Diabetologia

, Volume 60, Issue 12, pp 2514–2524 | Cite as

Circulating adipokines are associated with pre-eclampsia in women with type 1 diabetes

  • Clare B. Kelly
  • Michelle B. Hookham
  • Jeremy Y. Yu
  • Samuel M. Lockhart
  • Mei Du
  • Alicia J. Jenkins
  • Alison Nankervis
  • Kristian F. Hanssen
  • Tore Henriksen
  • Satish K. Garg
  • Samar M. Hammad
  • James A. Scardo
  • Christopher E. Aston
  • Christopher C. Patterson
  • Timothy J. Lyons
Article

Abstract

Aims/hypothesis

The incidence of pre-eclampsia, a multisystem disorder of pregnancy, is fourfold higher in type 1 diabetic than non-diabetic women; it is also increased in women with features of the metabolic syndrome and insulin resistance. In a prospective study of pregnant women with type 1 diabetes, we measured plasma levels of adipokines known to be associated with insulin resistance: leptin, fatty acid binding protein 4 (FABP4), adiponectin (total and high molecular weight [HMW]; also known as high molecular mass), retinol binding protein 4 (RBP4) and resistin and evaluated associations with the subsequent development of pre-eclampsia.

Methods

From an established prospective cohort of pregnant type 1 diabetic women, we studied 23 who developed pre-eclampsia and 24 who remained normotensive; for reference values we included 19 healthy non-diabetic normotensive pregnant women. Plasma adipokines were measured (by ELISA) in stored samples from three study visits (Visit 1– Visit 3) at different gestational ages (mean ± SD): Visit 1, 12.4 ± 1.8 weeks; Visit 2, 21.7 ± 1.4 weeks; and Visit 3, 31.4 ± 1.5 weeks. All the women were free of microalbuminuria and hypertension at enrolment. All study visits preceded the clinical onset of pre-eclampsia.

Results

In all groups, leptin, the ratio of leptin to total or HMW adiponectin, FABP4 concentration, ratio of FABP4 to total or HMW adiponectin and resistin level increased, while total and HMW adiponectin decreased, with gestational age. At Visit 1: (1) in diabetic women with vs without subsequent pre-eclampsia, leptin, ratio of leptin to total or HMW adiponectin, and ratio of FABP4 to total or HMW adiponectin, were increased (p < 0.05), while total adiponectin was decreased (p < 0.05); and (2) in normotensive diabetic vs non-diabetic women, total adiponectin was elevated (p < 0.05). At Visits 2 and 3: (1) the primary findings in the two diabetic groups persisted, and FABP4 also increased in women with subsequent pre-eclampsia (p < 0.05); and (2) there were no differences between the two normotensive groups. By logistic regression analyses after covariate adjustment (HbA1c, insulin kg−1 day−1 and gestational age), the best predictive models for pre-eclampsia were as follows: Visit 1, doubling of leptin, OR 9.0 (p < 0.01); Visit 2, doubling of the leptin:total adiponectin ratio, OR 3.7 (p < 0.05); and Visit 3, doubling of FABP4 concentration, OR 25.1 (p < 0.01). The associations were independent of BMI.

Conclusions/interpretation

As early as the first trimester in type 1 diabetic women, adipokine profiles that suggest insulin resistance are associated with subsequent pre-eclampsia, possibly reflecting maternal characteristics that precede pregnancy. These associations persist in the second and third trimesters, and are independent of BMI. Insulin resistance may predispose women with type 1 diabetes to pre-eclampsia.

Keywords

Adipokine Adiponectin Diabetes Fatty acid binding protein Leptin Pre-eclampsia Pregnancy 

Abbreviations

CRP

C-reactive protein

DM−

Non-diabetic normotensive (group)

DM+PE−

Type 1 diabetes mellitus, normotensive (group)

DM+PE+

Type 1 diabetes mellitus, pre-eclampsia (group)

FABP4

Fatty acid binding protein 4

GDM

Gestational diabetes mellitus

HMW

High molecular weight (also known as high molecular mass)

