PROJECT SUMMARY Cardiovascular disease (CVD) and diabetic kidney disease (DKD) are the leading causes of morbidity and premature death in youth and adults with type 1 diabetes (T1D). Recent advances in continuous glucose monitoring (CGM) and automated insulin delivery systems have facilitated improved glycemic control, but the residual risk of CVD and DKD remains high. Obesity and insulin resistance (IR) have also accompanied intensive glycemic therapy and may accentuate arterial stiffness and endothelial dysfunction, each of which is known to predict CVD in T1D. Thus, studies are needed to explore the cardio-renal impact of new adjunctive therapies in T1D informed by the transformative cardiovascular outcome trials in type 2 diabetes (T2D). Glucagon-like peptide-1 receptor agonists (GLP-1RAs) mitigate major adverse cardiac events in adults with T2D and support weight loss. Our group has characterized subclinical cardiorenal disease in young persons with T1D, reporting abnormalities in cardiac function, central arterial stiffness, endothelial function, kidney function, and insulin sensitivity. These cardiorenal abnormalities were also worse with increasing BMI. Our group has also documented attenuated subclinical cardiac dysfunction and aortic stiffness with GLP-1RA without increased risk of hypoglycemia or diabetic ketoacidosis, in both adults with T2D and in animal models of diabetes. To date, limited data exist regarding CVD, IR or DKD-related outcomes in young adults with T1D in response to GLP-1RA. Indeed in T1D, studies with GLP-1RA have focused primarily on weight and glucose lowering. Thus, there is a gap in our understanding of the cardiorenal impact of these agents in T1D. To evaluate the effects and underlying mechanisms of GLP-1RA on cardiovascular and kidney function as well as insulin sensitivity in T1D, we propose a 6-month randomized, placebo-controlled, double-blind study in 52 young adults with T1D (ages 18-40 years) using once weekly subcutaneous semaglutide as a mechanistic probe. The primary outcomes will be change in central and peripheral pulse wave velocity (PWV) by aortic MRI and SphygmoCor. Additional outcomes will include subclinical cardiac function by cardiac MRI, endothelial function by flow mediated vasodilatation (FMDBA), insulin sensitivity by hyperinsulinemic euglycemic clamps, intraglomerular hemodynamic function by iohexol and p-aminohippurate clearance, albuminuria by urine albumin-to-creatinine ratio, and glycemic variability by CGM. Innovative translational assessments of nitric oxide (NO) bioavailability, endothelial NO synthase (eNOS) activation, reactive oxygen species (ROS)/oxidative stress from endovascular J-wire biopsies and endothelial glycocalyx from sublingual assessments will provide mechanistic insight.