed  CAS  Google Scholar 

  9. Burnicka-Turek O, Mohamed BA, Shirneshan K, Thanasupawat T, Hombach-Klonisch S, Klonisch T et al (2012) INSL5-deficient mice display an alteration in glucose homeostasis and an impaired fertility. Endocrinology 153:4655–4665. https://doi.org/10.1210/en.2012-1161

    Article  PubMed  CAS  Google Scholar 

  10. Mashima H, Ohno H, Yamada Y, Sakai T, Ohnishi H (2013) INSL5 may be a unique marker of colorectal endocrine cells and neuroendocrine tumors. Biochem Biophys Res Commun 432:586–592. https://doi.org/10.1016/j.bbrc.2013.02.042

    Article  PubMed  CAS  Google Scholar 

  11. Hu M-J, Wei D, Shao X-X, Wang J-H, Liu Y-L, Xu Z-G et al (2017) Interaction mechanism of insulin-like peptide 5 with relaxin family peptide receptor 4. Arch Biochem Biophys 619:27–34. https://doi.org/10.1016/j.abb.2017.03.001

    Article  PubMed  CAS  Google Scholar 

  12. Grosse J, Heffron H, Burling K, Akhter Hossain M, Habib AM, Rogers GJ et al (2014) Insulin-like peptide 5 is an orexigenic gastrointestinal hormone. Proc Natl Acad Sci USA 111:11133–11138. https://doi.org/10.1073/pnas.1411413111

    Article  PubMed  CAS  Google Scholar 

  13. Luo X, Li T, Zhu Y, Dai Y, Zhao J, Guo Z-Y et al (2015) The insulinotrophic effect of insulin-like peptide 5 in vitro and in vivo. Biochem J 466:467–473. https://doi.org/10.1042/BJ20141113

    Article  PubMed  CAS  Google Scholar 

  14. Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop group (2004) Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod 19(1):41–47. https://doi.org/10.1093/humrep/deh098

    Article  Google Scholar 

  15. Ferriman D, Gallwey JD (1961) Clinical assessment of body hair growth in women. J Clin Endocrinol Metab 21:1440–1447. https://doi.org/10.1210/jcem-21-11-1440

    Article  PubMed  CAS  Google Scholar 

  16. Al Kindi MK, Al Essry FS, Al Essry FS, Mula-Abed W-AS (2012) Validity of serum testosterone, free androgen index, and calculated free testosterone in women with suspected hyperandrogenism. Oman Med J 27:471–474. https://doi.org/10.5001/omj.2012.112

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC (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. Sidhu PS, Desai SR (1997) A simple and reproducible method for assessing intimal-medial thickness of the common carotid artery. Br J Radiol 70:85–89. https://doi.org/10.1016/0929-8266(96)88371-6

    Article  PubMed  CAS  Google Scholar 

  19. Faul F, Erdfelder E, Lang A-G, Buchner A (2007) G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav Res Methods 39:175–191. https://doi.org/10.3758/BF03193146

    Article  PubMed  Google Scholar 

  20. Geloneze B, Repetto EM, Geloneze SR, Tambascia MA, Ermetice MN (2006) The threshold value for insulin resistance (HOMA-IR) in an admixtured population. IR in the Brazilian Metabolic Syndrome Study. Diabetes Res Clin Pract 72:219–220. https://doi.org/10.1016/j.diabres.2005.10.017

    Article  PubMed  CAS  Google Scholar 

  21. Spanel-Borowski K, Schäfer I, Zimmermann S, Engel W, Adham IM (2001) Increase in final stages of follicular atresia and premature decay of corpora lutea in Insl3-deficient mice. Mol Reprod Dev 58:281–286. https://doi.org/10.1002/1098-2795(200103)58:3<281:AID-MRD6>3.0.CO;2-0

  22. Irving-Rodgers HF, Bathgate RAD, Ivell R, Domagalski R, Rodgers RJ (2002) Dynamic changes in the expression of relaxin-like factor (INSL3), cholesterol side-chain cleavage cytochrome p450, and 3beta-hydroxysteroid dehydrogenase in bovine ovarian follicles during growth and atresia. Biol Reprod 66:934–943

    Article  PubMed  CAS  Google Scholar 

  23. Satchell L, Glister C, Bleach EC, Glencross RG, Bicknell AB, Dai Y et al (2013) Ovarian expression of insulin-like peptide 3 (INSL3) and its receptor (RXFP2) during development of bovine antral follicles and corpora lutea and measurement of circulating INSL3 levels during synchronized estrous cycles. Endocrinology 154:1897–1906. https://doi.org/10.1210/en.2012-2232

