PROJECT SUMMARY/ABSTRACT This proposal aims to characterize the impact of GLP-1 analogue obesity treatment on mechanisms of modifiable cardiometabolic risk factors in young people with type 1 diabetes (T1D) complicated by obesity through assessment of adipose, glucose, and lipid physiology. Obesity and overweight impact 40% of adolescents and young adults with T1D, a population in whom T1D alone already drastically increases future cardiovascular disease risk. Our preliminary data indicate that regardless of BMI category, most adolescents with T1D have a visceral to subcutaneous adipose tissue ratio as high as youth with obesity and prediabetes. This visceral fat ratio in youth with T1D is proportional to the degree of hepatic insulin resistance. The study will comprehensively assess drivers of cardiometabolic risk factors in young people with T1D and obesity while examining the impact of GLP-1 analogue obesity treatment on visceral adipose tissue (the ratio of visceral to visceral+subcutaneous adipose tissue), insulin resistance, and postprandial lipemia. To achieve these aims, we will utilize 1) an abdominal MRI to quantify abdominal adipose distribution, 2) the stepped euglycemic hyperinsulinemic clamp with stable isotope tracers to assess insulin resistance and gluconeogenesis, 3) a DEXA scan to measure body composition, and 4) a high-fat mixed meal tolerance test to quantify postprandial changes in atherogenic lipoproteins. After completing these assessments, 54 young adults with T1D and obesity who meet the criteria for anti-obesity pharmacotherapy will be randomized to 1- year of treatment with oral semaglutide or placebo. The metabolic assessments will be repeated at 1-year of the treatment. A comparator group of 15 young adults with T1D and lean body mass index will undergo the metabolic studies at one-time point. Carrying out the proposed research program is critical to advance the understanding of the strategies to reduce cardiometabolic risk and impact the pathophysiologic mechanisms promoting cardiometabolic risk in young patients with T1D and obesity. This is consistent with the NIDDK's mission to improve the health and quality of life of individuals with diabetes. Results will reveal the intricacies of cardiometabolic disease risk and potential treatment in young people with T1D complicated by obesity.