Intermittent Fasting for Metabolic Health, Does Meal Timing Matter?
Condition: Type 2 Diabetes; Insulin Resistance
MeSH terms: Insulin Resistance
Study type: Interventional

Summary: 
      Obesity is a serious medical condition, the adverse consequences of which include increased
      risk of cardiovascular disease, diabetes mellitus, reduced fertility and cancer. The economic
      cost of obesity was placed at $58 billion dollars in Australia in 2008. Studies in mice and
      non-human primates have shown that moderate caloric restriction (CR) increases lifespan and
      reduces the incidence of cardiovascular disease, cancer, and type 2 diabetes. Reduced risk of
      chronic diseases is also observed in humans following CR. However, daily CR is difficult to
      maintain long term, since the body defends against weight loss by inducing "metabolic
      adaptation" and altering the hormonal appetite response. An emerging number of studies are
      examining the effects of limiting food intake to prescribed time periods per day, or every
      other day. Intermittent, or time restricted feeding describes a dieting approach where food
      is available ad libitum, however only for a limited period of time (i.e. 3-12 hours). This
      study will examine the effects of fasting for 15h/day and eating for 9-h per day on glycemic
      control and metabolic health. This study will build on the existing knowledge base in humans
      as to whether meal timing, rather than caloric restriction per se, is important to provide
      the stimulus required to improve metabolic health and reduce risk of chronic disease.
      Moreover, it will examine whether restricting feeding to later in the day is of lesser
      benefit to health.
    

Detailed description: 
      The timing of meal intakes distributed across the wake cycle may play a role in body weight
      regulation and metabolic health in humans. However, only a limited number of studies have
      interrogated this in humans. Epidemiological evidence shows that individuals who report
      consuming more of their daily energy intake at the evening meal were more overweight, than
      those who reported consumed more of their energy intake before lunch. Similarly, eating lunch
      late in the day (after 15:00 hrs) was predictive of poorer weight loss during a 20-week
      dietary intervention study and individuals randomized to consume more calories at breakfast
      had greater weight loss versus those randomized to eat more calories at dinner after 12
      weeks. Taken together these data suggest that consuming more calories in the morning may be
      beneficial for weight management.

      Randomised controlled cross-over intervention, where lean individuals were instructed either
      to consume all of their calories required for weight maintenance over a 4 hour period from
      1700-2100h, or as 3 meals/d for 8 weeks. Significant reductions in body weight and body fat
      mass, by 1.4 and 2.1 kg respectively, were noted when following the TRF protocol. Consumption
      of the evening meal was supervised within the laboratory, to ensure subjects consumed the
      entire meal. In light of evidence that rats switched from a nibbling diet to 1 meal/d
      increased gluconeogenesis and free fatty acid flux from fat depots, the authors postulated
      that the greater weight loss may be associated with changes in metabolism. Despite this small
      amount of weight loss, fasting blood glucose levels were increased, and TRF resulted in
      poorer glucose tolerance in response to an oral glucose tolerance test (OGTT). Thus,
      consuming a single, large "dinner" meal was detrimental for metabolic health, although no
      differences in insulinemia were noted. It is unclear whether responses may have differed if
      the food allowance was prescribed at breakfast or lunch times. Just one other study has
      performed a randomised controlled TRF protocol in humans. In this study, healthy, lean male
      subjects were allowed to eat ad libitum for 13h per day (6am-7pm) for 2 weeks. Participants
      reported eating significantly less on the TRF versus the control condition, and lost -0.4kg
      compared with a gain of +0.6kg in the control condition. Whilst this is a minor change in
      body weight, this pattern is not that atypical of modern eating patterns, and further
      restriction of eating times, and assessment of obese individuals under these conditions is
      warranted. The metabolic health impacts were not reported in that study.

