EARLY MARKERS OF PRE-ECLAMPSIA IN NATIVE AMERICAN WITH TYPE 2 DIABETES

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Pre-eclampsia (PE), characterized by de novo hypertension and proteinuria during pregnancy, is a major cause of maternal and fetal death, and the leading cause of premature delivery worldwide. Currently there is no effective treatment, and delivery of the baby is the only "cure". The incidence of PE is dramatically increased in pregnancies complicated by any form of diabetes (~20% vs ~5% in general population), especially pre-gestational diabetes, and in Native American and Hispanic populations, who are currently experiencing a major epidemic of Type 2 diabetes. Most previous studies are cross-sectional and late in pregnancy, and few address diabetes and minority populations. More recent discoveries in PE in nondiabetic population suggest that circulating anti-angiogenic factors from the placenta may mediate PE, and may be of predictive value. To identify early predictors of PE and to elucidate mechanisms in Type 2 diabetes in Native American and Hispanic populations, we will recruit a longitudinal cohort of 300 Type 2 diabetic pregnant women and 60 non-diabetic pregnant controls at two Oklahoma tribal clinics, and at OUHSC. Blood and urine samples will be obtained at -12, ~22 and ~32 weeks' gestation and at term. We expect 60 (20%) Type 2 diabetic subjects will develop PE. Our hypothesis is that 1) inter-related maternal factors of endothelial dysfunction and vascular inflammation, oxidative stress and dyslipidemia are associated with PE, and contribute to the initiation and development of PE in Type 2 diabetes, and 2) alteration of the circulating angiogenic/anti-angiogenic balance is mechanistic in and predictive of PE development in Type 2 diabetes. Our Specific Aims are to define, in the minority populations: 1) the role of endothelial dysfunction and vascular inflammation, oxidative stress, and dyslipidemia in the increased incidence of PE in Type 2 diabetic women; 2) the role of angiogenic and anti-angiogenic factors in the increased incidence of PE in Type 2 diabetic women; and 3) cellular mechanisms of altered angiogenic/antiangiogenic balance in the development of PE using endothelial cell cultures. The outcome of this study will have a major influence on future research to discern markers and mechanisms for PE, and on the rational development of treatments to prevent or arrest PE in pregnant diabetic women, particularly those from minority populations.