Abstract Excessive postprandial glycemia has emerged as a key factor regulating energy intakes and driving obesity and cardiometabolic diseases, and recent studies highlight the rising importance and urgent need of mapping the individual variability of postprandial glycemic response in precision nutrition and diet interventions. The proposed systems study aims to fill this significant research gap. Our study will build upon the unparalleled and complementary resources from three diet intervention trials and cohort: The OmniCarb trial, The POUNDS LOST trial, and The Precision Health Study (PHS). We will analyze associations of the usual levels of fasting plasma metabolome and postprandial metabolomic changes with postprandial glycemic response in the meal challenge tests (Aim 1); and analyze the dynamic changes (5 weeks, 6 and 24 months) in postprandial glycemic variability-related metabolites in response to diet interventions varying in glycemic index (GI) and/or carbohydrate intakes (Aim 2). We will also examine the relations of changes in postprandial glycemic variability-related metabolites with changes in appetite, energy intake and expenditure (Aim 3). In addition, we will examine the temporal sequence and mediation effects of postprandial glycemic variability-related metabolites in the relation between diet interventions and cardiometabolic changes (Aim 4). The proposed project aligns well with the special interest of NIH in ‘Nutrigenetics and Nutrigenomics Approaches for Nutrition Research (NOT-DK-19-019)’ and precision nutrition. Our study will provide novel insights into the intrinsic determinants of individual variability in postprandial glycemic response, and contribute significantly to the development of novel precision diet interventions. The findings from our study will have wide public health applicability and clinical implications.

Narrative In three complementary diet intervention trials and free-living cohort, our systems study investigates the dynamic relations of circulating metabolome and postprandial metabolomic changes with postprandial glycemic variability, energy intake and expenditure, as well as cardiometabolic changes in response to diets varying in glycemic index (GI) and/or carbohydrates. Our study will contribute significantly to identification of the intrinsic determinants of individual variability in postprandial glycemic response, and the development of novel precision diet interventions.