    Article  PubMed  CAS  Google Scholar 

  24. Anand-Ivell R, Tremellen K, Dai Y, Heng K, Yoshida M, Knight PG et al (2013) Circulating insulin-like factor 3 (INSL3) in healthy and infertile women. Hum Reprod 28:3093–3102. https://doi.org/10.1093/humrep/det349

    Article  PubMed  CAS  Google Scholar 

  25. Pelusi C, Fanelli F, Pariali M, Zanotti L, Gambineri A, Pasquali R (2013) Parallel variations of insulin-like peptide 3 (INSL3) and antimüllerian hormone (AMH) in women with the polycystic ovary syndrome according to menstrual cycle pattern. J Clin Endocrinol Metab 98:E1575–E1582. https://doi.org/10.1210/jc.2013-1107

    Article  PubMed  CAS  Google Scholar 

  26. Gambineri A, Patton L, De Iasio R, Palladoro F, Pagotto U, Pasquali R (2007) Insulin-like factor 3: a new circulating hormone related to luteinizing hormone-dependent ovarian hyperandrogenism in the polycystic ovary syndrome. J Clin Endocrinol Metab 92:2066–2073. https://doi.org/10.1210/jc.2006-1678

    Article  PubMed  CAS  Google Scholar 

  27. Wagner IV, Flehmig G, Scheuermann K, Löffler D, Körner A, Kiess W et al (2016) Insulin-like peptide 5 interacts with sex hormones and metabolic parameters in a gender and adiposity dependent manner in humans. Horm Metab Res 48:589–594. https://doi.org/10.1055/s-0042-109869

    Article  PubMed  CAS  Google Scholar 

  28. Lee YS, De Vadder F, Tremaroli V, Wichmann A, Mithieux G, Bäckhed F (2016) Insulin-like peptide 5 is a microbially regulated peptide that promotes hepatic glucose production. Mol Metab 5:263–270. https://doi.org/10.1016/j.molmet.2016.01.007

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Diamanti-Kandarakis E, Dunaif A (2012) Insulin resistance and the polycystic ovary syndrome revisited: an update on mechanisms and implications. Endocr Rev 33:981–1030. https://doi.org/10.1210/er.2011-1034

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Dunaif A, Segal KR, DA Futterweit W (1989) Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome. Diabetes 38:1165–1174

    Article  PubMed  CAS  Google Scholar 

  31. Järvisalo MJ, Harmoinen A, Hakanen M, Paakkunainen U, Viikari J, Hartiala J et al (2002) Elevated serum C-reactive protein levels and early arterial changes in healthy children. Arterioscler Thromb Vasc Biol 22:1323–1328. https://doi.org/10.1161/01.ATV.0000024222.06463.21

    Article  PubMed  CAS  Google Scholar 

  32. Polak JF, Szklo M, Kronmal RA, Burke GL, Shea S, Zavodni AEH et al (2013) The value of carotid artery plaque and intima-media thickness for incident cardiovascular disease: the multi-ethnic study of atherosclerosis. J Am Heart Assoc 2:e000087–e000087. https://doi.org/10.1161/JAHA.113.000087

    Article  PubMed  PubMed Central  Google Scholar 

  33. O’Leary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL, Wolfson SK (1999) Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group. N Engl J Med 340:14–22. https://doi.org/10.1056/NEJM199901073400103

    Article  PubMed  Google Scholar 

Download references

Funding

This study has not been funded by any organizations.

Author information

Authors and Affiliations

Authors

Contributions

MC, AG, MB, MA, PA, GUK participated in study design, and GB and MA performed ELISA. MB, MC, AG, MA, AB, AMI, BA and CI participated in study design, analyzed the data, wrote, reviewed and edited the manuscript. MB, AG, MC, GUK and PA provided serum samples and contributed to discussions of data interpretation. CI measured carotid intima media thickness of the participants. All authors reviewed and edited the manuscript. MC is the guarantor of this work and, as such, has 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.

Corresponding author

Correspondence to Mehmet Calan.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

The study adhered strictly to the principles of the Declaration of Helsinki as revised in 2008.

Informed consent

The subjects gave their oral and written informed consent before their inclusion in the study.

Disclosure statement

The authors have nothing to disclose.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bicer, M., Alan, M., Alarslan, P. et al. Circulating insulin-like peptide 5 levels and its association with metabolic and hormonal parameters in women with polycystic ovary syndrome. J Endocrinol Invest 42, 303–312 (2019). https://doi.org/10.1007/s40618-018-0917-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40618-018-0917-x

Keywords

Navigation