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，这些疾病推高了医疗保健成本，并导致过早死亡。代谢综合征的病因尚不清楚(S)。代谢综合征的种族/民族表现各不相同，特别是在儿童中。肥胖的拉丁裔儿童表现出最高的血脂异常、内脏肥胖症和非酒精性脂肪性肝病(NAFLD)的患病率；相反，非裔美国儿童表现为高血压、胰岛素抵抗恶化和葡萄糖耐量减低。 了解代谢综合征的这些表现形式的变化，对于了解其发病机制，从而预防和治疗具有关键意义。症状患病率的遗传和环境差异的证据比比皆是，并表明存在基因/种族-饮食相互作用。 导致代谢综合征的一个可能因素是果糖。果糖消费的长期趋势与肥胖、2型糖尿病和儿童代谢综合征的三重流行病平行。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非酒精性脂肪肝；以及肝脏尿酸合成，被认为是高血压的重要因素。 我们假设，果糖代谢的种族/民族差异导致了所观察到的代谢综合征的种族/民族差异：在拉丁裔，果糖主要由DNL转化为甘油三酯，这导致肝脏脂肪含量、极低密度脂蛋白-甘油三酯产量和甘油三酯水平增加；但在非裔美国人中，更大比例的果糖转化为葡萄糖，这导致血糖和胰岛素抵抗增加。我们进一步假设，10天等卡路里的果糖限制将降低拉丁裔的DNL和IHL，改善血脂谱；并改善非裔美国人的血糖控制、胰岛素敏感性和血压。 我们将检测代谢综合征儿童的胰岛素敏感性和葡萄糖处置(通过OGTT)，新生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)，组织内脂肪分配(通过磁共振光谱)，以及一氧化氮代谢产物(通过HLPC和ELISA法)，按种族和性别分层；然后在限制果糖10天后再次检测。我们预计，合并症将以种族/民族特有的方式改善。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变化；3)世界各地预防和治疗肥胖症、糖尿病和代谢综合征的公共卫生努力；以及4)对食品业声称和食品广告的监管。

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.