Fructose: Substrate, Stimulus, or Both?

摘要 尽管努力实施改革，但2型糖尿病发病率的惊人增长仍未减弱 饮食等因素无疑起到了一定作用。其中一个障碍是饮食上的不一致 建议，特别是果糖的作用。尽管人口研究将过剩与 摄入果糖到2型糖尿病和其他代谢紊乱，关于其作用仍有疑问 由果糖发挥作用，部分原因是这些联系背后的确切机制尚未得到 在人类身上被阐明。例如，多项示踪剂研究表明，果糖的摄入量 与脂肪酸合成率增加(从头脂肪生成[DNL])有关，但这一发现 考虑到几乎没有标记的果糖实际上被结合到新的 合成脂肪。我们建议通过确定果糖是否使DNL增加 转化为脂肪(直接影响)或果糖优先用于合成新糖 (葡萄糖异生作用[GNG])，而其他典型的GNG底物，如丙酮酸，在 果糖的存在(间接影响)。另一个矛盾的中心是果糖如何导致高水平的葡萄糖。 在一顿饭后的血液中。在这笔赠款中，我们将检验这样一个假设，即高果糖膳食压倒了 GNG途径并导致进入血液的葡萄糖产量增加。我们进一步假设用餐时 空腹胰岛素和血糖水平正常的人可以忍受较低的果糖含量，但不能 那些有糖尿病前期的人。为了解决这些问题，我们将对男性和女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 过量摄入果糖造成的不受控制的肝脏流量在脂肪和碳水化合物-- 与之相关的调节失调。我们将使用定义的流质餐食和组合使用 口服和静脉注射示踪剂和非示踪剂的稳定(非放射性)同位素，以同时 测量GNG和DNL途径中果糖摄入量低或高时的通量。我们还将测试 糖尿病前期患者与正常对照组相比，这些通路中的流量是否发生了变化 血糖和胰岛素水平。通过同时测量GNG和DNL通路，该建议具有 两者都有可能在理解餐后果糖动态方面取得重要进展 并提供重要的机制信息来支持或加强循证营养 关于限制果糖摄入量的建议。

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.