Childhood Metabolic Markers of Adult Morbidity in Blacks

描述（由申请人提供）：这是一份修订后的申请，旨在对我们的生产性研究进行竞争性更新，该研究涉及“黑人成年人发病的儿童期代谢标志物”，HD27503-09。 黑人患肥胖症、2型糖尿病和心血管疾病的风险增加。这些实体之间的共同发病联系是胰岛素抵抗/高胰岛素血症。在上一个项目期间，我们的研究结果表明：1）与白色同龄人相比，黑人儿童的胰岛素敏感性较低，胰岛素分泌量较高。然而，黑人的胰岛素分泌过多超过了对较低胰岛素敏感性的代偿反应。2)黑人儿童的全身脂肪分解率比白色儿童低40%。3)在需要增加胰岛细胞胰岛素分泌的情况下，黑人儿童这样做的能力有限。基于这些发现，我们提出了以下理论：黑人儿童脂肪分解减少导致1）骨骼肌中脂肪积累，导致胰岛素抵抗，2）脂肪积累在最初导致胰岛素分泌过多的细胞中。这种高胰岛素血症进一步增强组织脂肪捕获。随着时间的推移，在过量能量摄入和/或体力活动减少的情况下，胰岛素抵抗加剧，并且细胞“脂毒性”使胰岛不能进一步增加胰岛素分泌以匹配胰岛素抵抗。 本竞争性更新的具体目的是：1）通过大腿中部的计算机断层扫描（CT）比较黑人与白色儿童的骨骼肌脂质含量（SMLC），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色青少年SMLC较大增加相关的假设; 3）检查青春期前黑人儿童的<$-细胞胰岛素分泌是否比白人对FFA的刺激作用更敏感; 4）测试黑人肥胖青少年的<$-细胞是否比白人更容易受到FFA的脂毒性作用。使用的方法包括：用于评估SMLC的成熟CT方法;用于升高循环FFA水平的胰岛素输注;用于测量胰岛素敏感性和底物转换的稳定同位素和间接量热法高胰岛素-正葡萄糖钳夹;用于评估胰岛素分泌的高葡萄糖钳夹;用于身体成分评估的DEXA和腹部CT。全面了解胰岛素抵抗/高胰岛素血症种族差异的机制对于靶向相关代谢组织的特定治疗非常重要。最终目标是通过儿童早期干预/预防策略降低美国黑人肥胖、T2 DM和CVD相关的发病率和死亡率。

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.