Metabolic impact of fructose restriction in obese children

过去 30 年来，患有肥胖、糖尿病和代谢综合征的儿童比例急剧增加，这增加了医疗费用并导致过早死亡。代谢综合征的病因仍不清楚。代谢综合征的种族/民族表现各不相同，尤其是在儿童中。肥胖的拉丁裔儿童血脂异常、内脏肥胖和非酒精性脂肪肝 (NAFLD) 的患病率最高；相反，非裔美国儿童出现高血压、胰岛素抵抗恶化和葡萄糖耐受不良。 了解代谢综合征表现的这些变化是了解其发病机制及其预防和治疗的关键。症状患病率存在​​遗传和环境差异的证据比比皆是，并表明基因/种族-饮食之间存在相互作用。 代谢综合征的病因之一可能是果糖。果糖消费的长期趋势与儿童肥胖、2 型糖尿病和代谢综合征的三重流行并行。果糖刺激肝脏从头脂肪生成，我们已证明这会导致血脂异常和 NAFLD；和肝脏尿酸合成，被认为对高血压很重要。 我们假设果糖代谢的种族/民族差异导致了代谢综合征表现中观察到的种族/民族差异：在拉丁裔中，果糖主要通过 DNL 转化为 TG，这导致肝脏脂肪含量、VLDL-TG 输出和 TG 水平增加；但在非裔美国人中，更大比例的果糖转化为葡萄糖，从而导致血糖​​升高和胰岛素抵抗。我们进一步假设，10 天的等热量果糖限制将降低拉丁裔的 DNL 和 IHL，并改善血脂状况；改善非裔美国人的血糖控制、胰岛素敏感性和血压。 我们将检查代谢综合征儿童的胰岛素敏感性和葡萄糖处理（通过 OGTT）、从头脂肪生成和富含甘油三酯的脂蛋白动力学（通过稳定同位素测量）、组织内的脂质分配（通过磁共振波谱）和一氧化氮代谢物（通过 HLPC 和 ELISA），并按种族和性别分层；然后在 10 天果糖限制后再次进行。我们预计合并症将以特定种族/民族的方式得到改善。这项研究的结果将直接影响：1）胰岛素抵抗和肥胖的种族/民族差异的原因； 2）营养信息和食物金字塔的改变； 3）世界各地预防和治疗肥胖、糖尿病和代谢综合征的公共卫生工作； 4) 食品行业声明和食品广告的监管。

The past 30 years have seen a dramatic increase in the proportion of children with from obesity, diabetes, and metabolic syndrome, which drive up health care costs and contribute to premature mortality. The etiology(ies) of metabolic syndrome remain(s) unknown. The racial/ethnic presentations of metabolic syndrome differ, especially in children. Obese Latino children exhibit the highest prevalence of dyslipidemia, visceral adiposity, and non-alcoholic fatty liver disease (NAFLD); African American children present instead with hypertension, worsened insulin resistance, and glucose intolerance. Understanding these variations in presentation of metabolic syndrome holds the key to understanding its pathogenesis and, therefore, its prevention and treatment. Evidence for both genetic and environmental differences in symptom prevalence abound, and suggest a gene/race-diet interaction. One likely contributor to the etiology of metabolic syndrome is fructose. The secular trend in fructose consumption parallels the triple epidemics of obesity, type 2 diabetes, and metabolic syndrome in children. Fructose stimulates hepatic de novo lipogenesis, which we have demonstrated contributes to dyslipidemia and NAFLD; and hepatic uric acid synthesis, thought to be important in hypertension. We hypothesize that racial/ethnic differences in fructose metabolism contribute to the observed racial/ethnic differences in presentation of the metabolic syndrome: that in Latinos, fructose is primarily converted to TG by DNL, which leads to an increase in liver fat content, VLDL-TG output, and TG levels; but in African Americans, a greater proportion of fructose is converted to glucose, which leads to increased glycemia and insulin resistance. We further hypothesize that 10 days of isocaloric fructose restriction will decrease DNL and IHL and improve lipid profiles in Latinos; and improve glucose control, insulin sensitivity, and blood pressure in African Americans. We will examine insulin sensitivity and glucose disposal (by OGTT), de novo lipogenesis and triglyceride-rich lipoprotein kinetics (by stable isotope measurement), lipid partitioning within tissues (by magnetic resonance spectroscopy), and nitric oxide metabolites (by HLPC and ELISA) in children with metabolic syndrome, stratified by race and gender; and then again after 10 days fructose restriction. We anticipate that comorbidities will improve in a race/ethnic specific fashion. The results of this study will have immediate impact on: 1) reasons for racial/ethnic differences in insulin resistance and obesity; 2) alterations of nutritional information and the Food Pyramid; 3) public health efforts regarding prevention and treatment of obesity, diabetes, and metabolic syndrome around the world; and 4) the regulation of food industry claims and food advertising.