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(Hypertension. 2004;43:988.)
© 2004 American Heart Association, Inc.

Scientific Contributions

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; 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.

Correspondence to Ravi Thadhani, MD, MPH, Bullfinch 127, 55 Fruit Street, Massachusetts General Hospital, Boston, MA 02114. E-mail thadhani.r{at}mgh.harvard.edu

	Abstract

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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

	Introduction

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Preeclampsia is associated with considerable maternal and neonatal morbidity and mortality, and although most agree that preeclampsia is an endothelial cell disorder, the pathogenesis of preeclampsia is not well understood.¹ Recently, preeclampsia has been associated with alterations in expression of angiogenesis-related proteins such that administration of placental soluble fms-like tyrosine kinase 1 (sFlt-1), an endogenous inhibitor to vascular endothelial growth factor (VEGF) and placental growth factor (PlGF), to rats resulted in hypertension, proteinuria, and glomerular endotheliosis, a phenotype with similarities to human preeclampsia.² Indeed, low levels of serum PlGF and VEGF (proangiogenic) and increased levels of sFlt-1 (antiangiogenic) appear to antedate the onset of clinical symptoms.^3–7

In addition to alterations in angiogenesis, however, women who develop preeclampsia also have evidence of insulin resistance.^8,9 Large studies suggest women with pregestational diabetes mellitus¹⁰ and women who develop gestational diabetes mellitus¹¹ have an increased risk for developing preeclampsia. Importantly, recent data from in vitro models outside of pregnancy suggest insulin signaling and angiogenesis are intimately related at a molecular level.^12–14 Because both normal insulin signaling and angiogenesis maintain endothelial cell health, it is plausible that women with pre-existing alterations in insulin metabolism have an exaggerated response to alterations in angiogenic factors, and alterations in both pathways may interact to magnify the risk for preeclampsia. In an effort to identify early pregnancy markers that are biologically linked to the pathogenesis of preeclampsia, we tested the hypothesis that an epidemiological interaction exists between insulin resistance and angiogenesis by measuring markers for both in a prospective nested case-control study.

	Methods

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Study Population and Data Acquisition
We performed a prospective nested case-control study of patients who had enrolled in the Massachusetts General Hospital Obstetrical Maternal Study (MOMS), a prospective pregnancy cohort described previously.⁸ For this study, consecutive women with singleton gestations between June 1, 2001, and May 1, 2003, who enrolled in the MOMS cohort at approximately 12 weeks of gestation and delivered after 20 weeks were eligible for inclusion. All subjects for the current study had no history of preexisting hypertension, diabetes mellitus, thyroid disease, liver disease, or chronic kidney disease; initiated and completed their prenatal care and pregnancy within our network; delivered a live infant; and had no evidence of hypertension 6 weeks following delivery. The Institutional Review Board of the Massachusetts General Hospital approved this study.

Exposures
After providing informed written consent, eligible women had serum samples collected at the first prenatal visit. Samples were stored on ice for less than 3 hours, and then frozen at –80°C for future analysis. The primary exposures were serum sex-hormone binding globulin (SHBG), PlGF, and sFlt1. SHBG was measured using an immunoradiometric assay (Diagnostic Products Corporation) with an intra-assay coefficient of variation (CV) <4%, and an interassay CV<7.8%. The sensitivity of the SHBG assay is 2 nmol/L. Commercial assay ELISA kits for sFlt1 and free PlGF (R&D Systems) were used as previously described.² The intra-assay precision CV (%) for sFlt1 and PlGF were 3.5 and 5.6, respectively. The interassay precision CV (%) for sFlt1 and PlGF were 8.1 and 10.9, respectively. All samples were run in duplicate, and if >10% variation existed between duplicates, the assay was repeated and averages reported. The corresponding laboratory was blinded to case status, and all samples were randomly ordered.

