Calories or Time Restriction to Alter Biomarkers of Aging and Diabetes

Study Overview
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Brief Summary
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Type 2 diabetes and cardiovascular disease are an increasing problem in Australia and around the world, and are partly linked to increased rates of obesity, together with sedentary lifestyles. This study will compare caloric restriction (CR) diets that restrict the amount of food that is eaten with CR diets that also restrict the time that the food is eaten, to either early or late in the day, on risk factors for type 2 diabetes and cardiovascular diseases over 2 months.

Detailed Description
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In a parallel groups design, a total of 114 individuals will be recruited. After a two-week lead in and collection of data from activity monitors and continuous glucose monitors, plus a 28 hour (h) metabolic ward in-patient stay, participants will be randomised into one of three groups (eCR, 8-hour early time restriction + calorie restriction (e.g. 8:00-16:00); dCR, 8-hour delayed time restriction + calorie restriction (e.g. 12:00-20:00); CR, caloric restriction (>12 hour eating window (e.g. 8:00-20:00). All participants will receive individualised menus and foods that will be delivered to their homes by a supermarket delivery service at energy balance for 1 week (baseline) and at 70% of energy balance for a further 8 weeks. Repeat assessment occurs from 6-8 weeks with the final metabolic ward stay at 8-weeks to assess changes in primary and secondary outcomes.

Official Title
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The Effects of Caloric Restriction Plus Time Restriction on Glycemia, Circadian Rhythms and Cardiometabolic Health

Conditions
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Obesity

Intervention / Treatment
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* Other: eCR
* Other: dCR
* Other: CR


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Overweight or obesity (BMI 25.1 - 44.9 kg/m2) Elevated waist circumference (race specific), Elevated fasting blood glucose (>5.6 mmol/L). Exclusion Criteria: A personal history/diagnosis (self-reported) of: diabetes (type 1 or 2) major psychiatric disorders (schizophrenia, major depressive disorder, bipolar disorder, eating disorders) gastrointestinal disorders/disease (including malabsorption) haematological disorders (i.e. thalassemia, iron-deficiency anaemia) insomnia obstructive sleep apnea night eating syndrome diagnosis or treatment of cancer in the past 3 years (excluding non-melanoma skin cancer) significant liver or kidney diseases that require ongoing medical care previous or planned gastro-intestinal surgery (including bariatric surgery) Congestive heart failure (NYHA stage 2 or above) Previous myocardial infarction or significant cardiac event ≤ 6 months prior to screening Previous cerebrovascular event ≤ 12 months prior to screening Any autoimmune disease (i.e. rheumatoid arthritis) Coeliac disease Score less than 12 of the Australian Diabetes (AUSD) risk assessment tool Do not eat for a 12 hour window each day for 5 or more days per week Have extreme or restricted patterns of eating (i.e. following an intermittent fasting diet) or already engage in CR Other dietary restrictions including vegans, gluten or nut allergies Night shift-workers (>3 shifts per month) pregnant, planning a pregnancy or currently breastfeeding those who have lost or gained >5% of body weight in the last 6 months donated blood in past 3 months current smokers of cigarettes/marijuana/e-cigarettes/vaporisers anyone unable to comprehend the study protocol or provide informed consent (i.e. due to English language or cognitive difficulties) do not own, or are not comfortable using, a smart phone and applications Currently taking the following medications: Anti-diabetic medications that lower blood glucose including, but not limited to: SGLT2 inhibitors, metformin, sulfonylureas, glucagon-like peptide-1 (GLP-1) analogues [i.e. semaglutide], thiazolidinediones affecting weight, appetite or gut motility, including, but not limited to semaglutide, domperidone, cisapride, orlistat, phentermine, topiramate. Diuretics (i.e. frusemide, thiazides) or combination blood pressure medications containing a diuretic Beta-blockers Glucocorticoids Anti-epileptic medications (i.e. pregabalin and gabapentin) Tricyclic antidepressants Some serotonin and norepinephrine reuptake inhibitors (i.e. vortioxetine, mirtazapine and venlafaxine) Regular use of benzodiazepines or other sleep aids, including melatonin Antipsychotic medications Opioid medications unless combined with paracetamol in a single formulation and used occasionally on as needs basis

Ages Eligible for Study
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Minimum Age: 35 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The OMIT study will be a parallel, single-blinded, 3-arm randomised controlled trial.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: early calorie restriction (eCR)<br>Individuals will be provided with menus prescribed at 70% of calculated energy requirements and instructed to eat within 8 h/day (e.g. 8:00 - 16:00) every day for 8 weeks, except 1 evening meal per week off the program (i.e. Saturday nights) to assist with overall adherence. | Other: eCR<br>* Eating time window from 8:00 to 16:00<br>|
| Experimental: delayed calorie restriction (dCR)<br>Individuals will be provided with menus prescribed at 70% of calculated energy requirements and instructed to eat within 8 h/day (e.g 12:00 - 20:00) every day for 8 weeks, except 1 evening meal per week off the program (i.e. Saturday nights) to assist with overall adherence. | Other: dCR<br>* Eating time window from 12:00 to 20:00<br>|
| Active Comparator: Calorie restriction (CR)<br>Individuals will be provided with menus prescribed at 70% of calculated energy requirements every day for 8 weeks. The menus will encourage breakfast and after-dinner consumption of the snack to eat over at least a 12 hour time frame per day (e.g. 8:00 - 20:00), except 1 evening meal per week off the program (i.e. Saturday nights) to assist with overall adherence. | Other: CR<br>* Eating time window from 8:00 to 20:00<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Glucose area under curve (AUC) after 3 meals | Change in glucose AUC after 3 meals | 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 24 h glucose on ward (by continuous glucose monitor (CGM) | Change in 24 h glucose on ward by CGM | 8 weeks | 
| Insulin AUCs | Change in insulin AUC after 3 meals | 8 weeks | 
| Insulin sensitivity (calculated by Matsuda index where a higher score means greater insulin sensitivity) | Change in insulin sensitivity | 8 weeks | 
| Fasting glucose | Change in fasting glucose | 8 weeks | 
| Fasting insulin | Change in fasting insulin | 8 weeks | 
| C-reactive protein (CRP) | Change in hs-CRP | 8 weeks | 
| Body weight | Change in body weight | 8 weeks | 
| Physical activity by activity monitor | Change in step count | 8 weeks | 
| Adherence to the prescribed eating window (+/- 1 hour) by smart phone application | Adherence to the prescribed eating window(+/- 1 hour) by smart phone application | 8 weeks | 
| Change in fat mass | Change in fat mass by bio-electrical impedance analysis | 8 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dietary intervention, Inflammation, Circadian rhythms, Cardiometabolic health