Level and timing of diabetic hyperglycemia in utero: the transgenerational effect on adult morbidity (TEAM Study)

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Project Summary / Abstract Exposure to maternal diabetes mellitus, regardless of type, in utero increases the risk of obesity, insulin resistance, diabetes, renal compromise and cardiovascular disease in offspring. However, the level and timing of hyperglycemic exposure during fetal development, triggering these remote, transgenerational morbid outcomes, remain unknown. The identification of offspring at risk, and of the optimal times to initiate potential preventive measures are each critical for improving the health outcomes of these vulnerable fetuses. Over the past half century, type 1 diabetes control during pregnancy has improved exponentially, resulting in decreased incidence of congenital malformations (most commonly cardiac) and of perinatal mortality from 17% and16%, respectively, to rates which now approach those in non-diabetic pregnancy. However, other offspring outcomes, including obesity, metabolic, and preclinical cardiovascular disease have failed to decline. It is critical to rapidly and directly determine specific contributions of the intrauterine environment to these more subtle pathophysiologies and preclinical diseases affecting adult offspring of women with type 1 diabetes during pregnancy. This proposal, capitalizing on a unique dataset and our ability to re-study an established cohort, will address this key gap, directly inform clinical management, and alert the pregnant woman herself, regarding the lifetime consequences for her offspring due to hyperglycemic excursions during gestation. The central hypothesis for this proposal is that adults exposed in utero to hyperglycemia, will have increased risk of obesity, insulin resistance, diabetes, and renal and cardiovascular compromise. To test this hypothesis we will complete the following specific aims. Specific Aim 1: To demonstrate the transgenerational effect of the hyperglycemic intrauterine environment on metabolic health of adult offspring of women with type 1 diabetes. We will identify sensitive gestational periods of hyperglycemia predictive of specific metabolic morbidities in the adult offspring. Specific Aim 2: To demonstrate the transgenerational effect of the hyperglycemic intrauterine environment on cardiac and peripheral vascular structure and function in adult offspring of women with type 1 diabetes. We will determine if cardiovascular compromise in the adult offspring may be predicted by an identified maternal glycemic profile, characterizing both level of glucose control and variability. This transgenerational cohort study will apply innovative statistical approaches to relate timing, level and variability of maternal glycemia to morbidity in adult offspring of women with type 1 diabetes. The remarkable granularity of data collected prospectively during the index pregnancies, combined with new data from the adult offspring and our novel statistical methods, will enable us to identify components of the intrauterine glycemic environment that contribute to specific morbidities and disease risk in the adult offspring.