Background Information

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 I diabetes control during pregnancy has improved exponentially, resulting in decreased incidence of congenital malformations (most commonly cardiac) and of perinatal mortality from 17% and 16%, respectively, to rates which now approach those in the 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 pre-gestational 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.

Goals

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 pre-gestational 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 pre-gestational 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.

Findings

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 pre-gestational 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.

The study is slated to be completed in August of 2023. At that time, findings will be reported.

Research Collaboration Opportunities

We encourage researchers to contact our study team regarding questions or comments pertaining to our research. We are willing to share methodologies regarding the challenging recruitment strategies involved in contacting a cohort left dormant for nearly 40 years. We plan to share our results through publication, and are willing to discuss potential future hypothesis testing not covered in our study aims.