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

Kristine Færch100 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

PREVENTION

Masking

NONE

Enrollment

100

Conditions

Overweight and Obesity PreDiabetes

Interventions

Time-restricted eatingOTHER

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: 1. The first food item/beverage of the day should optimally be ingested at least 2 hours after usual wake-up time 2. 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.

Eligibility

Sex: ALLMin age: 30 YearsMax age: 70 YearsHealthy volunteers:

Medical Language ↔ Plain English

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

Locations (1)

Steno Diabetes Center Copenhagen

Gentofte Municipality, Denmark

Outcomes

Primary Outcomes

Change in body weight (kg)

Measured in fasted state on a digital scale

Time frame: Change from baseline to the end of the intervention (after 12 weeks)

Secondary Outcomes

Body weight (kg)

Measured on a digital scale

Time frame: Changes from baseline. Fasted state at all four visits (Baseline and after 6, 12, and 26 weeks)

Body mass index (kg/m^2)

Calculated from body weight (kg) and height (m)

Time frame: Changes from baseline. Fasted state at all four visits (Baseline and after 6, 12, and 26 weeks)

Fat mass (kg)

Measured by Dual-energy X-ray Absorptiometry

Time frame: Changes from baseline. Fasted state at all four visits (Baseline and after 6, 12, and 26 weeks)

Fat free mass (kg)

Measured by Dual-energy X-ray Absorptiometry

Time frame: Changes from baseline. Fasted state at all four visits (Baseline and after 6, 12, and 26 weeks)

Fat percentage (%)

Measured by Dual-energy X-ray Absorptiometry

Time frame: Changes from baseline. Fasted state at all four visits (Baseline and after 6, 12, and 26 weeks)

Waist circumference (cm)

Measured using tape measure

Time frame: Changes from baseline. Fasted state at all four visits (Baseline and after 6, 12, and 26 weeks)

Hip circumference (cm)

Data from ClinicalTrials.gov

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Measured using tape measure

Time frame: Changes from baseline. Fasted state at all four visits (Baseline and after 6, 12, and 26 weeks)

HbA1c (mmol/mol and %)

Assessed from blood samples at all visits

Time frame: Changes from baseline. All four visits (Baseline and after 6, 12, and 26 weeks)

Systolic blood pressure (mmHg)

Measured under resting and fasting conditions

Time frame: Changes from baseline. Measured at all four visits (Baseline and after 6, 12, and 26 weeks)

Diastolic blood pressure (mmHg)

Measured under resting and fasting conditions

Time frame: Changes from baseline. Measured at all four visits (Baseline and after 6, 12, and 26 weeks)

Heart rate (bpm)

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

Time frame: Changes from baseline. Measured at all four visits (Baseline and after 6, 12, and 26 weeks)

Resting energy expenditure (kcal/day)

Measured by indirect calorimetry under resting and fasting conditions

Time frame: Changes from baseline. Measured at visits at baseline and after 12 weeks

Substrate oxidation (respiratory exchange ratio)

Measured by indirect calorimetry under resting and fasting conditions

Time frame: Changes from baseline. Measured at visits at baseline and after 12 weeks

Metabolites

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

Time frame: 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)

Hormones

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)).

Circulating proteins that associate with low-grade inflammation and lipid metabolism

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

Time frame: Changes from baseline. Fasted state at all four visits (Baseline and after 6, 12, and 26 weeks)

Respiratory and glycolytic capacities of isolated peripheral blood mononuclear cells (PBMCs)

Measured using the Seahorse method, which measures mitochondrial respiration

Time frame: 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)

Heart rate response to standing up from the supine position

Measured by a handheld ECG measuring device (Vagus™).

Time frame: Changes from baseline. Measured at visits at baseline and end of the intervention (after 12 weeks)

Heart rate response to inhalation and exhalation

Measured by a handheld ECG measuring device (Vagus™).

Time frame: Changes from baseline. Measured at visits at baseline and end of the intervention (after 12 weeks)

Heart rate response to forced exhalation during rest (valsalva maneuver)

Measured by a handheld ECG measuring device (Vagus™).

