Meal Time Effects on Metabolic Health.

描述（由申请人提供）：肥胖症和2型糖尿病（T2 D）非常普遍，并逐渐成为流行病。饮食被认为是维持或改善代谢健康的两大支柱之一（与运动一起）。然而，在饮食干预中，很少考虑进餐时间，尽管流行病学数据显示，不吃早餐和晚上吃零食与肥胖和T2 D风险增加有关。最近在动物模型中进行的实验研究为进餐时间的因果作用提供了直接证据，表明改变进餐时间本身，而不改变热量摄入，会导致肥胖和葡萄糖耐量受损。在受控条件下，还没有实验测试过，是否仅仅是不定时的进餐就能引起人类类似的不良代谢变化。在这项提议中，我们克服了先前工作中的一些限制，我们的目标是确定在非糖尿病个体中，不吃早餐和消耗这些卡路里作为晚餐是否会降低葡萄糖耐量，恶化离体脂肪细胞胰岛素敏感性，导致代谢变化，刺激体重增加，并导致热量摄入增加。我们还将在糖尿病前期受试者中实现这些目标，因为这是经常依赖饮食调整来预防糖尿病的人群。一种可以解释为什么在一天中晚些时候进食会产生不良代谢影响的生理机制是报告的葡萄糖耐量的每日节律，从早上到晚上，但在糖尿病患者中，它是颠倒的，而是从早上到晚上改善。因此，描述糖尿病前期患者从早到晚的葡萄糖耐量模式，并确定它是否能预测早餐或晚餐时间表是否对血糖控制最佳，这将是至关重要的。为了解决机制，我们将确定葡萄糖耐量是否存在内源性昼夜节律（而不是由睡眠/觉醒和禁食/进食周期驱动），并测试与非糖尿病个体相比，非药物治疗的前驱糖尿病个体中该节律的时间是否发生变化。我们将通过安排非糖尿病和糖尿病前期个体接受两个10天的实验室方案来测试我们的假设，在此期间，他们接受等热量饮食：（a）早餐，午餐和晚餐;或（B）午餐晚餐和深夜餐，采用随机交叉设计。我们将在基线、暴露第一天和暴露最后一天评估三餐中每餐的餐后血糖反应和调节能量平衡的措施（血浆瘦素和胃饥饿素、间接热量测定法测定的能量消耗、饥饿感和食欲），以及脂肪细胞胰岛素敏感性。恒定常规方案将能够评估葡萄糖耐量的内源性昼夜节律控制，而在整个清醒期的自由进食将测试热量摄入的变化。这项研究将为改变进餐时间的代谢后果提供机制性见解，并可能有助于以证据为基础的方法来改善饮食干预，以对抗肥胖和T2 D。

DESCRIPTION (provided by applicant): Obesity and type 2 diabetes (T2D) are highly prevalent and increasing to epidemic proportions. Diet is recognized as one of the two pillars (together with exercise) of maintaining or improving metabolic health. However, in dietary interventions meal timing is rarely considered despite the epidemiologic data showing that skipping breakfast and evening snacking are associated with an increased risk for obesity and T2D. Recent experimental studies in animal models have provided direct evidence for a causal role of meal timing, showing that altered meal timing itself, without changes in caloric intake, leads to obesity and impaired glucose tolerance. Whether mis-timed meals alone can cause similar adverse metabolic changes in humans has not been tested experimentally under controlled conditions. In this proposal, we overcome a number of limitations in prior work, and we aim to determine in non-diabetic individuals whether skipping breakfast and consuming those calories as a late meal worsens glucose tolerance, worsen ex vivo adipocyte insulin sensitivity, leads to metabolic changes that would stimulate weight gain, and leads to increased caloric intake. We will also pursue these aims in subjects with prediabetes, as this is the population that frequently relies on diet modification to prevent diabetes. One physiological mechanism that could explain why eating late in the day has adverse metabolic effects is the reported daily rhythm in glucose tolerance, which worsens from morning to evening, but in patients with diabetes, it is inverted, instead improving from morning to evening. It will be critial therefore to describe the morning to evening pattern of glucose tolerance also in prediabetes, and determine whether it predicts whether early or late meal schedules are optimal for their glycemic control. To address mechanism, we will determine whether there exists an endogenous circadian rhythm in glucose tolerance (as opposed to driven by the sleep/wake and fasting/feeding cycle) and to test whether the timing of this rhythm is shifted in non-medicated prediabetic individuals as compared to non-diabetic individuals. We will test our hypotheses by scheduling non-diabetic and prediabetic individuals to undergo two 10-day in-laboratory protocols during which they receive isocaloric diets: (a) breakfast, lunch and dinner; or (b) lunch dinner, and a late night meal, in a randomized, cross-over design. We will assess the postprandial glucose response for each of the three meals and measures involved in regulating energy balance (plasma leptin and ghrelin, energy expenditure by indirect calorimetry, and sensations of hunger and appetite) throughout the wake episodes at baseline, on the first day of exposure and on the last day of exposure, as well as adipocyte insulin sensitivity. Constant Routine protocols will enable assessment of endogenous circadian control of glucose tolerance, while ad libitum buffet throughout a full wake episode will test changes in caloric intake. This research will provide mechanistic insights into the metabolic consequences of changing meal timing and may help in evidence-based approaches to improve dietary interventions in the fight against obesity and T2D.