Published Online
on March 15, 2004

A more recent version of this article appeared on May 1, 2004

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Submitted on October 14, 2003
Revised on November 13, 2003

Insulin Resistance and Alterations in Angiogenesis. Additive Insults That May Lead to Preeclampsia

Ravi Thadhani^*; Jeffrey L. Ecker; Walter P. Mutter; Myles Wolf; Karen V. Smirnakis; Vikas P. Sukhatme; Richard J. Levine; and S. Ananth Karumanchi

From the Renal Unit, Massachusetts General Hospital, and Harvard Medical School (R.T, J.L.E., M.W., K.V.S.), Boston; Renal Unit, Beth Israel Deaconess Hospital and Harvard Medical School (W.P.M., V.P.S., S.A.K.), Boston; National Institute of Diabetes (R.J.L.), Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Md.

^* To whom correspondence should be addressed. E-mail: thadhani.r{at}mgh.harvard.edu.

Abstract--Altered angiogenesis and insulin resistance, which are intimately related at a molecular level, characterize preeclampsia. To test if an epidemiological interaction exists between these two alterations, we performed a nested case-control study of 28 women who developed preeclampsia and 57 contemporaneous controls. Serum samples at 12 weeks of gestation were measured for sex hormone binding globulin (SHBG; low levels correlate with insulin resistance) and placental growth factor (PlGF; a proangiogenic molecule). Compared with controls, women who developed preeclampsia had lower serum levels of SHBG (208±116 versus 256±101 nmol/L, P=0.05) and PlGF (16±14 versus 67±150 pg/mL, P<0.001), and in multivariable analysis, women with serum levels of PlGF 20 pg/mL had an increased risk of developing preeclampsia (odds ratio [OR] 7.6, 95% CI 1.4 to 38.4). Stratified by levels of serum SHBG (175 versus >175 mg/dL), women with low levels of SHBG and PlGF had a 25.5-fold increased risk of developing preeclampsia (P=0.10), compared with 1.8 (P=0.38) among women with high levels of SHBG and low levels of PlGF. Formal testing for interaction (PlGFxSHBG) was significant (P=0.02). In a model with 3 (n-1) interaction terms (high PlGF and high SHBG, reference), the risk for developing preeclampsia was as follows: low PlGF and low SHBG, OR 15.1, 95% CI 1.7 to 134.9; high PlGF and low SHBG, OR 4.1, 95% CI 0.45 to 38.2; low PlGF and high SHBG, OR 8.7, 95% CI 1.2 to 60.3. Altered angiogenesis and insulin resistance are additive insults that lead to preeclampsia.

Key words: pregnancy • insulin resistance • preeclampsia • clinical trials

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