Time frame: Changes from baseline. Measured at visits at baseline and end of the intervention (after 12 weeks)

Gastric emptying time (hours and minutes)

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

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

Small bowel transit time (hours and minutes)

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

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

Large bowel transit time (hours and minutes)

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

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

Total gastrointestinal transit time (hours and minutes)

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

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

Motility index

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

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

Attention measured using eye tracking

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

Time frame: 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)

Emotions measured using facial expression analyses

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

Time frame: 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)

Arousal measured using galvanic skin response

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

Time frame: 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

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

Time frame: 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

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.

Time frame: 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

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)

Time frame: 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

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).

Time frame: 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)

Insulin sensitivity (indices)

Including but not limited to the Matsuda index

Time frame: At all four visits (Baseline and after 6, 12, and 26 weeks)

Insulin resistance (indices)

Including but not limited to Homeostaic Model Assessment for Insulin Resistance (HOMA-IR)

Time frame: At all four visits (Baseline and after 6, 12, and 26 weeks)

Subjective appetite

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".

Time frame: 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)

Mean amplitude of glycaemic excursions (MAGE)

Measured using continous glucose monitoring

Time frame: Changes from baseline. Measured 7 days after the test days at baseline and after 6 and 12 weeks

Continuous overall net glycaemic action (CONGA)

Measured using continous glucose monitoring

Time frame: Changes from baseline. Measured 7 days after the test days at baseline and after 6 and 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)

Measured using continous glucose monitoring.

Time frame: Changes from baseline. Measured 7 days after the test days at baseline and after 6 and 12 weeks

Mean glucose concentrations

Measured using continous glucose monitoring.

Time frame: Changes from baseline. Measured 7 days after the test days at baseline and after 6 and 12 weeks

Standard deviation of glucose concentrations

Measured using continous glucose monitoring.

Time frame: Changes from baseline. Measured 7 days after the test days at baseline and after 6 and 12 weeks

Variation coefficients of glucose concentrations

Measured using continous glucose monitoring.

Time frame: Changes from baseline. Measured 7 days after the test days at baseline and after 6 and 12 weeks

Physical activity (time spent at different intensities)

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

Time frame: Changes from baseline. Measured 7 days after the test days at baseline and after 6 and 12 weeks

Physical activity (counts/min)

Assessed from 24 h/day accelerometry

Time frame: Changes from baseline. Measured 7 days after the test days at baseline and after 6 and 12 weeks

Physical activity energy expenditure (kcal/day)

Assessed from 24 h/day accelerometry

Time frame: Changes from baseline. Measured 7 days after the test days at baseline and after 6 and 12 weeks

Physical activity (MET hours)

Assessed from 24 h/day accelerometry

Time frame: Changes from baseline. Measured 7 days after the test days at baseline and after 6 and 12 weeks

Timing of physical activity (hh:mm)

Assessed from activity logs and 24 h/day accelerometry

Time frame: Changes from baseline. Measured 7 days after the test days at baseline and after 6 and 12 weeks

Energy intake (kcal/day)

Assessed from diet records

Time frame: Changes from baseline. Registered 3 days after the test days at baseline and after 6 and 12 weeks

Macronutrient intake (energy percentage)

Assessed from diet records

Time frame: Changes from baseline. Registered 3 days after the test days at baseline and after 6 and 12 weeks

Timing of dietary intake (hh:mm)

Assessed from diet records

Time frame: Changes from baseline. Registered 3 days after the test days at baseline and after 6 and 12 weeks

Sleep timing (hh:mm)

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

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

Sleep duration (min)

Assessed from sleep logs and 24 h/day accelerometry

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

Sleep variability (min)

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

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

Sleep onset latency (min)

Assessed from sleep logs and 24 h/day accelerometry

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

Sleep efficiency (%)

Assessed from 24 h/day accelerometry

Time frame: Changes from baseline. Measured for 7 days after the test days at baseline and after 6 and 12 weeks

Wakefulness (min)

Assessed from 24 h/day accelerometry

Time frame: Changes from baseline. Measured for 7 days after the test days at baseline and after 6 and 12 weeks

Self-reported gastrointestinal symptoms (part 1)

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.