Effect of adiposity on hepatic and peripheral insulin resistance and hepatic steatosis in pubertal adolescents with type 1 diabetes

肥胖对青春期1型糖尿病青少年肝脏和外周胰岛素抵抗及肝脏脂肪变性的影响

• 批准号: 10432508
• 负责人: Michelle Van Name
• 金额: $ 8.79万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10432508
• 关键词: Abdomen; Address; Adjuvant Analgesic; Adolescence; Adolescent; Adolescent obesity; Adult; Affect; American; Appointment; Biometry; Body Weight decreased; Body mass index; Cardiovascular system; Child; Childhood; Clinical Oncology Supplement (K12); Closure by clamp; Complications of Diabetes Mellitus; Data; Data Analyses; Defect; Deposition; Development; Diabetes Mellitus; Dose; Environment; Evaluation; Excretory function; Fatty Liver; Fatty acid glycerol esters; Future; Glucose; Glucose Clamp; Glucose Clamp Technique; Glycerol; Glycosylated hemoglobin A; Goals; Grant; Health; Hepatic; High Prevalence; Impairment; Indirect Calorimetry; Infusion procedures; Insulin; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Intervention; Intra-abdominal; Isotopes; Kidney; Knowledge; Lipolysis; Liver diseases; Magnetic Resonance Imaging; Measures; Memory; Mentorship; Metabolic; Metabolic Control; Metabolism; Mission; National Institute of Diabetes and Digestive and Kidney Diseases; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Obesity Epidemic; Outcome; Overweight; Patients; Peripheral; Phenotype; Physicians; Physiological; Population; Populations at Risk; Preparation; Protons; Puberty; Quality of life; Research; Research Design; Resistance; Resources; Risk Factors; Role; Science; Scientist; Site; Sodium; Teenagers; Testing; Therapeutic Intervention; Thinness; Time; Tissues; Tracer; Weight; Weight Gain; Work; Writing; Youth; abdominal fat; adult obesity; base; blood pressure reduction; cardioprotection; cardiovascular disorder risk; cardiovascular health; density; diabetes control; diabetes management; excessive weight gain; experience; glucose metabolism; glucose production; glucose uptake; glycemic control; improved; improved outcome; inhibitor/antagonist; insight; insulin sensitivity; lipid metabolism; medical schools; novel strategies; oxidation; programs; research study; response; skills; stable isotope; urinary; young adult

PROJECT SUMMARY/ABSTRACT The purpose of this research study is to elucidate how the insulin resistance of obesity affects glucose and fat metabolism and hepatic fat deposition in pubertal adolescents with type 1 diabetes (T1D). With improved glycemic control and increased rates of obesity nationally, obesity is now prevalent in youth with T1D. Understanding how obesity affects metabolism in T1D has implications for treatment decisions. This knowledge will provide insights into potential adjunctive therapy interventions that may be applied in the future to improve insulin resistance and mitigate weight gain, both which would vastly thus improve management of T1D patients who have obesity. The specific aims of this project are to assess the effects of adiposity and puberty on resistance to insulin's ability to suppress hepatic glucose production, stimulate peripheral glucose metabolism, and suppress rates of lipolysis in pubertal youth with T1D and to examine the role of fatty liver disease on insulin resistance in adolescents with obesity and T1D. The first aim will be conducted using the stepped, hyperinsulinemic- euglycemic glucose clamp technique with stable isotope tracer infusions to assess changes in endogenous glucose production, peripheral glucose uptake, and glycerol turnover in response to graded increases in rates of insulin infusion. The second aim will assess the impact of fatty liver disease and fat distribution on the insulin resistance of obesity in adolescents with T1D using abdominal MRI. The clamp and MRI studies will be carried out in 36 obese and 36 lean pubertal adolescents with T1D and the clamp study will also include 36 lean young adults with T1D. Carrying out the proposed program of research and analyzing the results, under the guidance of my outstanding mentorship team, will further my development into an independent pediatric physician-scientist. I will gain expertise in sophisticated measures of glucose and fat metabolism, as well as advanced skills in all aspects of study design, implementation, and evaluation and complete coursework in isotope tracers, biostatistics, and grant writing. The academic environment at Yale School of Medicine is rich in intellectual stimulation and houses ample resources critical to the completion of this proposal. Results obtained will reveal intricacies of metabolism in youth with T1D and become essential components of the NIDDK mission to “improve people's health and quality of life” by “disseminat[ing] science-based information on diabetes.” Furthermore, the results obtained will be critical in the preparation of my initial R01 application to evaluate the impact of adjunctive medications to decrease weight and insulin dose while improving glycemic control and outcomes in youth with obesity and T1D.

项目概要/摘要 本研究的目的是阐明肥胖的胰岛素抵抗如何影响血糖和 患有 1 型糖尿病 (T1D) 的青春期青少年的脂肪代谢和肝脏脂肪沉积。 随着全国范围内血糖控制的改善和肥胖率的增加，肥胖现在在年轻人中普遍存在 了解肥胖如何影响 T1D 的代谢对于治疗决策具有重要意义。 知识将为未来可能应用的潜在辅助治疗干预措施提供见解 改善胰岛素抵抗并减轻体重增加，这两者都将大大改善对胰岛素的管理 患有肥胖症的 T1D 患者。 该项目的具体目标是评估肥胖和青春期对胰岛素抵抗的影响 抑制肝脏葡萄糖生成、刺激外周葡萄糖代谢并抑制葡萄糖代谢率的能力 患有 T1D 的青春期青少年的脂肪分解，并检查脂肪肝疾病对胰岛素抵抗的作用 第一个目标将是使用阶梯式、高胰岛素血症的青少年。 采用稳定同位素示踪剂输注的正常血糖葡萄糖钳夹技术来评估内源性变化 葡萄糖产生、外周葡萄糖摄取和甘油周转率响应梯度增加 胰岛素输注的第二个目标是评估脂肪肝疾病和脂肪分布对胰岛素的影响。 将使用腹部 MRI 进行钳夹和 MRI 研究，以评估患有 T1D 的青少年对肥胖的抵抗力。 在 36 名肥胖和 36 名患有 T1D 的青春期瘦弱青少年中进行了钳制研究，钳制研究还将包括 36 名瘦弱的年轻人 患有 T1D 的成人。 在我的指导下实施拟议的研究计划并分析结果 优秀的导师团队，将进一步发展我成为一名独立的儿科医师科学家。 获得葡萄糖和脂肪代谢复杂测量方面的专业知识，以及各个方面的先进技能 研究设计、实施和评估，并完成同位素示踪剂、生物统计学和 耶鲁大学医学院的学术环境充满智力刺激和宿舍。 充足的资源对于完成该提案至关重要。所获得的结果将揭示新陈代谢的复杂性。 并成为 NIDDK 使命的重要组成部分，即“改善人们的健康和 通过“传播基于科学的糖尿病信息”来提高生活质量。 在准备我最初的 R01 申请时至关重要，以评估辅助药物对 减少体重和胰岛素剂量，同时改善肥胖和 T1D 青少年的血糖控制和结果。