PROJECT SUMMARY/ABSTRACT This administrative supplement is for a pilot and feasibility study with Alyssa Huang as the Principal Investigator. One in five adolescents and young adults with type 1 diabetes (AYAD) exhibit disordered eating behaviors (DEB)—nearly twice the rate among healthy peers. Several studies show that AYAD with DEB have worse glycemic control, higher rates of obesity, and higher risk of acute and long-term diabetes related complications including diabetic ketoacidosis, microvascular complications, and mortality. The mechanisms that drive DEB are not well understood, limiting effective clinical treatment. The mediobasal hypothalamus in the central nervous system is a key area of feeding regulation. Hypothalamic gliosis is associated with impaired satiety, hyperphagia, and glucose dysregulation in rodents and humans. It is unknown whether AYAD have hypothalamic gliosis related to DEB, insulin resistance, and/or obesity, or if hyperglycemia independently drives the development of hypothalamic gliosis, promoting changes in eating behavior and weight gain. We propose to apply complementary strategies to systematically uncover these complex interrelationships. To assess our hypothesis that DEB is a risk factor for poor glycemic control, adiposity, and/or insulin resistance (all of which have been associated with hypothalamic gliosis in non-AYAD populations), we will use a large, prospective longitudinal cohort (SEARCH for Diabetes in Youth) to test whether baseline DEB predicts these outcomes at 5-year follow-up. Additionally, we propose a cross-sectional study to validate that findings from the SEARCH cohort are applicable to our local AYAD clinic population. Our preliminary data suggest that AYAD with DEB have evidence of hypothalamic gliosis, but the relative contributions of hyperglycemia, eating behavior, and adiposity are unclear. We hypothesize AYAD with high DEPS-R scores and poor glycemic control have higher degree of hypothalamic gliosis, independent of adiposity. To assess independent effects of glycemic control and DEB on hypothalamic gliosis, we will use non-invasive structural MRI on non-obese AYAD females with or without DEB, and with good or poor glycemic control. Understanding the relative associations of glycemic control, adiposity, and DEB with clinical health outcomes and with hypothalamic gliosis is important in designing effective interventions in AYAD. Data from this proposal, together with our prior DEB findings, will provide scientific rationale for future cross-sectional and intervention studies (e.g., GLP-1 agonists or cognitive behavioral treatment) to define the role of hypothalamic gliosis in DEB. My future research will focus on whether interventions that reduce hyperglycemia and/or hypothalamic gliosis can address DEB and improve diabetes-related outcomes in this vulnerable population.