Childhood Metabolic Markers of Adult Morbidity in Blacks

黑人成人发病率的儿童代谢标志物

基本信息

批准号：
7932474
负责人：
SILVA A ARSLANIAN
金额：
$ 8.22万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7932474
关键词：
Abdomen Adipose tissue Adolescence Adolescent Adult African American Age Body Composition Body fat Body mass index Cardiovascular Diseases Cells Central obesity Child Childhood DEXA Defect Development Energy Intake Environment Fat emulsion Fatty acid glycerol esters Floods Funding Genetic Glucose Goals Homeostasis Hyperglycemia Hyperinsulinism Hypertriglyceridemia Indirect Calorimetry Individual Infusion procedures Insulin Insulin Resistance Intervention Investigation Link Lipids Lipolysis Measures Metabolic Metabolic Marker Methods Morbidity - disease rate Muscle Fibers Non-Insulin-Dependent Diabetes Mellitus Nonesterified Fatty Acids Obesity Pancreas Physical activity Prevalence Prevention strategy Progress Reports Puberty Publishing Request for Proposals Risk Scanning Signal Transduction Skeletal Muscle Testing Thigh structure Time Tissues Triglycerides Visceral Weight X-Ray Computed Tomography base in vivo insight insulin secretion insulin sensitivity islet mortality obesity risk peer prepuberty racial difference response sex stable isotope theories

项目摘要

DESCRIPTION (provided by applicant): This is a revised application for the competitive renewal of our productive investigations with respect to "Childhood Metabolic Markers of Adult Morbidity in Blacks", HD27503-09. Blacks are at increased risk for obesity, type 2 diabetes mellitus and cardiovascular disease. A common pathogenetic link among these entities is insulin resistance/hyperinsulinemia. During the previous project period, our results demonstrated that: 1) black children have lower insulin sensitivity and higher insulin secretion compared with their white peers. However, the insulin hypersecretion in blacks is over and above the compensatory response to lower insulin sensitivity. 2) Rates of total body lipolysis are 40% lower in black vs white children. 3) In situations where there is a demand to increase ¿-cell insulin secretion, black children have a limited capacity to do so. Based on these findings we propose the following theory: decreased lipolysis in black children leads to 1) accumulation of fat in skeletal muscle responsible for the insulin resistance, and 2) accumulation of fat in the ¿-cell responsible for the insulin hypersecretion initially. This hyperinsulinemia further augments tissue fat trapping. With time, in the presence of excess energy intake and/or diminished physical activity, insulin resistance intensifies and ¿-cell "lipotoxicity" renders the islets incapable of further increases in insulin secretion to match insulin resistance. The specific aims of this competitive renewal are: 1) to compare skeletal muscle lipid content (SMLC) in black vs white children by computed tomography (CT) scan of the mid-thigh, and assess the relationship to in vivo insulin sensitivity; 2) to test the hypothesis that free fatty acid (FFA) -induced insulin resistance is associated with larger increases in SMLC in black vs white adolescents; 3) to examine if ¿-cell insulin secretion in prepubertal black children is more sensitive to the stimulatory effect of FFA than in whites; and 4) to test if the ¿-cell in black obese adolescents is more susceptible to the lipotoxic effect of FFA compared with whites. The methods to be used are: the well-established CT method to assess SMLC; intralipid infusion to elevate circulating FFA levels; the hyperinsulinemiceuglycemic clamp with stable isotopes and indirect calorimetry to measure insulin sensitivity and substrate turnover; the hyperglycemic clamp to assess insulin secretion; DEXA and abdominal CT for body composition assessments. A comprehensive understanding of the mechanism(s) of racial differences in insulin resistance/hyperinsulinemia is important in targeting specific therapies to the metabolic tissue(s) involved. The ultimate goal is to reduce the morbidity and mortality related to obesity, T2DM and CVD in black Americans by intervention/prevention strategies early in childhood.

描述（由申请人提供）：这是我们关于“黑人成人发病率的儿童代谢标志物”HD27503-09 的富有成效的调查的竞争性更新的修订申请，黑人患肥胖症和 2 型糖尿病的风险增加。这些实体之间的常见致病联系是胰岛素抵抗/高胰岛素血症。在之前的项目期间，我们的结果表明：1）黑人儿童的胰岛素敏感性较低，并且与白人同龄人相比，胰岛素分泌过多。然而，黑人的胰岛素分泌过多超出了对胰岛素敏感性较低的补偿反应。2) 黑人儿童的全身脂肪分解率比白人儿童低 40%。有增加的需求 ¿ -细胞胰岛素分泌，黑人儿童的胰岛素分泌能力有限根据这些发现，我们提出以下理论：黑人儿童的脂肪分解减少导致 1) 骨骼肌中脂肪的积累，导致胰岛素抵抗，2) 脂肪的积累。 ¿ 中的脂肪随着时间的推移，在能量摄入过多和/或体力活动减少的情况下，这种高胰岛素血症会进一步加剧胰岛素抵抗。 -细胞“脂毒性”使胰岛无法进一步增加胰岛素分泌以匹配胰岛素抵抗。这种竞争性更新的具体目的是：1）通过计算机断层扫描（CT）比较黑人和白人儿童的骨骼肌脂质含量（SMLC）。 ) 扫描大腿中部，并评估与体内胰岛素敏感性的关系；2) 检验游离脂肪酸 (FFA) 诱导的胰岛素抵抗与黑人与白人 SMLC 较大增加相关的假设；青少年；3) 检查是否 ¿ -青春期前黑人儿童的细胞胰岛素分泌对 FFA 的刺激作用比白人更敏感；4) 测试 ¿与白人相比，黑人肥胖青少年的细胞更容易受到 FFA 的脂毒性作用，使用的方法有：评估 SMLC 的成熟 CT 方法；输注脂肪乳以提高循环 FFA 水平；使用稳定同位素进行高胰岛素正常血糖钳夹。间接量热法测量胰岛素敏感性和底物周转率；高血糖钳夹评估胰岛素分泌；以及腹部 CT 评估身体成分。胰岛素抵抗/高胰岛素血症的种族差异机制对于针对相关代谢组织进行针对性治疗非常重要，最终目标是通过干预/减少美国黑人与肥胖、T2DM 和 CVD 相关的发病率和死亡率。儿童早期的预防策略。