Daily vs Intermittent Restriction of Energy: Controlled Trial to Reduce Diabetes Risk (DIRECT)

Study Overview
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Brief Summary
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In this randomized controlled trial, the investigators will compare the long term effectiveness of intermittent fasting (IF) versus an energy matched moderate calorie restriction (CR) over 18 months, and relative to a non-active intervention standard control (SC) in individuals who are at increased risk of developing type 2 diabetes. All participants will be required to attend the blood tests following a 12-hour overnight fast for the A visit at Month 0, 2, 6 (active) and 18 (follow up). Fast424hGlucose: A subset of 100 participants enrolled in either IF or CR group in the parent study will be fitted with a continuous glucose monitor (CGM) to measure 24-hour glycaemic profile at month 0 and month 6. Fast4Switch: Additional bloods will be collected after a B visit at month 6 to compare the fed to fasted switch. The B samples will be collected after a 12-hour overnight fast (CR, SC) or 20-hour fast (IF) to assess the metabolic switch to fasting in metabolites and hormones. Fast4Stress: Additional subcutaneous adipose tissue, urine and saliva samples will be collected in  32 men in IF and CR groups at month 0 and 6 at A and B visits to examine changes in stress response and resistance markers. Experience2Fast: In-depth, semi-structured interviews will be carried out at month-8 follow-up visit in a subset of completers from IF or CR groups to explore the experience of intervention diets and understand contributing factors towards change and maintenance of dietary behaviours. Fast4Flux: Additional blood samples will be collected in  100 individuals in SC, IF and CR groups at month 0, month 2 and month 6 at A visit to measure autophagic flux in peripheral blood mononuclear cells following treatment of whole blood.

Official Title
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Daily vs Intermittent Restriction of Energy: Randomised Controlled Trial to Reduce Diabetes Risk (DIRECT)

Conditions
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Individuals at Risk of Developing Diabetes

Intervention / Treatment
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* Other: Intermittent Fasting (IF)
* Other: Daily Restriction (DR)
* Other: standard care (SC)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: weight-stable (< 5 % fluctuation in their body weight for past 6-months at study entry) score 12 or greater on the AUSDRISK calculator HbA1c <48 mmol/mol (measured at screening) Exclusion Criteria: Personal history/diagnosis (self-reported) of diabetes (type 1 or 2), major psychiatric disorders (schizophrenia, major depressive disorder, bipolar disorder, eating disorders), gastrointestinal disorders, haematological disorders (i.e. thalassemia, iron-deficiency anaemia) insomnia, or any other medical condition, deemed unstable by the study physician. Participants currently taking the following medications will be excluded from participating: any medication used to lower blood glucose or antidiabetic medications (metformin, sulfonylureas, Glucagon-like peptide-1 GLP-1 analogues [i.e. exenatide], thiazolidinediones or DPP-IV inhibitors [i.e. 'gliptins']), medications affecting weight, appetite or gut motility (i.e. domperidone, cisapride, orlistat, phentermine, topiramate). Participants who are taking stable doses (i.e. > 12 months) of androgenic medications (i.e. testosterone) or SSRI's will not be excluded. weight change in past 3 months (> 5% screening weight) uncontrolled asthma, current fever, upper respiratory infections individuals who regularly perform high intensity exercise (>2 week) current intake of > 140g alcohol/week current smokers of cigarettes/cigars/marijuana/e-cigarettes/vaporisers current intake of any recreational drugs regular blood donor unable to comprehend study protocol due to English language or cognitive difficulties

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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Accepts Healthy Volunteers

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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intermittent Fasting (IF)<br>3 days fasting per week | Other: Intermittent Fasting (IF)<br>* Participants will fast 3 days per week. In fasting days, meal replacements at 30% of daily energy requirements will be provided for the first 6 months. Participants will have fortnightly nutrition assessment.<br>|
| Experimental: Daily Restriction (DR)<br>daily energy restriction | Other: Daily Restriction (DR)<br>* Participants are instructed to restrict energy intake by 30% of daily energy requirements. Meal replacements will be provided for the first 6 months. Participants will have fortnightly nutrition assessment.<br>|
| Other: standard care (SC)<br>usual care | Other: standard care (SC)<br>* Participants will receive current practice guidelines in a static information format, will not take part in any counselling or receive meal replacements.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Postprandial glucose AUC | Change in postprandial glucose AUC | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HbA1c | Change in HbA1c | 2 months, 6 months, 18 months | 
| Postprandial glucose | Change in postprandial glucose | 18 months | 
| Body weight | Change in body weight in kilograms | 2 months, 6 months, 18 months | 
| Body composition | Change in body fat mass (kg) and fat free mass (kg) | 6 months, 18 months | 
| Waist and hip circumference | Change in waist and hip circumference | 2 months, 6 months, 18 months | 
| Blood lipids | Changes in blood lipid profile (total cholesterol, HDL-, LDL-cholesterol and triglycerides) | 2 months, 6 months, 18 months | 
| Dietary intake | Change in food intake measured by self-reported food diaries | 2 months, 6 months, 18 months | 
| Blood pressure | Change in systolic blood pressure and diastolic blood pressure (mmHg) | 2 months, 6 months, 18 months | 
| Changes in physical Activity assessed by accelerometer | Change in average step counts measured with waist-worn actigraphy monitors | 2 months, 6 months, 18 months | 
| Fasting glucose | Change in fasting glucose | 2 months, 6 months, 18 months | 
| Fasting insulin | Change in fasting insulin | 2 months, 6 months, 18 months | 
| Fasting non-esterified fatty acids (NEFA) | Change in fasting NEFA levels | 2 months, 6 months, 18 months | 
| Fasting triglyceride | Change in fasting triglyceride levels | 2 months, 6 months, 18 months | 
| Postprandial insulin | Change in postprandial insulin | 6 months, 18 months | 
| Postprandial non-esterified fatty acids (NEFA) | Change in postprandial NEFA levels | 6 months, 18 months | 
| Postprandial triglyceride | Change in postprandial triglyceride levels | 6 months, 18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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intermittent fasting, calorie restriction, overweight and obesity