PROJECT SUMMARY Type 2 diabetes (T2D) has reached epidemic proportions affecting more than 30.3 million Americans. Hispanics are 64% more likely to have T2D than non-Hispanic whites. Among Hispanic sub-groups, Puerto Ricans have a high prevalence of cardiometabolic risk factors including less healthful diets and have the nation's highest rates of severe periodontal disease. They are twice as likely as Mexican Americans to be hospitalized for diabetes related conditions and have established health disparities. Despite the high prevalence of cardiometabolic risk, an understanding of the metabolic signatures and pathways that underlie the progression of diabetes remains limited in Puerto Ricans. While most studies have used plasma as a biofluid to measure metabolites, saliva is a non-invasive easily accessible alternative to plasma to measure metabolites related to diabetes risk. Saliva may also present with distinct metabolic pathways for disease progression. In the proposed project, we plan to examine both plasma and saliva metabolomic profiles of diabetes progression. The study will be conducted among participants from the San Juan Overweight Adults Longitudinal Study (SOALS). Participants are overweight/obese, Hispanic, 40-65 years of age, and have a large burden of risk factors that contribute to diabetes progression. Extensive data and specimens were collected at baseline and three-year follow-up. Our primary aims are: 1) To identify baseline saliva and plasma metabolomic profiles and networks associated with diabetes progression in over 900 participants, using supervised and unsupervised network analyses. 2) To determine the association between saliva and plasma metabolomic profiles identified in aim 1 and three-year changes in cardiometabolic risk factors, including markers of dyslipidemia, endothelial dysfunction, adiponectin, and systemic and local (periodontitis) inflammation. In secondary analyses, we will examine whether periodontitis modifies the association between saliva metabolites and diabetes progression. We will also evaluate inter-relationships between known metabolites present in plasma and saliva. In addition, we will evaluate cross-sectional associations between metabolites and baseline diet and lifestyle factors. This research will identify objective saliva and plasma biomarkers of T2D progression in a high-risk overweight minority population. This study is likely to have important public health implications because the novel plasma and saliva metabolites identified from this study may be amenable to interventions, thus helping to reduce diabetes progression and lower health disparities. The proposed project is built on the numerous strengths of an existing cohort in a high-risk population, and supporting results from the preliminary work conducted by our multi-disciplinary team. This project has the potential to advance our understanding of diabetes pathophysiology in an understudied minority population and the knowledge produced can directly inform future interventions to ameliorate diabetes risk.