Effect of Time-restricted Eating on Behaviour and Metabolism in Overweight Individuals at High Risk of Type 2 Diabetes (RESET)

Effect of Time-restricted Eating on Behaviour and Metabolism in Overweight Individuals at High Risk of Type 2 Diabetes

Effect of Time-restricted Eating on Behaviour and Metabolism in Overweight Individuals at High Risk of Type 2 Diabetes - the RESET Study

University of Copenhagen, Aalborg University Hospital, IMotions A/S, University of Leeds, Salk Institute for Biological Studies

The aim of the present study is to investigate effects of 12 weeks time-restricted eating on behaviour and metabolism in individuals with overweight or obesity at high risk of type 2 diabetes.

Overweight and obese individuals with pre-diabetes or with a family history of diabetes or cardiovascular disease (CVD) are at high risk for developing type 2 diabetes (T2D) and CVD. Current prevention and treatment of obesity and T2D include energy restricted diets and increased levels of physical activity; however, adequate adherence to such strategies is difficult, and maintenance is challenging for most individuals, which stresses the need for feasible and sustainable interventions. Circadian rhythms of behaviour and metabolism are closely related to the daily light/dark cycle and sleep-wake patterns and timing of food intake and fasting periods may affect the circadian rhythms of metabolic organs. In an evolutionary perspective, the pattern of food consumption has been characterised by periods of caloric intake when food was available and subsequent periods of fasting 9. This cyclic pattern leads to cycles of absorption and storage of energy and utilisation of the energy for e.g. tissue repair, stress resistance and vitality where expression of metabolic regulators coordinates with cellular processes, leading to efficient metabolism 10. Factors including the 24-hour availability of energy-dense foods, busy time schedules, different eating and sleep patterns during weekdays and weekends (i.e. 'social jetlag') challenge the feeding-fasting paradigm. Recent data suggest that an erratic diurnal eating pattern characterised by food intake largely spread throughout hours awake (≥15 h) and a concomitant short fasting period is highly prevalent in humans and animal suggest that circadian misalignment of food intake is associated with adverse metabolic effects. A number of animal studies and a few small studies in humans have reported promising effects of time-restricted eating (TRE), without concomitant dietary restrictions, on body weight and other cardiometabolic risk factors. There is a lack of randomized controlled trials investigating effect of TRE in individuals at high risk of type 2 diabetes and cardiovascular diseases. The aim of the present study is to investigate effects of 12 weeks TRE on behaviour and metabolism in individuals with overweight or obesity at high risk of type 2 diabetes. Maintenance will be assessed at a follow-up visit 13 weeks after completion of the trial (26 weeks). Testing will be conducted at baseline and after 6, 12, and 26 weeks. Participants are instructed to follow randomization during one week assessment periods after testing at 6 and 12 weeks. Therefore, the total duration of the intervention is 13 weeks.

Control group for 13 weeks (n=50). Participants will receive advice about a healthy lifestyle according to the national dietary recommendations from the Danish Health Authority.

Time-restricted eating for 13 weeks (n=50). In addition to the intervention, participants will receive advice about a healthy lifestyle according to the national dietary recommendations from the Danish Health Authority.

Participants will be instructed to eat within a self-selected 10-hour timeframe between 6AM and 8PM every day. All food/beverages except water must be consumed within the time-interval. Staff will help participants select a time-interval that fits into their daily life and optimally fulfil the following guiding principles: The first food item/beverage of the day should optimally be ingested at least 2 hours after usual wake-up time The last food item/beverage of the day should optimally be ingested at least 3 hours before usual bed time Diet is ad libitum and with no further dietary restrictions. Participants will receive advice about a healthy lifestyle according to the national dietary recommendations from the Danish Health Authority.

Measured under resting and fasting conditions during measurements of blood pressure and in the supine position by a handheld ECG measuring device (Vagus™)

Fasting and postprandial (after a standard mixed breakfast meal) concentrations of metabolites including but not limited to: glucose, lipids, cholesterol, free-fatty acids, and amino acids

Changes from baseline. Measured in the blood in the fasted state at all four visits (Baseline and after 6, 12, and 26 weeks) and during a mixed meal test (4 hours) at baseline and end of the intervention (after 12 weeks)

Fasting and postprandial (after a standard mixed breakfast meal) concentrations of hormones related to regulation of appetite, glucose and lipid metabolism (including but not limited to: insulin, glucagon, ghrelin, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and peptide YY (PYY), leptin, fibroblast growth factor 19 (FGF-19), fibroblast growth factor 21 (FGF-21), growth differentiation factor 15 (GDF-15)).