IDI

Integrated Discrimination Improvement

MAP

Mean arterial pressure

NPV

Negative predictive value

NRI

Net Reclassification Improvement

PlGF

Placental growth factor

PPV

Positive predictive value

RBP4

Retinol binding protein 4

ROC

Receiver operating characteristic

sFlt-1

Soluble fms-like tyrosine kinase-1

Notes

Acknowledgements

The skilled and dedicated assistance of the following individuals for the clinical components of the study is acknowledged: M.K. Menard (University of North Carolina, Chapel Hill, NC, USA); J. Cole (Spartanburg Regional Hospital, Spartanburg, SC, USA); C. Knight, J. Conn, S. Hiscock, J. Oats and P. Wein (University of Melbourne, VIC, Australia); A. Dashti and M. Leyva (University of Oklahoma, Oklahoma City, OK, USA); H. Scholz (University of Oslo, Oslo, Norway); and J. R. Stanley (Mercy Health Center, Oklahoma City, OK, USA). We thank D. McCance (Queen’s University, Belfast, UK) for helpful discussions.

Data availability

The dataset is not publicly available for reasons of patient confidentiality. Please contact the authors for further information.

Funding

This work was supported by Research Grants from the Juvenile Diabetes Research Foundation (JDRF 1-2001-844) and Novo Nordisk to TJL, and by National Institutes of Health (National Center for Research Resources) Grants M01-RR-1070 and M01 RR-14467 to the General Clinical Research Centers at the Medical University of South Carolina and University of Oklahoma Health Sciences Center, respectively. Support from Novo Nordisk enabled the participation of the Barbara Davis Diabetes Center for Childhood Diabetes at the University of Colorado, Denver, CO, USA.

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Contribution statement

All authors made significant contributions to the study concept, design and acquisition of data. CBK, CEA, CCP and TJL undertook the statistical analysis of the data, and all authors engaged in its interpretation. CBK and TJL drafted the manuscript and all authors participated critically in its revision. All authors approved the final version to be published, and agree to be accountable for all aspects of the work.

