PROJECT SUMMARY/ ABSTRACT Severe hypoglycemia remains a common and life-threatening issue for patients living with type 1 diabetes (T1D). Research has consistently shown that patients with impaired awareness of hypoglycemia (IAH), which typically coexists with a diminished counterregulatory response (CRR), are at the highest risk for severe hypoglycemia. However, we currently do not have clinically available tools to identify patients with IAH, and even if identified, we lack interventions to reduce their risk. The ultimate goal of this research is to address these large, unmet needs. Specifically, we plan to utilize continuous glucose monitoring (CGM) to identify which CGM metrics are associated with IAH and a diminished CRR (AIM 1). We will then determine if modern T1D management with hybrid closed loop (HCL) systems can restore hypoglycemia awareness (AIM 2). AIM 1: Identify the CGM metrics associated with hypoglycemia awareness Our first hypothesis is that time below range (TBR) by CGM will inversely correlate with epinephrine AUC during a hypoglycemic clamp. This hypothesis is strongly supported by our preliminary data detailed in our research strategy. To test this hypothesis, we propose that the consortium enroll a total of 112 subjects with T1D. Subjects will wear a blinded CGM for 10 days prior to a hypoglycemic clamp. Data to be collected will include counterregulatory hormones during hypoglycemia, hypoglycemia symptom scores (Edinburgh), and hypoglycemic awareness questionnaires (Clarke, Gold, Pederson, and hypo A-Q) as we have previously done. CGM metrics will be correlated with CRR, symptom scores, and currently used questionnaires to define awareness. The study design will determine which CGM metrics predict hypoglycemia awareness and CRR. AIM 2: Determine if hypoglycemia awareness can be restored in individuals with T1D using up-to-date management of diabetes Our second hypothesis is that reducing TBR using modern diabetes management with HCL systems will improve awareness of hypoglycemia and the CRR. To test this hypothesis, all 112 subjects will be randomized 1:1 to either a control arm or a hypoglycemia reduction arm for 2 years. In the control arm, all insulin delivery methods will be allowed and CGM targets will follow current standards of care that allow up to 4% TBR (~1 hour/day). The hypoglycemia avoidance arm will provide all patients with a HCL system and target <1% TBR. Hypoglycemic clamps will be conducted at baseline and months 3, 6, 12, 18, and 24 with 10 days of blinded CGM prior to each clamp. The primary outcome will be the difference in epinephrine AUC during hypoglycemic clamp between study arms. This study design will determine if up-to-date T1D management can restore the CRR and hypoglycemia awareness.