For decades, type 1 diabetes (T1D) has been considered a disorder resulting from chronic autoimmune destruction of insulin-producing pancreatic β-cells. While a broad number of intellectual advances have improved our understanding of the natural history of T1D, significant gaps remain in the complex series of physiological events, both immunologic and metabolic, that initiate β-cell autoimmunity, spur the loss of functional β-cell mass, and culminate in clinical diabetes. People with a first-degree relative (FDR) with T1D have ~15-fold increased lifetime risk of T1D. Importantly, natural history studies have informed the use of islet-associated autoantibodies (AAb) as biomarkers to track progression to overt disease, and these biomarkers were transformative for the field. Nevertheless, there remains significant heterogeneity in T1D progression, and additional biomarkers of T1D risk are urgently needed. Studies by this group demonstrated that pancreas weights from organ donors with T1D were significantly reduced, including at diabetes onset, and provided essential data using the ratio of pancreas weight to body weight or BMI (relative pancreas volume, RPV) to normalize for subjects’ sex and age. Yet more profound in terms of T1D pathogenesis, reductions in pancreas size were also observed in single AAb+ donors compared to autoantibody-negative (AAb-) control donors. Subsequently, a pilot cross-sectional DP3 trial in NIH-NIDDK TrialNet (TN) subjects was completed using magnetic resonance imaging (MRI) to quantify RPV in FDR in comparison to controls and patients with recent-onset T1D (< 1-year duration). Strikingly, a reduction in RPV was observed in FDR without AAb (AAb-) with further reductions in RPV for FDR with single and multiple AAb+. We hypothesize that a smaller pancreas size is predictive of T1D risk and a decline in pancreas size over time is predictive for diabetes progression. This hypothesis will be tested at four TrialNet centers in FDR subjects. To test our hypothesis, we will: Aim 1: Quantify pancreas volume (PV) and morphology in FDR subjects by AAb status and test for longitudinal changes in PV. Aim 2: Correlate PV and morphology with surrogate markers of β-cell function and mass. Aim 3: Correlate PV and morphology with surrogate markers of acinar function. Aim 4: Perform SNP analyses for genetic determinants of pancreas size. The successful completion of these studies will serve to expand the prognostic utility of pancreas MRI in understanding T1D pathophysiology. Non-contrast pancreas MRI is safe and readily performed in children and could add to biomarkers informing T1D risk predication, and potentially, progression. Endocrine-exocrine interactions are novel and are expected to provide a new understanding of diabetes pathogenesis. Earlier identification of subjects at highest risk for T1D progression is expected to significantly impact prevention strategies and their successful application before the loss of functional β-cell ...