Anti-obesity pharmacotherapy to decrease BMI and improve insulin sensitivity in adolescents with obesity and type 2 diabetes

项目摘要/摘要 在20岁之前发生2型糖尿病（T2 D）与快速疾病相关 1此外，T2 D青少年更有可能 更早出现糖尿病相关的合并症，如高血压、动脉粥样硬化和肾脏疾病 与成年人相比，强调需要一种根本不同的（也许更积极的）治疗方法 肥胖（体重指数[BMI] >年龄和性别的第95百分位）是主要风险 T2 D的发展和进展的因素。2，3然而，目前的T2 D治疗指南， 青少年推荐生活方式管理和二甲双胍（+胰岛素）作为一线治疗， 1，4 -7因此，有意义地降低BMI或减缓T2 D疾病进展的新治疗方法 需要研究BMI、延迟外源性胰岛素依赖和潜在减缓T2 D进展的可能性 在T2 D青少年中胰高血糖素样肽-1受体激动剂（GLP-1 RA）可能是理想的首选药物， 青少年T2 D的线治疗。GLP-1 RA增加餐后胰岛素分泌并降低胰高血糖素 在较高剂量下，可通过抑制食欲， 8利拉鲁肽（一种每日注射的GLP-1 RA）以1.8 mg/天的剂量获批用于青少年 在2019年的T2 D患者中，尚未对利拉鲁肽进行研究，主要关注BMI降低和胰岛素敏感性 因此，本研究的总体目标是：1）评价 利拉鲁肽以其肥胖药物剂量（3.0 mg/天）与标准治疗相比对BMI降低的影响，以及 2)评估其对患有T2 D和肥胖的青少年的胰岛素敏感性和β细胞功能的影响。整体 假设利拉鲁肽3.0 mg/天将导致更大的平均BMI百分比变化，以及 与安慰剂加标准治疗相比，胰岛素敏感性和β细胞功能改善。重点 在T2 D青少年中使用肥胖药物剂量的利拉鲁肽是新颖且重要的;之前的研究 评价利拉鲁肽尚未推广至患有这种侵袭性疾病的青少年， 研究中大多数患者接受最大利拉鲁肽剂量，使体重减轻呈剂量依赖性 评价困难。拟议的研究将产生初步数据，为设计一个更大的 强大的R 01试验。重要的是，这个指导项目将提供临床试验的基本培训 在独特且具有挑战性的患者人群中设计和实施，以及胰岛素的测量 敏感性/β细胞功能。这些技能将促进我的学术独立性，并作为基础， 我未来的职业生涯专注于肥胖医学原则在青少年治疗中的应用， 2型糖尿病

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 with T2D.