PROJECT SUMMARY/ABSTRACT Cardiovascular disease (CVD) is a major cause of death in individuals with type 1 diabetes (T1DM), but the underlying mechanisms are not well understood. Despite efforts to control blood glucose levels, patients with T1DM who meet glycemic targets (i.e., HbA1c ≤ 6.9%) are still at a 3-fold increased risk of CVD death. By contrast, studies of a different type of diabetes called glucokinase maturity onset diabetes of the young (GCK- MODY) have found that these individuals do not have an increased risk of CVD, despite having a similar level of long-term high blood glucose. Our previous research suggested that one important difference in CVD risk is that people with T1DM have insulin resistance and those with GCK-MODY do not. Our data suggested that the presence of iatrogenic hyperinsulinemia in T1DM—not hyperglycemia—was the principal factor contributing to the decreased insulin sensitivity. This iatrogenic hyperinsulinemia occurs because patients with T1DM must deliver insulin into the peripheral circulation rather than more physiologically into the hepatic portal circulation. Because this delivery route bypasses first-pass hepatic clearance, people with T1DM have 2½-fold higher peripheral insulin levels than people who have normal insulin secretion. These studies imply that reducing iatrogenic hyperinsulinemia can improve insulin sensitivity and possibly other aspects of cardiometabolic risk. Insulin adjunctive therapies may facilitate the needed reduction in hyperinsulinemia. We will conduct paired experiments to investigate the effects of modifying iatrogenic hyperinsulinemia on three markers of cardiometabolic risk: nitric oxide bioavailability (Aim 1), insulin sensitivity (Aim 2), and thrombotic potential (Aim 3). We will compare the effect of lowering iatrogenic hyperinsulinemia in T1DM to the effect of raising insulinemia by the same amount in individuals at low risk for cardiometabolic disease: those with GCK- MODY and those without diabetes (control). We will compare the three cardiometabolic risk markers in T1DM patients (n=13), GCK-MODY patients (n=7), and those without diabetes (n=7) under conditions of high insulin levels (Hi-Ins, 20-25 μU/mL as seen in T1DM) and normal insulin levels (Eu-Ins, 5-10 μU/mL, as seen in CGK-MODY and control). To allow T1DM participants to acutely lower peripheral insulinemia to normal levels without consequent hyperglycemia, we will use a sodium-glucose cotransporter-2 inhibitor (SGLT2i) as a research tool. Overall, our goal is to determine how much reducing iatrogenic hyperinsulinemia using insulin adjunctive therapy can improve CVD outcomes, and to understand the underlying mechanisms behind this effect. This small, mechanistic pilot study will provide needed data to inform the development of larger trials of insulin adjunctive insulin therapy in T1DM.