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.

项目摘要/摘要 这项研究的目的是阐明肥胖的胰岛素抵抗如何影响葡萄糖和 1型糖尿病（T1D）的青春期青少年中的脂肪代谢和肝脂肪沉积。 随着血糖控制的改善和全国肥胖率提高，肥胖症现在在青年中普遍存在 与T1D。了解肥胖症如何影响T1D的代谢对治疗决策有影响。这 知识将提供对未来可能应用的潜在辅助治疗干预措施的见解 为了提高胰岛素抵抗并减轻体重增加，这两个都将大大改善 具有肥胖症的T1D患者。 该项目的具体目的是评估肥胖和青春期对胰岛素抵抗的影响 能够抑制肝葡萄糖产生，刺激外周葡萄糖代谢并抑制速率的能力 T1D青春期青年的脂解，并检查脂肪肝病在胰岛素耐药性中的作用 肥胖和T1D的青少年。第一个目标将使用阶梯式高胰岛素 - 具有稳定的同位素示踪剂输注的葡萄糖夹夹技术，以评估内源性的变化 葡萄糖产生，外周葡萄糖摄取和甘油周转，以响应分级的增加速率 胰岛素输注。第二个目标将评估脂肪肝病和脂肪分布对胰岛素的影响 使用腹部MRI的T1D青少年肥胖症的抗性。将进行夹具和MRI研究 在36位肥胖和36个带有T1D和夹具研究的精益青春期青少年中也将包括36个瘦年Young T1D的成年人。 在我的指导下执行拟议的研究计划并分析结果 杰出的心态团队将进一步发展成为独立的儿科身体科学家。我会 在葡萄糖和脂肪代谢的复杂度量方面获得专业知识，以及各个方面的高级技能 在同位素示踪剂，生物统计学和 授予写作。耶鲁大学医学学院的学术环境富含智力刺激和房屋 足够的资源对于完成此提案至关重要。获得的结果将揭示代谢的复杂性 在具有T1D的青年中，成为NIDDK使命的重要组成部分，以“改善人们的健康和 “生活质量”通过“基于科学的糖尿病信息”。此外，获得的结果将 在准备我最初的R01应用程序以评估辅助药物对 减轻体重和胰岛素剂量，同时改善肥胖和T1D青年血糖控制和结果。