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

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

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.

Study Overview

• Status: Completed
• Conditions: Individuals at Risk of Developing Diabetes
• Intervention / Treatment: Other: Intermittent Fasting (IF); Other: Daily Restriction (DR); Other: standard care (SC)

• Study Type: Interventional
• Enrollment (Actual): 209
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Australia
  • South Australia
    • Adelaide, South Australia, Australia
      • University of Adelaide

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 35 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intermittent Fasting (IF); 3 days fasting per week	Other: Intermittent Fasting (IF); 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.
Experimental: Daily Restriction (DR); daily energy restriction	Other: Daily Restriction (DR); 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.
Other: standard care (SC); usual care	Other: standard care (SC); Participants will receive current practice guidelines in a static information format, will not take part in any counselling or receive meal replacements.

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in perceived hunger and fullness assessed by visual analogue scales (VAS)	Change in subjective hunger and fullness ratings measured by 0-100 mm VAS scales	6 months, 18 months
Change in perceived sleep quality	Change in perceived sleep quality assessed by Pittsburgh Sleep Quality Index (PSQI), with a range from 0-21 scores, higher score reflect poorer sleep quality	2 months, 6 months, 18 months
Change in perceived eating behaviour	Change in perceived eating behaviour assessed by Three Factor Eating Questionnaire (TFEQ), which consists of 51 items to assess dietary restraint (21 items), disinhibition (16 items) and hunger (14 items), higher scores reflect higher levels on each subscale	2 months, 6 months, 18 months
Change in perceived quality of life	Change in perceived quality of life assessed by 36-item Short Form (SF-36) health survey, with a range from 0-100 scores, higher scores reflect better quality of life	2 months, 6 months, 18 months
Change in perceived well-being	Change in perceived well-being assessed by Personal Well-being Index, with a range from 0-10 scores, higher scores reflect greater satisfication	2 months, 6 months, 18 months
Change in food addition score	Change in self-reported food addiction assessed by Yale Food Addiction Score (YFAS), with a range from 0-7 scores, higher scores reflect greater food addiction symptoms	6 months, 18 months
Change in psychological distress	Change in self-reported psychological distress assessed by Kessler Psychological Distress Scale (K10) , with a range from 10-50 scores, higher scores reflect higher psychological distress	6 months, 18 months
Change in self-reported depression, anxiety and stress level	Change in self-reported depression, anxiety and stress level assessed by Depression, Anxiety and Stress Scale (DASS), with a range from 0-42 scores on each subscale, higher scores reflect higher levels on each subscale	2 months, 6 months, 18 months
Change in self-reported mood	Change in self-reported mood assessed by Positive and Negative Affect Schedule (PANAS), with a range from 0-100 scores, higher scores reflect more positive mood and negative mood.	2 months, 6 months, 18 months
Change in glucagon-like peptide 1 (GLP-1)	Change in glucagon-like peptide 1 (GLP-1)	6 months
Change in peptide YY	Change in peptide YY	6 months
Change in ghrelin	Change in ghrelin	6 months
Change in gastric inhibitory polypeptide (GIP)	Change in gastric inhibitory polypeptide (GIP)	6 months
Change in estradiol	Change in estradiol	6 months
Change in testosterone	Change in testosterone	6 months
Change in glucose (DIRECT- Fast4Switch)	Change in glucose levels	6 months
Change in non-esterified fatty acids (DIRECT- Fast4Switch)	Change in non-esterified fatty acids levels (NEFA)	6 months
Change in insulin (DIRECT- Fast4Switch)	Change in insulin levels	6 months
Change in triglycerides (DIRECT- Fast4Switch)	Change in triglycerides levels	6 months
24 hours glycaemia (DIRECT-Fast424hGlucose)	Changes in 24 hours glycaemia assessed by continuous glucose monitor	6 months
Salivary cortisol (DIRECT-Fast4Stress)	Change in salivary cortisol	6 months
Gene expression (DIRECT- Fast4Stress)	Change in gene expression	6 months
Change in urinary adrenaline (DIRECT- Fast4Stress)	Change in urinary adrenaline	6 months
Change in urinary noradrenaline (DIRECT- Fast4Stress)	Change in urinary noradrenaline	6 months
Qualitative analysis (DIRECT-Experience2Fast)	Patterns of participant's behaviour, characteristics and motivation that assist in or hinder from weight loss achievement by semi-structured interviews	8 months
Change in autophagic flux (DIRECT-Fast4flux)	Change in autophagic machinery protein LC3B-II in peripheral blood mononuclear cells following treatment of whole blood.	2 months, 6 months

Collaborators and Investigators

• Sponsor: University of Adelaide
• Investigators: Principal Investigator: Leonie Heilbronn, PhD, The University of Adelaide

Publications and helpful links

General Publications

• Teong XT, Liu K, Hutchison AT, Liu B, Feinle-Bisset C, Wittert GA, Lange K, Vincent AD, Heilbronn LK. Rationale and protocol for a randomized controlled trial comparing daily calorie restriction versus intermittent fasting to improve glycaemia in individuals at increased risk of developing type 2 diabetes. Obes Res Clin Pract. 2020 Mar-Apr;14(2):176-183. doi: 10.1016/j.orcp.2020.01.005. Epub 2020 Feb 11.

Study record dates

Study Major Dates

• Study Start (Actual): September 26, 2018
• Primary Completion (Actual): November 30, 2020
• Study Completion (Actual): November 30, 2021

Study Registration Dates

• First Submitted: September 26, 2018
• First Submitted That Met QC Criteria: September 27, 2018
• First Posted (Actual): September 28, 2018

Study Record Updates

• Last Update Posted (Actual): January 11, 2022
• Last Update Submitted That Met QC Criteria: December 20, 2021
• Last Verified: December 1, 2021

More Information

Terms related to this study

• Keywords: intermittent fasting; calorie restriction; overweight and obesity
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus
• Other Study ID Numbers: R20180319

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No