Pathophysiology of Metabolic Defects of Juvenile Obesity

青少年肥胖代谢缺陷的病理生理学

• 批准号: 7262561
• 负责人: SONIA CAPRIO
• 金额: $ 18.33万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-05 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7262561
• 关键词: 2,4-thiazolidinedione; Adipocytes; Adolescent; Affect; Area; Award; Beta Cell; Cell physiology; Child; Clinical; Clinical Research; Commit; Defect; Deposition; Development; Doctor of Medicine; Fatty acid glycerol esters; Functional disorder; Funding; Glycerol; Goals; High Prevalence; Inflammatory; Insulin; Insulin Resistance; Intra-abdominal; Lipids; Lipolysis; Liver diseases; Longitudinal Studies; Mentors; Metabolic; Metabolic syndrome; Mid-Career Clinical Scientist Award (K24); Modeling; Muscle; N.I.H. Research Support; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pattern; Peripheral; Phenotype; Physiological; Request for Applications; Research Project Grants; Scientist; Skeletal Muscle; Thiazolidinediones; Time; Visceral; Youth; adiponectin; blood glucose regulation; career; cohort; cytokine; experience; impaired glucose tolerance; improved; insulin sensitivity; non-alcoholic fatty liver; patient oriented research; programs; rosiglitazone; subcutaneous

DESCRIPTION (provided by applicant): This application requests renewed funding for a K24 Mid-Career Award for Patient Oriented Research (FOR) for Sonia Caprio, M.D. During the previous cycle of this award, Dr. Caprio and her group used the model of impaired glucose tolerance to study early changes in insulin resistance and beta-cell function in the development of T2DM in obese children and adolescents. Using epidemiological and physiological approaches, we revealed: 1) a high prevalence of IGT and the metabolic syndrome in obese children and adolescents, 2) adolescents with IGT have profound peripheral insulin resistance associated with increased intramyocellular lipid accumulation and visceral fat, beta-cell dysfunction and low adiponectin levels, 3) in only 2 years, 25% of the obese youth with IGT progressed to T2DM. The goal of this proposal is to provide continued support for Dr. Caprio so that a greater proportion of her time can be devoted to developing research projects and mentoring clinical scientists. The studies that are involved in this proposal include mechanistic studies that utilize rosiglitazone to assess whether the dysfunctional fat cells can be converted to healthy adipocytes and whether the abnormal pattern of fat distribution can be reversed in obese adolescents with IGT, thereby leading to enhanced muscle insulin sensitivity and improved beta-cell function (R01 HD 47878). Other studies are proposed to characterize the metabolic phenotype of obese children and adolescents with non-alcoholic fatty liver disease (NAFLD) and compare them to weightmatched controls. A new longitudinal study has been added to determine the relationship between adiposity and inflammatory markers and their contribution to insulin resistance and the metabolic syndrome in an established well-characterized cohort of obese youth. This longitudinal analysis will help to define the factors responsible for the development of the metabolic syndrome in obese youth. The impact of inflammatory markers on the progression of the metabolic syndrome will be examined. My productive, ongoing NIHfunded clinical research program and 15 years of experience in patient-oriented research make me wellsuited to receive continuation of the K24 award. The additional funds would allow me to raise my effort of NIH research support commensurate with the amount of time I currently commit to patient-oriented research and mentoring, and would allow me to continue to expand in both these areas.

描述（由申请人提供）：本申请要求为医学博士索尼娅·卡普里奥 (Sonia Caprio) 的 K24 职业生涯中期奖以患者为导向的研究 (FOR) 续订资金。在该奖项的上一个周期中，卡普里奥博士和她的团队使用了受损模型葡萄糖耐量研究肥胖儿童和青少年 T2DM 发展过程中胰岛素抵抗和 β 细胞功能的早期变化。利用流行病学和生理学方法，我们发现：1）肥胖儿童和青少年中 IGT 和代谢综合征的患病率很高，2）患有 IGT 的青少年具有严重的外周胰岛素抵抗，与肌细胞内脂质积累和内脏脂肪、β 细胞功能障碍增加相关脂联素水平低，3) 仅在两年内，25% 患有 IGT 的肥胖青少年就发展为 T2DM。该提案的目标是为卡普里奥博士提供持续的支持，以便她将更多的时间用于开发研究项目和指导临床科学家。该提案涉及的研究包括利用罗格列酮来评估功能失调的脂肪细胞是否可以转化为健康的脂肪细胞以及是否可以在患有IGT的肥胖青少年中逆转脂肪分布的异常模式，从而增强肌肉胰岛素的机​​制研究敏感性和改善的 β 细胞功能 (R01 HD 47878)。其他研究旨在描述患有非酒精性脂肪肝疾病 (NAFLD) 的肥胖儿童和青少年的代谢表型，并将其与体重匹配的对照进行比较。增加了一项新的纵向研究，以确定肥胖和炎症标志物之间的关系，以及它们对已建立的明确的肥胖青年队列中的胰岛素抵抗和代谢综合征的影响。这种纵向分析将有助于确定导致肥胖青少年代谢综合征发生的因素。将检查炎症标志物对代谢综合征进展的影响。我富有成效、正在进行的 NIH 资助的临床研究项目以及 15 年以患者为导向的研究经验使我非常适合继续获得 K24 奖项。额外的资金将使我能够提高 NIH 研究支持的力度，与我目前致力于以患者为导向的研究和指导的时间相称，并使我能够继续在这两个领域进行扩展。