PROJECT SUMMARY / ABSTRACT This application “Restoring awareness of hypoglycemia in type 1 diabetes” proposes to elucidate the heterogeneity of impaired awareness of hypoglycemia (IAH) in type 1 diabetes through completion of a 24-month Sequential Multiple Assignment Randomized Trial (SMART) designed to better inform our understanding of the clinical and physiologic factors which contribute to restoration of counterregulatory defenses against hypoglycemia in response to educational, technologic, and pharmacologic interventions. Given the persistent barrier of hypoglycemia to the realization of achieving adequate glycemic control for most individuals with type 1 diabetes, there is a critical need to further understand the mechanisms contributing to hypoglycemia in type 1 diabetes in order to advance treatment approaches that may realize the benefits of near-normal glycemic control without the accompanying risk for severe hypoglycemia. The present proposal aims 1) to determine whether counterregulatory responses to a hyperinsulinemic hypoglycemic clamp can be restored in individuals with long standing type 1 diabetes and IAH using an adaptive randomized clinical trial design implementing state-of-the- art interventions including hypoglycemia avoidance education (standard-of-care; SOC), automated insulin delivery with hybrid closed loop technology (HCL), and novel mini-dose glucagon (MDG) pharmacology; 2) to determine the physiological factors associated with improved counterregulatory responses following intervention, including but not limited to age, diabetes duration, and continuous glucose monitoring (CGM) metrics; and 3) to validate a HypoA-Q short form questionnaire as a self-report measure for identifying IAH with measurement of counterregulatory responses derived from the hypoglycemic clamp. The proposed SMART study design will allow for rigorously determining both the degree of hypoglycemia avoidance necessary for improvement of counterregulatory epinephrine and autonomic symptom responses to insulin-induced hypoglycemia, as well as the additional factors such as age, diabetes duration, other CGM metrics, and validated IAH self-report that may predict individual responsiveness to SOC, HCL, and MDG interventions.