Obesity complicating type 1 diabetes in young people: Physiology and Impact of GLP-1 analogue anti-obesity treatment on cardiometabolic risk factors

年轻人肥胖并发 1 型糖尿病：GLP-1 类似物抗肥胖治疗的生理学和对心脏代谢危险因素的影响

• 批准号: 10736906
• 负责人: Michelle Van Name
• 金额: $ 72.4万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10736906
• 关键词: Abdomen; Acetyl Coenzyme A; Adipose tissue; Adolescent; Adolescent and Young Adult; Affect; Agonist; Apolipoproteins C; Automobile Driving; Biological Markers; Body Composition; Body Weight; Body Weight decreased; Body fat; Body mass index; Body measure procedure; Cardiometabolic Disease; Cardiovascular Diseases; Cardiovascular system; Categories; Circulation; Clinic; Clinical; Clinical Trials; Closure by clamp; Complications of Diabetes Mellitus; Continuous Glucose Monitor; Control Groups; Data; Diabetes Mellitus; Drug or chemical Tissue Distribution; Dual-Energy X-Ray Absorptiometry; Dyslipidemias; Enrollment; Event; Fatty Liver; Fatty acid glycerol esters; Future; Gluconeogenesis; Glucose; Glucose Clamp; Glycerol; Glycosylated hemoglobin A; Health; Hepatic; Hyperinsulinism; Individual; Insulin; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Isotopes; Lipids; Lipolysis; Lipoproteins; Magnetic Resonance Imaging; Measures; Mediator; Metabolic; Metabolic syndrome; Methods; Mission; National Institute of Diabetes and Digestive and Kidney Diseases; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oral; Outcome; Overweight; Participant; Patients; Persons; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Physiology; Placebos; Population; Prediabetes syndrome; Predisposition; Prevalence; Production; Quality of life; Randomized; Research; Risk; Risk Factors; Scanning; Surrogate Markers; Testing; Tracer; Triglycerides; Visceral; Visceral fat; Weaning; Youth; adult obesity; aged; analog; beta-Hydroxybutyrate; cardiometabolic risk; cardiometabolism; cardiovascular disorder risk; comparison group; disorder risk; euglycemia; experience; glucagon-like peptide; glucagon-like peptide 1; glucose production; hepatic gluconeogenesis; impaired glucose tolerance; improved; inclusion criteria; insulin secretion; lean body mass; meetings; metabolic abnormality assessment; obesity in children; obesity treatment; programs; stable isotope; subcutaneous; young adult

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.

项目总结/摘要 该提案旨在表征GLP-1类似物肥胖治疗对肥胖症发生机制的影响。 合并肥胖的1型糖尿病（T1 D）青年患者中可改变的心脏代谢危险因素 通过评估脂肪、葡萄糖和脂质生理学。 肥胖和超重影响了40%的T1 D青少年和年轻人，T1 D患者中 单是这一项就已经大大增加了未来患心血管疾病的风险。我们的初步数据显示， 无论BMI类别如何，大多数T1 D青少年的内脏与皮下脂肪组织的比例 与肥胖和糖尿病前期的年轻人一样高。T1 D青年的内脏脂肪比例与 肝脏胰岛素抵抗程度。 这项研究将全面评估T1 D年轻人心脏代谢风险因素的驱动因素， 同时检查GLP-1类似物肥胖治疗对内脏脂肪组织的影响（与对照组相比， 内脏到内脏+皮下脂肪组织）、胰岛素抵抗和餐后脂血。实现 这些目标，我们将利用1）腹部MRI来量化腹部脂肪分布，2）阶梯式 具有稳定同位素示踪剂的正葡萄糖高胰岛素钳夹以评估胰岛素抵抗， 胚胎发育，3）DEXA扫描测量身体成分，以及4）高脂肪混合餐耐受性测试 定量餐后致动脉粥样硬化脂蛋白的变化。在完成这些评估后，54名青年 符合抗肥胖药物治疗标准的T1 D和肥胖成人将被随机分配至1- 口服semaglutide或安慰剂治疗年。将在1年时重复进行代谢评估 用药一个由15名患有T1 D和瘦体重指数的年轻人组成的对照组将接受 在一个时间点进行代谢研究。 实施拟议的研究计划对于促进对战略的理解至关重要， 降低心脏代谢风险并影响促进心脏代谢风险的病理生理机制， 患有T1 D和肥胖症的年轻患者。这与NIDDK的使命是一致的， 糖尿病患者的生活质量。结果将揭示心脏代谢疾病风险的复杂性， T1 D合并肥胖的年轻人的潜在治疗。