Meal Time Effects on Metabolic Health.

描述(由申请人提供)：肥胖症和2型糖尿病(T2D)非常普遍，并呈上升趋势。饮食被认为是维持或改善新陈代谢健康的两大支柱之一(与锻炼一起)。然而，在饮食干预中，很少考虑进餐时机，尽管流行病学数据表明，不吃早餐和晚上吃零食与肥胖和T2D的风险增加有关。最近在动物模型上的实验研究为进餐时机的因果关系提供了直接证据，表明改变进餐时机本身，而不改变卡路里摄入量，会导致肥胖和糖耐量受损。在受控条件下，不当进餐是否单独会在人类身上引起类似的不利代谢变化还没有得到实验测试。在这项建议中，我们克服了以前工作中的一些限制，我们的目标是确定在非糖尿病患者中，不吃早餐和晚餐摄入这些卡路里是否会恶化葡萄糖耐量，恶化体外脂肪细胞对胰岛素的敏感性，导致代谢变化，从而刺激体重增加，并导致卡路里摄入量增加。我们还将在糖尿病前期患者中实现这些目标，因为这是经常依赖改变饮食来预防糖尿病的人群。可以解释为什么一天中吃得晚会对新陈代谢产生不利影响的一个生理机制是，据报道，糖耐量的每日节律从早上到晚上都会恶化，但在糖尿病患者中，情况恰恰相反，从早上到晚上都在改善。因此，描述糖尿病前期患者从早到晚的糖耐量模式，并确定它是否预测早餐或晚餐对他们的血糖控制是最佳的，这将是至关重要的。为了解决这一机制，我们将确定糖耐量是否存在内源性昼夜节律(而不是由睡眠/清醒和禁食/进食周期驱动)，并测试与非糖尿病患者相比，非药物治疗的糖尿病前期患者这种节律的时间是否发生了变化。我们将通过安排非糖尿病患者和糖尿病前期患者接受两种为期10天的实验室方案来检验我们的假设，在此期间，他们接受等卡路里饮食：(A)早餐、午餐和晚餐；或(B)午餐晚餐和深夜晚餐，采用随机交叉设计。我们将评估三餐中每一餐的餐后血糖反应，以及在基线、暴露第一天和暴露最后一天的觉醒过程中涉及到的调节能量平衡的措施(血浆瘦素和Ghrelin，间接热量测量的能量消耗，以及饥饿和食欲)，以及脂肪细胞的胰岛素敏感性。恒定的常规方案将能够评估葡萄糖耐量的内源性昼夜节律控制，而整个清醒过程中的临时自助餐将测试卡路里摄入量的变化。这项研究将为改变进餐时间对新陈代谢的影响提供机械性的见解，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T2D。

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.