Fructose: Substrate, Stimulus, or Both?

果糖：底物、刺激物，还是两者兼而有之？

• 批准号: 10553588
• 负责人: JEAN-MARC SCHWARZ
• 金额: $ 71.5万
• 依托单位: TOURO UNIVERSITY OF CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10553588
• 关键词: Address; Adult; Affect; Blood; Blood Glucose; Carbohydrates; Cardiometabolic Disease; Child; Chronic Disease; Consumption; Cross-Over Studies; Data; Diabetes Mellitus; Diet; Distress; Dyslipidemias; Energy Intake; Fasting; Fatty Acids; Fatty acid glycerol esters; Fructose; Gene Combinations; Gluconeogenesis; Glucose; Glycogen; Grant; Health; Hepatic; Human; Hyperglycemia; Hyperlipidemia; Individual; Insulin; Intake; Intravenous; Isotopes; Kinetics; Knowledge; Label; Link; Lipids; Liquid substance; Liver; Liver Glycogen; Measures; Metabolic; Metabolic Diseases; Metabolism; Methodology; Non-Insulin-Dependent Diabetes Mellitus; Nutritional; Obesity; Oral; Pathway interactions; Persons; Play; Population; Population Study; Prediabetes syndrome; Production; Public Health; Pyruvate; Recommendation; Research; Role; Stimulus; Testing; Time; Tracer; Triglycerides; Up-Regulation; Woman; blood glucose regulation; comparison control; design; dietary; evidence base; feeding; glucose metabolism; glucose output; glucose production; improved; insulin sensitivity; lipid biosynthesis; liver metabolism; men; non-alcoholic fatty liver disease; prevent; response; sound; stable isotope; sugar

ABSTRACT The alarming increase in rates of type 2 diabetes has remained unabated despite efforts to implement changes to diet and other factors that undoubtedly play a role. One obstacle has been inconsistency in dietary recommendations and, in particular, the role of fructose. Although population studies have linked excess fructose consumption to type 2 diabetes and other metabolic disorders, questions remain regarding the role played by fructose, in part because the precise mechanisms underlying these associations have not been elucidated in humans. For example, multiple tracer studies have demonstrated that fructose consumption is associated with increased rates of fatty acid synthesis (de novo lipogenesis [DNL]), but this finding is questioned in view of studies in which very little labeled fructose was actually incorporated into newly synthesized fat. We propose to resolve this paradox by determining whether fructose increases DNL by its conversion to fat (direct effect) or if fructose is instead preferentially directed into synthesis of new sugar (gluconeogenesis [GNG]), while other typical GNG substrates such as pyruvate are redirected into DNL in the presence of fructose (indirect effect). Another paradox centers on how fructose leads to high levels of glucose in the blood following a meal. In this grant we will test the hypothesis that meals high in fructose overwhelm the GNG pathway and lead to increased glucose output into the blood. We further hypothesize that meals with lower fructose content can be tolerated by persons with normal fasting insulin and glucose levels but not by those with pre-diabetes. To address these questions, we will perform four one-day dietary studies in men and women with either pre-diabetes or normal glucose and insulin levels. The study is based on the premise that uncontrolled hepatic fluxes from excess fructose consumption play a key role in lipid- and carbohydrate- associated dysregulation. We will employ a feeding paradigm using defined liquid meals and a combination of oral and intravenous stable (not radioactive) isotopes, in tracer and non-tracer amounts, to simultaneously measure fluxes in the GNG and DNL pathways in response to low or high fructose intake. We will also test whether fluxes in these pathways are altered in pre-diabetic individuals compared to controls with normal glucose and insulin levels. By simultaneously measuring the GNG and DNL pathways, this proposal has the potential to both generate important advances in understanding the dynamics of postprandial fructose metabolism and provide important mechanistic information to support or strengthen evidence-based nutritional recommendations regarding limitations on fructose intake.

摘要 2型糖尿病发病率的惊人增长仍然有增无减，尽管努力实施变革， 饮食和其他因素无疑起着作用。一个障碍是饮食不一致 建议，特别是果糖的作用。尽管人口研究表明 果糖消费对2型糖尿病和其他代谢紊乱的影响，关于其作用的问题仍然存在 果糖起作用，部分原因是这些关联背后的确切机制还没有被发现。 在人类身上得到了阐明。例如，多项示踪研究表明，果糖的摄入量 与脂肪酸合成速率增加（从头脂肪生成[DNL]）相关，但这一发现是 质疑鉴于研究中很少标记的果糖实际上被纳入新的 合成脂肪我们建议通过确定果糖是否通过其 转化为脂肪（直接作用），或者如果果糖优先被引导合成新糖 （DNL），而其他典型的GNG底物如丙酮酸盐在DNL中被重定向为DNL。 果糖的存在（间接作用）。另一个悖论是关于果糖如何导致高水平的葡萄糖 在血液中，饭后。在这项资助中，我们将测试这一假设，即高果糖膳食压倒了 GNG途径，并导致增加葡萄糖输出到血液中。我们进一步假设， 空腹胰岛素和葡萄糖水平正常的人可以耐受较低的果糖含量， 糖尿病前期患者。为了解决这些问题，我们将对男性进行四项为期一天的饮食研究， 糖尿病前期或血糖和胰岛素水平正常的女性。这项研究的前提是， 来自过量果糖消耗的不受控制的肝流量在脂质和碳水化合物中起关键作用， 相关失调。我们将采用一种喂养模式，使用定义的液体膳食和以下组合： 口服和静脉注射稳定（非放射性）同位素，示踪剂和非示踪剂量，同时 测量GNG和DNL途径对低或高果糖摄入量的响应。我们还将测试 与正常对照组相比，糖尿病前期个体中这些通路的通量是否发生了改变 血糖和胰岛素水平。通过同时测量GNG和DNL途径，该提议具有 有可能在了解餐后果糖的动力学方面产生重要进展 代谢和提供重要的机制信息，以支持或加强循证营养 关于限制果糖摄入量的建议。