2-A-Day Study: Twice a Day Meals Study.
Condition: PreDiabetes
MeSH terms: Prediabetic State
Study type: Interventional

Summary: 
      Caloric restriction increases lifespan and/or healthspan across multiple species. However
      implementation of long-term CR in humans is problematic and unacceptable to many individuals.
      As a result, intermittent fasting models have been developed to improve adherence. Such
      models have been shown to improve blood pressure, insulin sensitivity, decrease hepatic fat
      content and body weight. Investigators established an isocaloric twice-a-day (ITAD) feeding
      plan in mice, wherein test mice were acclimatized to consume over two hour periods (8-10am
      and 5-7pm), the same amount of food as ad-libitum mice. This intervention prevented obesity
      and age-associated type 2 diabetes via system-wide activation of autophagy. The investigators
      will perform further studies of the same feeding model in humans in a randomized crossover
      design. The objective is to test the hypothesis that restricting eating periods to twice a
      day (TAD), when compared to isocaloric ad lib meal timing (ALMT), will have beneficial
      effects on glucose metabolism, body composition, energy expenditure and autophagy in human
      subjects at risk for diabetes
    

Detailed description: 
      Caloric restriction (CR) increases lifespan and/or healthspan across multiple species
      including non-human primates. However, implementation of long-term CR in humans is
      problematic and unacceptable to many individuals. Further, since CR leads to loss of muscle
      mass in mice, it is likely that its implementation as a restorative strategy during aging may
      exacerbate age-associated muscle loss. As a result, intermittent fasting models, e.g.,
      alternate-day fasting, alternate day-modified fasting, the 5:2 diet, and the more recently
      elucidated early time-restricted feeding (eTRF)3 were developed as alternative strategies to
      improve adherence. Intermittent fasting increases glucose clearance/improves insulin
      sensitivity, decreases hepatic fat content, lowers blood pressure and body weight by varying
      degrees (at least when calories were unmatched). Despite these metabolic advantages, these
      approaches have also shown poor adherence in humans. For instance, alternate-day fasted
      subjects remained hungry on the fast days, which led to the conclusion that this approach
      cannot be continued for extended periods of time, and that adding one small meal on the
      fasting day may make this model more acceptable. Accordingly, in alternate day-modified
      fasting, fasted days (25% caloric intake) alternated with feasting days (125% calories),
      which improved compliance although dropout rates remained relatively high (38%) when compared
      to control group (26%). In addition, this feeding approach was not found to be superior to
      daily caloric restricted controls in terms of adherence, weight loss or cardiovascular
      benefits. More recently, eTRF wherein men with prediabetes were subjected to a 6-hr feeding
      interval with dinner before 1 pm displayed a number of metabolic benefits when compared to
      individuals on a 12-hr feeding time-frame. Nevertheless, due to vocational or societal
      factors, it is plausible that a vast majority of individuals may not be able to adhere to a
      regimen requiring the consumption of three meals within the first 6 hr of the diurnal cycle.
      In the attempt to offset compliance-related issues and to pursue a simpler approach,
      investigators established an isocaloric twice-a-day (ITAD) feeding plan in mice, wherein test
      mice are acclimatized to consume over two 2hr-periods (8:00-10:00am and 5:00-7:00pm) the same
      amount of food as ad libitum-fed mice. This would effectively translate to a breakfast and
      dinner (two meals) in humans. It has been shown that two periods of food restriction per day
      in mice prevents obesity and age-associated type 2 diabetes via system-wide activation of
      autophagy. This study is to determine if twice-a-day feeding will restore normoglycemia and
      promote metabolic correction in older men with prediabetes.

      Autophagy is a lysosomal degradative pathway that plays key roles in maintaining "clean"
      cells. It is well-established that basal autophagy levels begin to decline progressively in
      aged organisms. Maintaining higher autophagy levels improves organ function and stress
      response. For instance, liver-specific overexpression of autophagy genes protects against
      diet-induced obesity and tumor necrosis factor-mediated acute hepatotoxicity. In the
      investigators' studies with ITAD feeding in mice, blocking autophagy in distinct tissues
      resulted in loss of the metabolic benefits from this feeding strategy. Consequently, it is
      propose that establishing ITAD feeding in humans will yield a cost-effective, practical and
      immediately translatable strategy to prolong health-span by preventing diabetes and
      sarcopenia as well as the vast number of secondary diseases caused by sustained
      hyperglycemia.

      This study will investigate the feasibility of a TAD eating regimen and collect preliminary
      data to inform a larger-scale and more definitive trial.

      Specific Aims:

      Aim 1: To assess the feasibility of implementing a structured TAD eating regimen using
      study-provided meals 1a. To design meal plans that are isocaloric with habitual intake and
      intended to maintain weight and to develop methods to prepare, package and deliver the meals.

      1b. To develop and evaluate methods to enhance and monitor participant adherence to TAD
      eating; this will include patient logs, photo records of food intake and continuous
      (participant blinded) glucose monitoring.

        1. c. To assess participant satisfaction with TAD meal restriction, using validated
           instruments to evaluate hunger, satiety and well-being Aim 2: To collect preliminary
           data on the effect of TAD meal restriction to inform design of an adequately powered RCT

        2. a. To collect preliminary data on the effect of TAD meal restriction on glucose
           tolerance, insulin sensitivity and secretion, body composition and energy expenditure

      2b. To collect preliminary data on the effect of TAD meal restriction on cellular processes
      related to autophagy
    

Intervention name(s): Ad libitum meal timing; Twice a day meals
Intervention type(s): Other; Other
Intervention description(s): Research participants will eat meals provided by the study throughout the day, ad libitum; Research participants will eat meals provided by the study at two intervals during the day, and fast in between.
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Caloric restriction; Fasting; intermittent fasting; isocaloric ad lib meal timing; Twice-a-day feeding; insulin; glucose metabolism; normoglycemia; hyperglycemia