      Several studies in animals have shown that, when fed in the "wrong" phase (i.e. eating when
      the animal would normally rest) the mice become obese, despite similar energy intake and
      expenditure, suggesting that the timing of food intake is important in driving the obese
      phenotype. Moreover, when high-fat energy intake is restricted to the active phase, the
      animals become obese, but do not develop the metabolic sequelae that are observed when the
      same foods are provided in the inactive phase. In humans, shift workers are at higher risks
      of metabolic disorders, including obesity and type 2 diabetes, possibly as a result of clock
      desynchronization. Alternatively, this may be the result of mis-timing of meals. For example,
      epidemiological evidence suggests that a shift toward consuming more calories at night is
      more likely to result in being overweight when compared with breakfast eaters, while eating a
      greater proportion of calories at the dinner meal is associated with a higher overall intake
      and an increased risk for obesity, metabolic syndrome and non-alcoholic fatty liver disease.
      When 10 healthy adults were subjected to a 28 hour "day" during which they consumed 4
      isocaloric meals, the resulting circadian misalignment was associated with increased blood
      glucose, even in the presence of increased insulin. Moreover, in 3 of the subjects, a
      postprandial glucose response was observed that would suggest a pre-diabetic state. Under
      these circumstances, it appears that consuming calories at "night" in humans may have
      deleterious effects on health, and suggests that meal timing may play a key role in
      mitigating the metabolic impairment that occurs when the circadian rhythm is disrupted. To
      further confuse the matter, among breakfast skippers, a higher eating frequency (i.e. ≥ 4
      eating occasions per day) has been shown to be associated with a higher risk for type 2
      diabetes, compared with breakfast eaters who consumed 1-3 meals per day. In light of this
      evidence, and the apparent beneficial effects of TRF on metabolic health, the importance of
      the morning meal and its synchronisation with circadian rhythms is unclear.

      Screening (S) - Participants will attend the South Australian Health and Medical Research
      Institute (SAHMRI) and have the research protocol explained to them in detail. Informed
      consent to participate in the study, including a verbal indication that they understand the
      general study protocol and requirements is then obtained. Participants will be assessed by a
      screening questionnaire for diet, medical, and exercise history to determine their
      eligibility according to the above criteria. Routine clinical checks are then performed
      (weight, height, waist circumference, blood pressure). If subjects meet eligibility criteria,
      they will be invited to take part in the study. Participants will have a dual energy x-ray
      absorptiometry scan and be fitted with a continuous glucose monitor for one week. During this
      time, participants will also wear an accelerometer and complete diet diaries to complete a
      baseline assessment of meal intake pattern. Participants will then be randomly assigned to
      undergo one of two study arms (TRF-b and TRF-d) for one week each. Conditions are separated
      by a 2-week washout period, during which participants will be encouraged to maintain their
      usual dietary pattern and physical activity levels.

      Metabolic Testing (D0, D7) during each study condition: Participants arrive at 0700 following
      an overnight fast. Weight and blood pressure is measured following a seated 10 min rest. A 20
      G cannula is inserted into an antecubital vein. A fasting blood sample is drawn for lipids,
      cytokines and glucoregulatory hormones. Resting metabolic rate and whole body nutrient
      oxidation is measured via indirect calorimetry. A second fasting blood sample is taken
      immediately prior to a standard test meal at 0800am or 1200pm, depending on study condition
      and gastric emptying, postprandial glucoregulatory and gut hormone response to re-feeding
      will be tested for 3 hours. At the first metabolic visit of each study condition,
      participants will be fitted with the continuous glucose monitor (CGM), and follow their
      assigned TRF protocol and assessments by CGM will continue for 7 days, before returning for
      the D7 metabolic visit. Diet records will be taken and accelerometers worn on the upper arm
      for each period during the study.
    

Intervention name(s): Lifestyle intervention B; Lifestyle Intervention D
Intervention type(s): Behavioral; Behavioral
Intervention description(s): Time limiting feeding from 8-5pm (TRFb); Time limiting feeding (12-9pm)
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Prevention