PROJECT SUMMARY As many as 42% of American Samoan women develop gestational diabetes (GDM) in pregnancy, which substantially elevates their risk of progressing to Type 2 diabetes (T2DM). Genetic factors play a substantial role in diabetes risk, underscoring the importance of utilizing genomic data for targeted screening, treatment, and prevention. However, historical exclusion of PI populations from genetic research has hindered advancements in inclusive precision health initiatives, particularly related to women's health. In >10 years of research with Samoan communities our team identified a novel missense variant (rs373863828) in the CREBRF gene that is common among Pacific Islanders, including American Samoans. The CREBRF variant is associated with increased body mass, but is paradoxically protective against T2DM, making it an attractive potential biomarker of diabetes risk. The impact of the CREBRF variant on GDM risk, progression to postpartum T2DM, and the variant's mechanism of action remain unclear. However, preliminary data suggest that CREBRF may protect against GDM and that the mechanism of protection may be improved insulin secretion. To test these hypotheses, we will recruit a prospective cohort of 350 pregnant American Samoan women enrolled in the first trimester and followed until 18 months postpartum. Through three pregnancy (10-14 weeks (w), 24-28w, and 32-26w) and four postpartum (6-12w, 6 months (m) 12 m, 18m) visits we will comprehensively evaluate glucose homeostasis (frequently sampled oral glucose tolerance tests, HbA1c, and continuous glucose monitoring) and insulin response. We will use cutting-edge statistical approaches to examine how changes in glucose homeostasis and insulin secretion/action associated with CREBRF, which are not currently captured by routine 24-28w oral glucose tolerance tests, influence GDM and postpartum T2DM risk. Specifically, we will examine associations of CREBRF with glucose homeostasis during pregnancy (Aim 1) and postpartum changes in glucose homeostasis and incident pre-DM/T2DM risk (Aim 2), whether improved insulin secretion mediates the protective effect of CREBRF on diabetes risk (Aim 3), and explore the connections between CREBRF, insulin secretion, and birth outcomes (Exploratory Aim 4). Our work has strong potential to shift clinical practice and reduce diabetes disparities by proving insight into the potential for CREBRF to serve as a genetic biomarker of GDM or T2DM risk. More broadly, uncovering important insight into how the CREBRF variant regulates glucose homeostasis will inform future molecular studies to further understand CREBRF's mechanism(s) of action, potentially leading to pharmacogenomic approaches and future diabetes therapeutic targets for all populations. With expertise in epidemiology, diabetes, obstetrics, endocrinology, and biostatistics, our team is ideally positioned to carry out this ground-breaking work to reduce diabetes-related health disparities for American Samoan women.

PROJECT NARRATIVE Up to 42% of women in American Samoa, a medically underserved US territory, develop gestational diabetes (GDM) in pregnancy, making them one of the highest risk groups for GDM and progression to postpartum type 2 diabetes mellitus (T2DM) in the United States. The goal of the proposed project is to investigate how a genetic variant in CREBRF that is common in Pacific Islanders, including American Samoans, influences glucose homeostasis, insulin response, GDM risk and risk of T2DM postpartum. As well as reducing diabetes- related disparities among Pacific Islanders, this work is expected to have a broad and far-reaching impact on the fundamental understanding of diabetes pathogenesis and the potential development of future diabetes therapies for all populations.