Metabolic impact of fructose restriction in obese children

在过去的30年里，患有肥胖症、糖尿病和代谢综合征的儿童比例急剧增加，这推高了医疗保健成本，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/民族表现不同，尤其是在儿童中。肥胖的拉丁裔儿童表现出血脂异常、内脏肥胖和非酒精性脂肪肝（NAFLD）的患病率最高;非裔美国儿童表现为高血压、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的关键，因此，它的预防和治疗。遗传和环境差异在症状患病率方面的证据比比皆是，并表明基因/种族-饮食相互作用。 果糖可能是代谢综合征的病因之一。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相平行。果糖刺激肝脏新生脂肪生成，我们已经证明这有助于血脂异常和NAFLD;以及肝脏尿酸合成，被认为在高血压中很重要。 我们假设，果糖代谢的种族/民族差异有助于观察到的代谢综合征表现的种族/民族差异：在拉丁美洲人中，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，这导致胰岛素抵抗和胰岛素抵抗增加。我们进一步假设，10天的等热量果糖限制将降低DNL和IHL，改善拉丁美洲人的血脂谱;并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患儿的胰岛素敏感性和葡萄糖处置（OGTT）、新生脂肪生成和富含甘油三酯的脂蛋白动力学（稳定同位素测量）、组织内脂质分配（磁共振光谱法）和一氧化氮代谢产物（HLPC和ELISA），并按种族和性别分层;然后在果糖限制10天后再次检查。我们预计合并症将以种族/民族特异性方式改善。这项研究的结果将对以下方面产生直接影响：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）全球预防和治疗肥胖、糖尿病和代谢综合征的公共卫生工作;以及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.