Project Abstract/Summary Development of type 2 diabetes (T2D) prior to the age of 20 years has been associated with rapid disease progression and early exogenous insulin dependence.1 Furthermore, adolescents with T2D are more likely to develop diabetes-related comorbidities, such as hypertension, atherosclerosis, and kidney disease earlier compared to adults, highlighting the need for a fundamentally different (and perhaps more aggressive) treatment approach in adolescents.1 Obesity (body mass index [BMI] >95th percentile for age and sex) is a primary risk factor for the development and progression of T2D.2,3 However, current treatment guidelines for T2D in adolescents recommend lifestyle management and metformin (+ insulin) as first-line therapy, which rarely result in BMI reduction or slowing of T2D disease progression.1,4-7 Therefore, novel treatments that meaningfully reduce BMI, delay exogenous insulin dependence, and potentially slow the progression of T2D need to be investigated in adolescents with T2D. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) may represent an ideal first- line therapy for adolescent T2D. GLP-1 RAs increase postprandial insulin secretion and reduce glucagon production, and at higher doses, can result in clinically meaningful BMI reduction by suppressing appetite and enhancing satiety.8 Liraglutide (a daily injectable GLP-1 RA) at its 1.8 mg/day dose was approved for adolescents with T2D in 2019, but liraglutide has not been studied with a primary focus on BMI reduction and insulin sensitivity or ß-cell function in adolescents with T2D.9,10 Therefore, the overall objectives of this study will be to 1) evaluate the effects of liraglutide at its obesity medicine dose (3.0 mg/day) versus standard-of-care on BMI reduction, and 2) evaluate its effect on insulin sensitivity and β-cell function in adolescents with T2D and obesity. The overall hypothesis is that liraglutide 3.0 mg/day will result in a greater mean BMI percent change as well as improvements in insulin sensitivity and β-cell function as compared to placebo plus standard-of-care. The focus on using liraglutide at its obesity medicine dose in adolescents with T2D is novel and important; prior studies evaluating liraglutide have not been generalizable to adolescents with this aggressive disease nor have prior studies had the majority of patients on the maximum liraglutide dose, making dose-dependent weight-loss evaluations difficult. The proposed study will generate preliminary data to inform the design of a larger and sufficiently-powered R01 trial. Importantly, this mentored project will provide essential training in clinical trial design and implementation in a unique and challenging patient population, as well as measures of insulin sensitivity/β-cell function. These skills will facilitate my scholarly independence and serve as the foundation of my future career focusing on the application of obesity medicine principles in the treatment of adolescents wi...