Changes from baseline. Measured in the blood in the fasted state at all four visits (Baseline and after 6, 12, and 26 weeks) and during a mixed meal test (4 hours) at baseline and end of the intervention (after 12 weeks)

Fasting levels of circulating proteins that associate with low-grade inflammation and lipid metabolism. Such proteins are captured by mass-spectrometry driven analyses of the plasma proteome i.e. proteins circulating in the blood

Changes from baseline. Fasted state at all four visits (Baseline and after 6, 12, and 26 weeks) and during a mixed meal test at baseline and end of the intervention (after 12 weeks)

Measured using the SmartPill™ technique. The SmartPill™ is ingested together with a standard mixed breakfast meal

Changes from baseline. Time after consumption of the standard mixed meal at baseline and end of the intervention (after 12 weeks).

Measured using the SmartPill™ technique. The SmartPill™ is ingested together with a standard mixed breakfast meal

Changes from baseline. Time after consumption of the standard mixed meal at baseline and end of the intervention (after 12 weeks).

Measured using the SmartPill™ technique. The SmartPill™ is ingested together with a standard mixed breakfast meal

Changes from baseline. Time after consumption of the standard mixed meal at baseline and end of the intervention (after 12 weeks).

Measured using the SmartPill™ technique. The SmartPill™ is ingested together with a standard mixed breakfast meal

Changes from baseline. Time after consumption of the standard mixed meal at baseline and end of the intervention (after 12 weeks).

Calculated based on amplitudes and number of contractions measured using the SmartPill™ technique. The SmartPill™ is ingested together with a standard mixed breakfast meal

Changes from baseline. Time after consumption of the standard mixed meal at baseline and end of the intervention (after 12 weeks).

Eye tracking metrics including gaze duration bias, gaze direction bias, fixations, saccades, pupil size/dilation, distance to screen, ocular vergence and blinks to measure attention in response to looking at food pictures during the computerized Leeds Food Preference Questionnaire

Changes from baseline. Fasted state at all four visits (Baseline and after 6, 12, and 26 weeks) and during a mixed meal test at baseline and end of the intervention (after 12 weeks)

Facial expression analyses using computer-vision algorithms (AFFDEX) to measure emotions in response to looking at food pictures during the computerized Leeds Food Preference Questionnaire

Changes from baseline. Fasted state at all four visits (baseline and after 6, 12, and 26 weeks) and during a mixed meal test at baseline and end of the intervention (after 12 weeks)

Changes in conductivity of the skin (galvanic skin response) in response to looking at food pictures during the computerized Leeds Food Preference Questionnaire

Changes from baseline. Fasted state at all four visits (Baseline and after 6, 12, and 26 weeks) and during a mixed meal test at baseline and end of the intervention (after 12 weeks)

Food choice of food items from four combined food categories (high-fat savoury, high-fat sweet, low-fat savoury and low-fat sweet foods) examined from the computerized Leeds Food Preference Questionnaire. Food choice is determined based on frequency of selection made within each food category. The scores range from 0-48 i.e. 0 = foods within a specific food category have not been selected at all to 48 = foods within a specific food category have been selected 48 times

Changes from baseline. Fasted state at all four visits (Baseline and after 6, 12, and 26 weeks) and during a mixed meal test at baseline and end of the intervention (after 12 weeks)

Implicit wanting of food items from four combined food categories (high-fat savoury, high-fat sweet, low-fat savoury and low-fat sweet foods) examined from the computerized Leeds Food Preference Questionnaire. Implicit wanting is assessed based on food choice and response time for selected and non-selected food items as well as mean response time.

Changes from baseline. Fasted state at all four visits (Baseline and after 6, 12, and 26 weeks) and during a mixed meal test at baseline and end of the intervention (after 12 weeks)

Explicit liking of 16 food items from four combined food categories (high-fat savoury, high-fat sweet, low-fat savoury and low-fat sweet foods) examined from the computerized Leeds Food Preference Questionnaire. Explicit liking is rated using visual analogue scales and the range is 0-100. Each end represents the extremes e.g. Question: "how pleasant would it be to taste this food right now?" Answer: "not at all" (rated 0 on the 0-100 scale) to "extremely" (rated 100 on the 0-100 scale)

Changes from baseline. Fasted state at all four visits (Baseline and after 6, 12, and 26 weeks) and during a mixed meal test at baseline and end of the intervention (after 12 weeks)

Explicit wanting of 16 food items from four combined food categories (high-fat savoury, high-fat sweet, low-fat savoury and low-fat sweet foods) examined from the computerized Leeds Food Preference Questionnaire. Explicit wanting is rated using visual analogue scales and the range is 0-100. Each end represents the extremes e.g. Question: "how much do you want some of this food now?" Answer: "not at all" (rated 0 on the 0-100 scale) to "extremely" (rated 100 on the 0-100 scale).

Changes from baseline. Fasted state at all four visits (Baseline and after 6, 12, and 26 weeks) and during a mixed meal test at baseline and end of the intervention (after 12 weeks)

Rated using visual analogue scales and includes sensations of: Hunger, fullness, satiety, prospective food consumption, wellbeing, nausea, thirst, desire to eat meat, salty, and sweet. The scale range is 0-100 and each end represent the extremes e.g. hunger rating: "I am not hungry at all" to "I have nerver been this hungry before".

