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.

项目摘要/摘要 该建议旨在表征GLP-1模拟肥胖治疗对机制的影响 1型糖尿病年轻人（T1D）复杂的年轻人的可修改心脏代谢危险因素因肥胖而复杂 通过评估脂肪，葡萄糖和脂质生理。 肥胖和超重影响40％的青少年和T1D的年轻人，其中T1D 仅凭就已经大大增加了未来的心血管疾病风险。我们的初步数据表明 无论BMI类别如何，大多数T1D的青少年都有内脏至皮下脂肪组织比率 与肥胖症和糖尿病前期的青年一样高。 T1D青年的这种内脏脂肪比与 肝胰岛素抵抗程度。 该研究将全面评估T1D和 肥胖症同时检查GLP-1模拟肥胖治疗对内脏脂肪组织的影响（该比率 内脏至内脏+皮下脂肪组织），胰岛素抵抗和餐后脂肪血症。实现 这些目的，我们将利用1）腹部MRI来量化腹部脂肪分布，2） 优质血糖高胰岛素夹和稳定的同位素示踪剂，以评估胰岛素抵抗和 糖异生，3）DEXA扫描以测量身体成分，4）高脂混合餐测试 量化动脉粥样硬化脂蛋白的餐后变化。完成这些评估后，54岁 符合抗肥胖药物标准的T1D和肥胖的成年人将随机分为1- 口服半卢皮德或安慰剂的治疗年份。代谢评估将在1年的1年重复 治疗。由15名具有T1D和瘦体重指数的年轻人组成的比较者组将经历 一个时间点的代谢研究。 执行拟议的研究计划对于促进对策略的理解至关重要 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 T1D和肥胖症的年轻患者。这与NIDDK改善健康的使命是一致的 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和 肥胖症患有T1D的年轻人的潜在治疗。