Outcomes
Eligible cases were consecutively identified during the study period. Preeclampsia was defined as systolic blood pressure elevation 140 or diastolic blood pressure 90 mm Hg after 20 weeks of gestation in association with proteinuria, either 2+ by dipstick or 300 mg/24 h in the absence of urinary tract infection.¹ Controls (2:1) were randomly selected from women who participated in the MOMS cohort within the same time period as cases, delivered appropriate for gestational age infants, and remained normotensive and nonproteinuric throughout pregnancy. All women with 1-hour glucose levels greater than 140 mg/dL on the 50-g nonfasting glucose loading test that is typically administered in the early third trimester of gestation¹⁵ were excluded.

Statistical Analysis
Continuous variables were analyzed by Student t test, and categorical variables were analyzed by the Wald ² test. Primary exposures were examined as continuous variables (log transformed when necessary to achieve normality), and as binomial variables with cut points based on the 25th percentile levels in the controls. Multivariable analysis was performed using logistic regression techniques, and effect modification was examined using interaction terms in the logistic regression model and stratified analyses. All P values were 2-tailed, and P<0.05 was considered statistically significant.

	Results

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Baseline characteristics of the study population are shown in Table 1. Women who developed preeclampsia were more likely to be nulliparous, had a higher body mass index and had a higher systolic blood pressure compared with normotensive controls. In addition, gestational ages at delivery were earlier and fetal birth weights were lower among women who developed preeclampsia compared with controls. In the group that developed preeclampsia, 18.5% of the infants were below the 10th percentile of weight for gestational age, whereas only 5.2% of infants born to control women were below the 10th percentile. Other baseline characteristics did not significantly differ, including gestational age of blood collection.¹⁶

View this table: [in this window] [in a new window]   TABLE 1. Baseline Characteristics of Women Who Developed Preeclampsia and Normotensive Controls*

First prenatal visit blood collections revealed that serum levels of PlGF and SHBG were significantly lower among women who subsequently developed preeclampsia compared with normotensive controls (Table 2). Because levels of PlGF were skewed, log transformed levels of PlGF between cases and controls are shown in the Figure. At this early stage of pregnancy, serum levels of sFlt1 did not markedly differ between the two groups. The correlation between PlGF and SHBG was strongly positive (r=0.58, P<0.001), suggesting that women with low baseline levels of PlGF also had low levels of serum SHBG. In contrast, the correlation between sFlt1 and SHBG was comparatively weaker (r=0.17, P=0.10).

View this table: [in this window] [in a new window]   TABLE 2. First Trimester Serum Levels of Free Placental Growth Factor, Total sFlt1, and Total Sex Hormone Binding Globulin in Women Who Developed Preeclampsia Compared to Controls*

View larger version (9K): [in this window] [in a new window]   Log transformed levels of placental growth factor (PlGF) in cases and controls.

Serum levels of PlGF were then divided into a binomial variable (low versus high) with cut points based on the 25th percentile of the control population (20 pg/mL versus >20 pg/mL). In the unadjusted analysis, women with low baseline serum PlGF levels had a 6-fold increased risk of developing preeclampsia compared with women with high baseline PlGF levels (Table 3). After adjusting for maternal age, gestational age of blood collection, race, parity, body mass index, systolic blood pressure, smoking history, and serum levels of sFlt-1 and SHBG, the point estimate increased slightly (Table 3). Importantly, the model fit (area under the curve) improved when SHBG was added to the model (0.80 to 0.86), suggesting that the inclusion of SHBG in the analyses did not represent an overadjustment of the model, but an improvement.

View this table: [in this window] [in a new window]   TABLE 3. Risk of Preeclampsia According to First Trimester Placental Growth Factor (PlGF) and Sex Hormone Binding Globulin (SHBG) levels

Next, stratum specific point estimates were examined based on low (175 mg/dL) and high (>175 mg/dL) levels of SHBG (again representing the 25th percentile among controls). These analyses revealed markedly different point estimates for PlGF between the two strata. In the strata of women with low serum levels of SHBG, the risk of preeclampsia among women with low serum levels of PlGF was 25.5, whereas the estimate among women with high levels of SHBG (and low levels of PlGF) was 1.8 (Table 3). Thus, differences in these observed point estimates in stratified analyses suggested that the effect of PlGF was modified by different degrees of insulin resistance. The wide confidence intervals and loss of statistical significance in these stratified models likely reflected the loss of precision with reduced sample sizes. Nonetheless, the suggestion of an interaction or effect modification was explored further.