Changes from baseline. Fasted state at all four visits (Baseline and after 6, 12, and 26 weeks) and during a mixed meal test at baseline and end of the intervention (after 12 weeks)

Daily time spent above different glucose concentrations (e.g. >6.1 mmol/L, >7.0 mmol/L, >7.8 mmol/L, and >11.1 mmol/L)

Sedentary time, light, moderate and vigorous intensity physical activity. Assessed from 24 h/day accelerometry

Including bedtime, sleep onset, wake-up, time out of bed, sleep midpoint. Assessed from sleep logs and 24 h/day accelerometry

Changes from baseline. Registered and measured for 7 days after the test days at baseline and after 6 and 12 weeks

Changes from baseline. Registered and measured for 7 days after the test days at baseline and after 6 and 12 weeks

Variability in bedtime, wake-up, sleep duration and sleep midpoint. Assessed from sleep logs and 24 h/day accelerometry

Changes from baseline. Registered and measured for 7 days after the test days at baseline and after 6 and 12 weeks

Changes from baseline. Registered and measured for 7 days after the test days at baseline and after 6 and 12 weeks

Assessed from the questionnaires the Gastrointestinal Symptom Rating Scale (GSRS). Rated on 7-point likert scales. Range: 1 = absence of symptoms to 7 = very severe symptoms.

Assessed from the Gastrointestinal Symptom Score (PAGI-SYM). Rated on 6-point likert scales. Range: 1 = absence of symptoms to 6 = very severe symptoms.

Determined from stool samples. Bacterial DNA and RNA will be purified from the stool samples and changes in the microbiome composition and function will be estimated based on sequencing of the microbiomes' DNA and RNA. Includes but is not limited to the Firmicute/Bacteroidete ratio.

Themes and aspects related to motivation for participation will be assessed based on interviews with the participants including completers and potential drop-outs.

Visits at baseline and after 12 and 26 weeks. Potential drop-outs will be interviewed at the specific time point.

Themes and aspects related to feasibility of the intervention will be assessed based on interviews with the participants including completers and potential drop-outs.

Visits at baseline and after 12 and 26 weeks. Potential drop-outs will be interviewed at the specific time point.

Themes and aspects related to satisfaction with the intervention will be assessed based on interviews with the participants including completers and potential drop-outs.

Visits at baseline and after 12 and 26 weeks. Potential drop-outs will be interviewed at the specific time point.

Inclusion Criteria: BMI ≥30 kg/m2 or BMI ≥25 kg/m2 in combination with pre-diabetes (HbA1c ≥39-<48 mmol/mol) Habitual eating/drinking window ≥12 hours (including foods/snacks and energy containing beverages e.g. soft drinks (except of water)) and an eating/drinking window of ≥14 hours minimum one day per week Exclusion criteria Daily smoking For women: pregnancy, planned pregnancy (within the study period) or lactating Frequent travels over time zones (max one return trip/travel over times zones (˃one hour time difference) during the 13 weeks intervention). Shift work or partner engaged in shift work (if it affects the person's sleep and eating pattern) Unable to understand the informed consent and the study procedures Self-reported history of an eating disorder during the past three years Self-reported weight change (>5 kg) within three months prior to inclusion Diabetes HbA1c ≥48 mmol/mol Uncontrolled medical issues including but not limited to cardiovascular pulmonary, rheumatologic, hematologic, oncologic, infectious, gastrointestinal or psychiatric disease; diabetes or other endocrine disease; immunosuppression Current treatment with medication or medical devices which significantly affect glucose metabolism, appetite, or energy balance Current treatment with antidepressants Bariatric surgery Implanted or portable electro-mechanical medical device such as a cardiac pacemaker, defibrillator or infusion pump Celiac disease, Crohn's disease, ulcerative colitis or proctitis Alcohol/drug abuse or in treatment with disulfiram at time of inclusion Concomitant participation in other intervention studies Not able to eat ≥85% of the test meal because of e.g. allergy Specific exclusion criteria for participants receiving SmartPillTM (n=60) Gastrointestinal symptoms or diseases such as regular (weekly) abdominal pain, dysphagia, gastric bezoars, strictures, fistulas, bowel obstructions or diverticulitis Current treatment with medication or medical devices which significantly affect gastrointestinal motility or transit time (prokinetics, antidiarrheals, laxatives, or opioids) Gastrointestinal surgery within 3 months before inclusion

Quist JS, Jensen MM, Clemmensen KKB, Pedersen H, Bjerre N, Storling J, Blond MB, Wewer Albrechtsen NJ, Holst JJ, Torekov SS, Vistisen D, Jorgensen ME, Panda S, Brock C, Finlayson G, Faerch K. Protocol for a single-centre, parallel-group, randomised, controlled, superiority trial on the effects of time-restricted eating on body weight, behaviour and metabolism in individuals at high risk of type 2 diabetes: the REStricted Eating Time (RESET) study. BMJ Open. 2020 Aug 26;10(8):e037166. doi: 10.1136/bmjopen-2020-037166.