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，要求我们就HD27503-09《黑人成人发病率的儿童代谢标记物》进行生产性调查的竞争性更新。黑人患肥胖症、2型糖尿病和心血管疾病的风险增加。这些实体之间常见的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低于白人同龄人，而胰岛素分泌高于白人同龄人。然而，黑人的胰岛素高分泌超过了对较低的胰岛素敏感性的代偿反应。2)黑人儿童全身脂解率比白人儿童低40%。3)在需要增加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，我们提出了如下理论：黑人儿童脂肪分解减少导致1)骨骼肌脂肪堆积导致胰岛素抵抗，2)脂肪堆积在细胞中最初导致胰岛素高分泌。这种高胰岛素血症进一步增加了组织脂肪的滞留。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，胰岛素抵抗加剧，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。这一竞争性更新的具体目的是：1)通过大腿中部的CT扫描比较黑人和白人儿童的骨骼肌脂含量(SMLC)，并评估其与体内胰岛素敏感性的关系；2)测试自由脂肪酸(FFA)诱导的胰岛素抵抗与黑人和白人青少年SMLC增加更大的假设；3)检查青春期前黑人儿童的β细胞胰岛素分泌是否比白人儿童对FFA的刺激作用更敏感；以及4)测试黑人肥胖青少年的细胞是否比白人更容易受到FFA的脂肪毒性作用的影响。可使用的方法包括：用于评估SMLC的成熟的CT方法；用于提高循环FFA水平的脂肪注射；用于测量胰岛素敏感性和底物转换的具有稳定同位素的高胰岛素正血糖钳；用于评估胰岛素分泌的高血糖钳；用于身体成分评估的DEXA和腹部CT。全面了解胰岛素抵抗/高胰岛素血症的种族差异的机制(S)对于针对所涉及的代谢组织进行特定治疗非常重要(S)。最终目标是通过在儿童早期采取干预/预防策略，降低美国黑人与肥胖、2型糖尿病和心血管疾病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.