In a univariate model, the interaction term PlGFxSHBG was statistically significant (Wald P=0.02). However, in the adjusted model (including other confounders, serum PlGF, sFlt1, and SHBG) the interaction term was no longer significant (Wald P=0.10) and the confidence intervals expectedly widened. We then included interaction terms, based on the previously examined cut points, into a multivariable model, adjusting for important confounders. In this model with 3 (n–1) interaction terms (high PlGF and high SHBG, reference), the risk of developing preeclampsia among women with low first trimester levels of PlGF and SHBG was approximately twice the risk found among women with low PlGF levels alone, and four times the risk among women with low SHBG levels alone (Table 3). Importantly, these estimates did not markedly differ when these analyses were restricted to nulliparous (low PlGF and low SHBG, odds ratio [OR] 13.8, 95% CI 1.5 to 124.2) or multiparous (OR, 15.7, 95% CI 0.9 to 276.6) women, suggesting baseline differences in parity did not explain our findings (other data not shown).

	Discussion

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In this prospective nested case-control study, we found that women with alterations in markers for circulating angiogenic factors and in markers for insulin resistance were at increased risk for developing preeclampsia compared with women with alterations in either measure, and compared with women with neither alteration. Specifically, women with low levels of serum PlGF in the first trimester were at increased risk for developing subsequent preeclampsia, and this risk was exaggerated in women who also had low levels of SHBG, a surrogate marker of insulin resistance. Statistical tests for interaction between these two markers were significant even in this relatively small sample of women.

Unlike confounding (which must be controlled for, in order to prevent drawing incorrect conclusions regarding associations), interaction or effect modification must be explored further, as such analyses may yield insight into pathogenesis.¹⁷ Importantly, identifying interactions between variables is often difficult because large sample sizes are typically needed for formal statistical testing; thus, such tests should only be used as a guide.¹⁷ Nonetheless, in this study of only 85 women, there was significant interaction between serum PlGF and SHBG such that the association between PlGF levels and the subsequent risk for preeclampsia was modified, depending on the serum level of SHBG. Hence, it may be necessary to take into account differences in the degree of insulin resistance when reporting associations between alterations of angiogenesis and the risk of preeclampsia, rather than combining all women into a single pooled analysis. This finding of a compelling statistical interaction may also suggest important insights into the pathogenesis of preeclampsia or a biological interaction, because biological models outside of pregnancy suggest plausible and perhaps critical molecular interactions between intracellular insulin signaling and angiogenesis.

Binding of insulin to the insulin receptor leads to the activation of a variety of signaling pathways involving specific protein kinases, most important of which includes protein kinase B /Akt kinase.¹⁸ Phosphorylation of Akt kinase governs cellular functions, including apoptosis, metabolism, and proliferation.¹⁹ In addition, insulin also regulates the expression of genes involved in angiogenesis, including the expression of VEGF mRNA,²⁰ and VEGF (and likely PlGF²¹) signaling also activates Akt phosphorylation.^22,23 Interestingly, diabetic rats demonstrate a reduced cellular expression of VEGF mRNA, a process that may be rescued by insulin.¹² Therefore, defects in the insulin receptor or in downstream insulin-signaling pathways may lead to alterations in angiogenic factors, and if a circulating inhibitor of VEGF and PlGF is also present (as is thought to be the case in preeclampsia²), a combination of these insults may interact to alter critical cellular functions, injure endothelial cells, and, subsequently, increase the risk for developing preeclampsia.

