PROJECT SUMMARY/ABSTRACT The first-line treatment of gestational diabetes (GDM), a disease rising in prevalence, is dietary therapy, yet the optimal diet for these patients is unknown. Guidelines have focused on carbohydrate restriction in GDM, with some evidence suggesting improved maternal and fetal outcomes, yet there is concern that low carbohydrate diets may have adverse fetal consequences. Research evaluating different nutritional macronutrients, specifically protein and fat, in pregnancy and GDM is lacking. The objectives of the proposed research projects are to understand the impact of dietary fat and protein on insulin physiology and glycemia in pregnancy and in GDM with the goal of discovering the optimal diet for women affected by GDM. The applicant will utilize data from a prospective longitudinal observational study of glucose metabolism in pregnancy to investigate the effects of dietary protein and fat exposure on insulin physiology in pregnant women. The applicant will also evaluate the acute effects of protein and fat on glycemia in women with GDM in an interventional cross-over randomized trial of two isocaloric breakfast meals with identical carbohydrate content and varying protein and fat content (high protein/low fat, low protein/high fat). The aims of this project are: 1. Define the relationship of dietary fat and protein with insulin physiology in pregnant women. The first hypothesis is that diets high in fat will lead to reduced insulin sensitivity as compared to diets low in fat; the second hypothesis is that diets high in protein will lead to increased insulin secretion (adjusted for insulin sensitivity) as compared to diets low in protein. 2. Prospectively test the acute effect of fat and protein on post-prandial glycemic response in women with GDM. The hypothesis is that the high protein/low fat meal will lead to lower peak post prandial glucose levels than the high fat/low protein meal. The results of these studies will determine the impact of protein and fat on insulin physiology and glycemia in pregnant women and in GDM and thus have the potential to inform clinical dietary recommendations in GDM. The training plan includes dedicated mentorship by Dr. Ellen Seely MD (sponsor) and Dr. Camille Powe MD (co-sponsor), each offering expertise tailored to the applicant’s needs and goals. Additionally, the applicant will complete formal training in biostatistics, nutrition and clinical research through the Harvard Catalyst Clinical/Translational Science Center, the Harvard T.H. Chan School of Public Health, the Massachusetts General Hospital Division of Clinical Research, and the National Institutes of Health Office of Behavioral and Social Sciences Research. These activities will provide the applicant with the tools critical for a career as an independent clinical researcher in the field of nutritional and lifestyle approaches to GDM.