References

  1. 1.
    Brown MA, Lindheimer MD, de Swiet M, Van Assche A, Moutquin JM (2001) The classification and diagnosis of the hypertensive disorders of pregnancy: statement from the International Society for the Study of Hypertension in Pregnancy (ISSHP). Hypertens Pregnancy 20:IX–XIVCrossRefPubMedGoogle Scholar
  2. 2.
    Roberts JM, Gammill HS (2005) Preeclampsia: recent insights. Hypertension 46:1243–1249CrossRefPubMedGoogle Scholar
  3. 3.
    American College of Obstetricians and Gynecologists; Task Force on Hypertension in Pregnancy (2013) Report. Obstet Gynecol 122:1122–1131CrossRefGoogle Scholar
  4. 4.
    Persson M, Norman M, Hanson U (2009) Obstetric and perinatal outcomes in type 1 diabetic pregnancies: a large, population-based study. Diabetes Care 32:2005–2009CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Briana DD, Malamitsi-Puchner A (2009) Reviews: adipocytokines in normal and complicated pregnancies. Reprod Sci 16:921–937CrossRefPubMedGoogle Scholar
  6. 6.
    Schindler K, Vila G, Hoppichler F et al (2012) The impact of type 2 diabetes on circulating adipokines in patients with metabolic syndrome. Obes Facts 5:270–276CrossRefPubMedGoogle Scholar
  7. 7.
    Syed Ikmal SI, Zaman Huri H, Vethakkan SR, Wan Ahmad WA (2013) Potential biomarkers of insulin resistance and atherosclerosis in type 2 diabetes mellitus patients with coronary artery disease. Int J Endocrinol 2013:698567CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    DeFronzo RA, Hendler R, Simonson D (1982) Insulin resistance is a prominent feature of insulin-dependent diabetes. Diabetes 31:795–801CrossRefPubMedGoogle Scholar
  9. 9.
    Williams KV, Erbey JR, Becker D, Arslanian S, Orchard TJ (2000) Can clinical factors estimate insulin resistance in type 1 diabetes? Diabetes 49:626–632CrossRefPubMedGoogle Scholar
  10. 10.
    Kilpatrick ES, Rigby AS, Atkin SL (2007) Insulin resistance, the metabolic syndrome, and complication risk in type 1 diabetes: “double diabetes” in the Diabetes Control and Complications Trial. Diabetes Care 30:707–712CrossRefPubMedGoogle Scholar
  11. 11.
    Cleland SJ, Fisher BM, Colhoun HM, Sattar N, Petrie JR (2013) Insulin resistance in type 1 diabetes: what is ‘double diabetes’ and what are the risks? Diabetologia 56:1462–1470CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Bjornstad P, Snell-Bergeon JK, Nadeau KJ, Maahs DM (2015) Insulin sensitivity and complications in type 1 diabetes: new insights. World J Diabetes 6:8–16CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Kirwan JP, Hauguel-De Mouzon S, Lepercq J et al (2002) TNF-alpha is a predictor of insulin resistance in human pregnancy. Diabetes 51:2207–2213CrossRefPubMedGoogle Scholar
  14. 14.
    Hauth JC, Clifton RG, Roberts JM et al (2011) Maternal insulin resistance and preeclampsia. Am J Obstet Gynecol 204:327.e321–327.e326Google Scholar
  15. 15.
    Wolf M, Sandler L, Munoz K, Hsu K, Ecker JL, Thadhani R (2002) First trimester insulin resistance and subsequent preeclampsia: a prospective study. J Clin Endocrinol Metab 87:1563–1568CrossRefPubMedGoogle Scholar
  16. 16.
    Seely EW, Solomon CG (2003) Insulin resistance and its potential role in pregnancy-induced hypertension. J Clin Endocrinol Metab 88:2393–2398CrossRefPubMedGoogle Scholar
  17. 17.
    Parretti E, Lapolla A, Dalfra M et al (2006) Preeclampsia in lean normotensive normotolerant pregnant women can be predicted by simple insulin sensitivity indexes. Hypertension 47:449–453CrossRefPubMedGoogle Scholar
  18. 18.
    Persson M, Pasupathy D, Hanson U, Westgren M, Norman M (2012) Pre-pregnancy body mass index and the risk of adverse outcome in type 1 diabetic pregnancies: a population-based cohort study. BMJ Open 2:e000601CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Kirwan JP, Huston-Presley L, Kalhan SC, Catalano PM (2001) Clinically useful estimates of insulin sensitivity during pregnancy. Validation studies in women with normal glucose tolerance and gestational diabetes mellitus. Diabetes Care 24:1602–1607CrossRefPubMedGoogle Scholar
  20. 20.
    Ryan EA, O'Sullivan MJ, Skyler JS (1985) Insulin action during pregnancy. Studies with the euglycemic clamp technique. Diabetes 34:380–389CrossRefPubMedGoogle Scholar
  21. 21.
    Xiang AH, Peters RK, Trigo E, Kjos SL, Lee WP, Buchanan TA (1999) Multiple metabolic defects during late pregnancy in women at high risk for type 2 diabetes. Diabetes 48:848–854CrossRefPubMedGoogle Scholar
  22. 22.
    Masuyama H, Inoue S, Hiramatsu Y (2011) Retinol-binding protein 4 and insulin resistance in preeclampsia. Endocr J 58:47–53CrossRefPubMedGoogle Scholar
  23. 23.
    Deng Y, Scherer PE (2010) Adipokines as novel biomarkers and regulators of the metabolic syndrome. Ann N Y Acad Sci 1212:E1–E19CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Wauters M, Considine RV, Van Gaal LF (2000) Human leptin: from an adipocyte hormone to an endocrine mediator. Eur J Endocrinol 143:293–311CrossRefPubMedGoogle Scholar
  25. 25.
    Hauguel-de Mouzon S, Lepercq J, Catalano P (2006) The known and unknown of leptin in pregnancy. Am J Obstet Gynecol 194:1537–1545CrossRefPubMedGoogle Scholar
  26. 26.
    Randeva HS, Vatish M, Tan BK et al (2006) Raised plasma adiponectin levels in type 1 diabetic pregnancies. Clin Endocrinol 65:17–21CrossRefGoogle Scholar
  27. 27.
    Nien JK, Mazaki-Tovi S, Romero R et al (2007) Adiponectin in severe preeclampsia. J Perinat Med 35:503–512PubMedPubMedCentralGoogle Scholar
  28. 28.
    Fasshauer M, Waldeyer T, Seeger J et al (2008) Circulating high-molecular-weight adiponectin is upregulated in preeclampsia and is related to insulin sensitivity and renal function. Eur J Endocrinol 158:197–201CrossRefPubMedGoogle Scholar
