PROJECT SUMMARY/ABSTRACT Dr. Egan is a physician trained in clinical endocrinology and will undertake a four-year mentored research and career development program in the pathophysiology of gestational diabetes mellitus (GDM) at Mayo Clinic. She will complete a master’s degree in Clinical and Translational Science, gain experience in the conduct of in vivo studies in an obstetric population, acquire new skills in analysis and modeling of human physiological data, and develop scientific leadership skills and collaborative relationships. These activities will fill current gaps in knowledge and allow Dr. Egan to become an independent clinical investigator. Dr. Egan will be guided by a team of prominent researchers with relevant areas of expertise and an excellent track record in mentoring young faculty. This team will be led by her primary mentor, Dr Adrian Vella, whose research focuses on the pathogenesis of type 2 diabetes mellitus (T2DM). GDM is a common pregnancy complication and while the associated hyperglycemia resolves postpartum, it is a strong risk factor for T2DM. There is little understanding of maternal β-cell function in early pregnancy, how this may predict GDM in later pregnancy, and what changes occur postpartum. Dr. Egan’s preliminary data suggest that α-cell function also changes during pregnancy, but its role in GDM development and postpartum glucose tolerance is unknown. In the proposed in vivo studies, Dr. Egan will determine the degree of β-cell (Aim 1) and α-cell (Aim 2) dysfunction needed to produce GDM and examine the islet cell recovery (or lack thereof) that occurs postpartum. Dr. Egan will assess if GDM can be predicted earlier in pregnancy which would facilitate more timely intervention. She will also identify the residual defects in glucose metabolism that persist at one year postpartum. Such defects could contribute to the accelerated progression to T2DM observed in women with GDM (Aim 3). To accomplish these aims, Dr. Egan will study women during pregnancy and post-partum using state-of-the-art, non-invasive techniques to collect and examine detailed physiologic data. In keeping with the NIDDK mission, the proposed studies will address important aspects of diabetes development in women and provide the foundation for a future R01 application with the goal of developing novel diabetes prevention and treatment approaches.