Circulating adipokines are associated with pre-eclampsia in women with type 1 diabetes
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.
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.
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.
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.
KeywordsAdipokine Adiponectin Diabetes Fatty acid binding protein Leptin Pre-eclampsia Pregnancy
Non-diabetic normotensive (group)
Type 1 diabetes mellitus, normotensive (group)
Type 1 diabetes mellitus, pre-eclampsia (group)
Fatty acid binding protein 4
Gestational diabetes mellitus
High molecular weight (also known as high molecular mass)
Integrated Discrimination Improvement
Mean arterial pressure
Negative predictive value
Net Reclassification Improvement
Placental growth factor
Positive predictive value
Retinol binding protein 4
Receiver operating characteristic
Soluble fms-like tyrosine kinase-1
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.
The dataset is not publicly available for reasons of patient confidentiality. Please contact the authors for further information.
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.
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.
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