  29. 29.
    Miehle K, Stepan H, Fasshauer M (2012) Leptin, adiponectin and other adipokines in gestational diabetes mellitus and pre-eclampsia. Clin Endocrinol 76:2–11CrossRefGoogle Scholar
  30. 30.
    Scifres CM, Catov JM, Simhan H (2012) Maternal serum fatty acid binding protein 4 (FABP4) and the development of preeclampsia. J Clin Endocrinol Metab 97:E349–E356CrossRefPubMedGoogle Scholar
  31. 31.
    Fuseya T, Furuhashi M, Yuda S et al (2014) Elevation of circulating fatty acid-binding protein 4 is independently associated with left ventricular diastolic dysfunction in a general population. Cardiovasc Diabetol 13:126CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Scifres CM, Chen B, Nelson DM, Sadovsky Y (2011) Fatty acid binding protein 4 regulates intracellular lipid accumulation in human trophoblasts. J Clin Endocrinol Metab 96:E1083–E1091CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Steppan CM, Bailey ST, Bhat S et al (2001) The hormone resistin links obesity to diabetes. Nature 409:307–312CrossRefPubMedGoogle Scholar
  34. 34.
    Yang Q, Graham TE, Mody N et al (2005) Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes. Nature 436:356–362CrossRefPubMedGoogle Scholar
  35. 35.
    Graham TE, Yang Q, Bluher M et al (2006) Retinol-binding protein 4 and insulin resistance in lean, obese, and diabetic subjects. N Engl J Med 354:2552–2563CrossRefPubMedGoogle Scholar
  36. 36.
    Yu Y, Jenkins AJ, Nankervis AJ et al (2009) Anti-angiogenic factors and pre-eclampsia in type 1 diabetic women. Diabetologia 52:160–168CrossRefPubMedGoogle Scholar
  37. 37.
    Basu A, Yu JY, Jenkins AJ et al (2015) Trace elements as predictors of preeclampsia in type 1 diabetic pregnancy. Nutr Res 35:421–430CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    DeLong ER, DeLong DM, Clarke-Pearson DL (1988) Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. Biometrics 44:837–845CrossRefPubMedGoogle Scholar
  39. 39.
    Pencina MJ, D'Agostino RB Sr, D'Agostino RB Jr, Vasan RS (2008) Evaluating the added predictive ability of a new marker: from area under the ROC curve to reclassification and beyond. Stat Med 27:157–172, discussion 207–212CrossRefPubMedGoogle Scholar
  40. 40.
    Pencina MJ, D'Agostino RB Sr, Steyerberg EW (2011) Extensions of net reclassification improvement calculations to measure usefulness of new biomarkers. Stat Med 30:11–21CrossRefPubMedGoogle Scholar
  41. 41.
    Jin J, Peng DQ, Yuan SG et al (2010) Serum adipocyte fatty acid binding proteins and adiponectin in patients with coronary artery disease: the significance of A-FABP/adiponectin ratio. Clin Chim Acta 411:1761–1765CrossRefPubMedGoogle Scholar
  42. 42.
    Lekva T, Michelsen AE, Aukrust P, Henriksen T, Bollerslev J, Ueland T (2017) Leptin and adiponectin as predictors of cardiovascular risk after gestational diabetes mellitus. Cardiovasc Diabetol 16:5CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Molvarec A, Szarka A, Walentin S et al (2011) Serum leptin levels in relation to circulating cytokines, chemokines, adhesion molecules and angiogenic factors in normal pregnancy and preeclampsia. Reprod Biol Endocrinol 9:124CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Sagawa N, Yura S, Itoh H et al (2002) Role of leptin in pregnancy—a review. Placenta 23 Suppl A:S80–S86CrossRefPubMedGoogle Scholar
  45. 45.
    Wotherspoon AC, Young IS, McCance DR et al (2016) Serum fatty acid binding protein 4 (FABP4) predicts pre-eclampsia in women with type 1 diabetes. Diabetes Care 39:1827–1829CrossRefPubMedGoogle Scholar
  46. 46.
    Fasshauer M, Seeger J, Waldeyer T et al (2008) Serum levels of the adipokine adipocyte fatty acid-binding protein are increased in preeclampsia. Am J Hypertens 21:582–586CrossRefPubMedGoogle Scholar
  47. 47.
    Shangguan X, Liu F, Wang H, He J, Dong M (2009) Alterations in serum adipocyte fatty acid binding protein and retinol binding protein-4 in normal pregnancy and preeclampsia. Clin Chim Acta 407:58–61CrossRefPubMedGoogle Scholar
  48. 48.
    Cortelazzi D, Corbetta S, Ronzoni S et al (2007) Maternal and foetal resistin and adiponectin concentrations in normal and complicated pregnancies. Clin Endocrinol 66:447–453CrossRefGoogle Scholar
  49. 49.
    Nanda S, Nikoletakis G, Markova D, Poon LC, Nicolaides KH (2013) Maternal serum retinol-binding protein-4 at 11-13 weeks’ gestation in normal and pathological pregnancies. Metabolism 62:814–819CrossRefPubMedGoogle Scholar
  50. 50.
    Ringholm L, Damm JA, Vestgaard M, Damm P, Mathiesen ER (2016) Diabetic nephropathy in women with preexisting diabetes: from pregnancy planning to breastfeeding. Curr Diab Rep 16(2):12CrossRefPubMedGoogle Scholar
  51. 51.
    Vestgaard M, Sommer MC, Ringholm L, Damm P, Mathiesen ER (2017) Prediction of preeclampsia in type 1 diabetes in early pregnancy by clinical predictors: a systematic review. J Matern Fetal Neonatal Med DOI: 10.1080/14767058.2017.1331429
  52. 52.
    Kenny LC, Black MA, Poston L et al (2014) Early pregnancy prediction of preeclampsia in nulliparous women, combining clinical risk and biomarkers: the Screening for Pregnancy Endpoints (SCOPE) international cohort study. Hypertension 64:644–652CrossRefPubMedGoogle Scholar
  53. 53.
    Wright D, Syngelaki A, Akolekar R, Poon LC, Nicolaides KH (2015) Competing risks model in screening for preeclampsia by maternal characteristics and medical history. Am J Obstet Gynecol 213:62.e61-e10Google Scholar
  54. 54.
    O'Gorman N, Wright D, Syngelaki A et al (2016) Competing risks model in screening for preeclampsia by maternal factors and biomarkers at 11-13 weeks gestation. Am J Obstet Gynecol 214:103.e101–103.e112Google Scholar

Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  • Clare B. Kelly
    • 1
    • 2
  • Michelle B. Hookham
    • 1
    • 3
  • Jeremy Y. Yu
    • 1
    • 2
  • Samuel M. Lockhart
    • 1
  • Mei Du
    • 4
  • Alicia J. Jenkins
    • 2
    • 5
  • Alison Nankervis
    • 6
  • Kristian F. Hanssen
    • 7
    • 8
  • Tore Henriksen
    • 8
  • Satish K. Garg
    • 9
  • Samar M. Hammad
    • 10
  • James A. Scardo
    • 11
  • Christopher E. Aston
    • 12
  • Christopher C. Patterson
    • 13
  • Timothy J. Lyons
    • 1
    • 2
  1. 1.Centre for Experimental MedicineQueen’s University BelfastBelfastUK
  2. 2.Division of Endocrinology and Diabetes, CSB Suite 822Medical University of South CarolinaCharlestonUSA
  3. 3.The Department of Clinical BiochemistryRoyal Victoria HospitalBelfastUK
  4. 4.Section of EndocrinologyUniversity of Oklahoma Health Sciences CenterOklahoma CityUSA
  5. 5.University of Sydney, NHMRC Clinical Trials CentreSydneyAustralia
  6. 6.Royal Women’s HospitalMelbourneAustralia
  7. 7.Department of EndocrinologyOslo University HospitalOsloNorway
  8. 8.Institute of Clinical MedicineUniversity of OsloOsloNorway
  9. 9.Barbara Davis Center for Childhood DiabetesUniversity of ColoradoDenverUSA
  10. 10.Department of Regenerative Medicine and Cell BiologyMedical University of South CarolinaCharlestonUSA
  11. 11.Spartanburg Regional HospitalSpartanburgUSA
  12. 12.Department of PediatricsUniversity of Oklahoma Health Sciences CenterOklahoma CityUSA
  13. 13.Centre for Public HealthQueen’s University BelfastBelfastUK

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