Limitations in the current study must be acknowledged. First, we used a surrogate measure of insulin resistance, namely, serum levels of SHBG, a glycoprotein that is synthesized by the liver and mediates the balance of inactive bound sex hormones and biologically active, free sex hormones.²⁴ Importantly, insulin suppresses hepatic SHBG secretion,²⁵ SHBG levels correlate inversely with glucose tolerance²⁶ and insulin levels,²⁷ and serum SHBG levels correlate with insulin resistance as determined by the euglycemic hyperinsulinemic clamp.²⁸ Unlike other markers of insulin resistance, SHBG is reliable in the nonfasting state²⁹ and it exhibits no diurnal variation,³⁰ rendering SHBG a unique marker of insulin resistance that is especially useful in clinical situations when fasting blood samples are not routinely collected, such as during prenatal care. Furthermore, reduced levels of SHBG have been shown to independently identify women at risk for type 2 diabetes mellitus,^31,32 and recently, SHBG levels demonstrated good correlations with other manifestations of the metabolic syndrome including altered lipids,³³ which are also characteristic of women with preeclampsia.³⁴ We have shown that low first trimester levels of SHBG are independently associated with subsequent development of preeclampsia⁸ and gestational diabetes mellitus,³⁵ other insulin-resistant states.^29,30 Nonetheless, to provide further support for our results and to potentially reduce misclassification introduced by the measurement of SHBG as a surrogate marker for insulin resistance, fasting insulin and glucose levels should be measured, and more accurate methods to assess insulin resistance (eg, homeostasis models) should be examined in relation to alterations in angiogenesis. A second limitation of this preliminary study is the small sample size. We acknowledge that a subsequent study with a larger sample size with other conditions associated with insulin resistance (eg, gestational hypertension³⁶) would improve the precision of our findings, including our results for nulliparous versus multiparous women. Finally, our results do not allow us to determine cut points for clinical risk. We chose the 25th percentile of controls to examine cut points in this study. Only a larger sample size will improve the precision of our estimates as to the appropriate cut point for establishing risk. The purpose of this study, however, was to identify potential biological mechanisms and not to establish cut points for assessing risk.

Perspectives
It is well established that altered placental angiogenesis is a key feature of preeclampsia, and recent studies demonstrate elevated levels of sFlt-1, low levels of free PlGF and VEGF, or an altered balance of antiangiogenic and proangiogenic factors identify women who develop preeclampsia. It is unclear, however, if these alterations reflect a primary event in the development of preeclampsia or a functional response to alteration in placental perfusion. Existing studies that characterize the signaling pathway following VEGF activation and binding of insulin to the insulin receptor, suggest that these 2 pathways intersect at critical downstream mediators that govern cell health, such as AKT activation. Therefore, alterations of VEGF (or PlGF) signaling and insulin signaling (eg, insulin resistance) may provide additive insults that lead to widespread cellular injury. In the current study, we have found that among women with low levels of free PlGF, the risk of preeclampsia is greatest for those who also have low levels of SHBG, a surrogate marker of insulin resistance. Thus, women who develop preeclampsia not only exhibit altered levels of PlGF and sFlt-1 in early pregnancy, but these alterations may act in concert with insulin resistance to confer subsequent risk for preeclampsia. Additional studies are needed to further characterize the relationship between insulin resistance, endothelial dysfunction, angiogenesis, and clinical outcomes. An understanding of this relationship may lend insight into the pathogenesis of preeclampsia and possibly into the pathogenesis of disorders such as type 2 diabetes and cardiovascular disease.

	Acknowledgments

 
This research was supported by grants HD39223 (R.T.), DK02825, and DK64255 (S.A.K.), from the National Institutes of Health, Bethesda, Md; the American Heart Association (M.W.); the McGuirk Family Research Foundation (R.T., J.E.); the American Kidney Fund (K.V.S.); and the Carl Gottschalk Award from the American Society of Nephrology (S.A.K.).

Received October 14, 2003; first decision November 13, 2003; accepted February 17, 2004.

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				M. Wolf, C. A. Hubel, C. Lam, M. Sampson, J. L. Ecker, R. B. Ness, A. Rajakumar, A. Daftary, A. S. M. Shakir, E. W. Seely, et al. Preeclampsia and Future Cardiovascular Disease: Potential Role of Altered Angiogenesis and Insulin Resistance J. Clin. Endocrinol. Metab., December 1, 2004; 89(12): 6239 - 6243. [Abstract] [Full Text] [PDF]

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