PROJECT ABSTRACT Gestational diabetes (GDM) is a significant clinical and public health burden, affecting over 400,000 pregnant women in the United States each year. Without adequate treatment, women with GDM and their infants are at risk for substantial morbidity. Because of this, experts recommend treatment focused on normalization of hyperglycemia to improve outcomes. However, providers have limited capacity to predict which treatment will achieve glycemic goals. This results in a choice based on provider and patient preference and a trial and error approach, which can create delays in glycemic control within the short (8-10 weeks) window between diagnosis and delivery. Maternal and fetal morbidity may be related to a mismatch between glycemic pathophysiology and the mechanism of action of glucose lowering agents. In fact, GDM is heterogeneous, with predominant insulin resistance in 50%, insulin secretion deficiency in 30%, and a combination of both in 20% of women as underlying mechanisms of hyperglycemia. This variation in GDM pathophysiology and clinical outcomes supports the use of an individualized treatment approach. The overall goal of this project is to investigate an individualized treatment approach for GDM where treatment is based on each woman’s GDM mechanism. Specifically, we plan to study this through the following aims: Aim 1: we will evaluate the feasibility of conducting a pilot randomized controlled trial comparing individualized treatment and usual care in 60 women with GDM. Aim 2: we will explore the effect of treatment on GDM mechanisms and the role of potential covariates. Aim 3: we will assess participant and provider acceptability of an RCT comparing individualized GDM treatment and usual care. Completion of these aims in this K23 award application will advance our knowledge of the underlying mechanisms of GDM and provide the foundation for a larger-scale clinical trial assessing individualized GDM treatment. The research plan will be augmented by intensive mentoring by experts in the field and didactic research training at the University of Pittsburgh. Together, the research project, mentoring and coursework described herein will provide the primary investigator with essential career development in the areas of: 1) design and implementation of interventional trials in pregnant women, 2) pharmacodynamic modeling to assess the effect of treatment on GDM mechanisms and 3) leadership, management, and research team building. Ultimately, this work will set the stage for research evaluating individualized GDM treatment strategies in a comprehensive R01-funded study, and uniquely position the primary investigator as a future leader focused on transforming diabetes care during pregnancy with individualized treatment models.