Meal Time Effects on Metabolic Health.

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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.