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: 9762889
• 负责人: Michelle Van Name
• 金额: $ 19.49万
• 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 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9762889
• 关键词: Abdomen; Address; Adjuvant Analgesic; Adolescence; Adolescent; Adolescent obesity; Adult; Affect; American; Appointment; Biometry; Body Weight decreased; 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; 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.

项目总结/摘要 本研究的目的是阐明肥胖的胰岛素抵抗如何影响葡萄糖， 青春期1型糖尿病（T1 D）青少年的脂肪代谢和肝脏脂肪沉积。 随着血糖控制的改善和全国肥胖率的增加，肥胖现在在青年中普遍存在 关于T1 D了解肥胖如何影响T1 D的代谢对治疗决策具有重要意义。这 知识将提供对未来可能应用的潜在连续性治疗干预的见解 改善胰岛素抵抗和减轻体重增加，这两个都将大大改善管理， 患有肥胖症的T1 D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， 抑制肝葡萄糖生成、刺激外周葡萄糖代谢和抑制 T1 D青春期青年的脂肪分解，并检查脂肪肝疾病对胰岛素抵抗的作用， 肥胖和T1 D青少年。第一个目标将使用阶梯式高胰岛素血症- 正葡萄糖钳夹技术与稳定同位素示踪剂输注，以评估内源性 葡萄糖生成、外周葡萄糖摄取和甘油周转率对葡萄糖代谢率分级增加的反应 胰岛素注射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。 T1 D青少年的肥胖抵抗力，使用腹部MRI。将进行钳夹和MRI研究 在36名肥胖和36名瘦型青春期T1 D青少年中，钳夹研究还将包括36名瘦型青少年。 成人T1 D 在我的指导下，对提出的研究方案进行了实施，并对结果进行了分析。 优秀的导师团队，将进一步我的发展成为一个独立的儿科医生，科学家。我会 获得葡萄糖和脂肪代谢的复杂措施的专业知识，以及在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， 授予写作。耶鲁医学院的学术环境充满了智力刺激和房屋 充足的资源对完成这项建议至关重要。获得的结果将揭示代谢的复杂性 并成为NIDDK使命的重要组成部分，以“改善人们的健康， 生活质量”通过“传播基于科学的糖尿病信息”。此外，所获得的结果将 在准备我的初始R 01申请时至关重要，以评估预防性药物的影响， 降低体重和胰岛素剂量，同时改善肥胖和T1 D青年的血糖控制和结局。