ANZCTR - Registration

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Trial registered on ANZCTR

Registration number

ACTRN12616001172493

Ethics application status

Approved

Date submitted

22/08/2016

Date registered

26/08/2016

Date last updated

3/03/2017

Type of registration

Prospectively registered

Titles & IDs

Public title

The effect of exercise timing on blood glucose control in individuals with Type 2 diabetes mellitus

Scientific title

Exercise and glycaemic control: A randomised controlled trial examining the role of exercise timing in individuals with Type 2 diabetes mellitus

Secondary ID [1]

Nil

Universal Trial Number (UTN)

U1111-1186-7232

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Type 2 Diabetes Mellitus

Condition category

Condition code

Metabolic and Endocrine

Diabetes

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Study Design:
Potential participants will initially be screened by the study coordinator. Participants will then be invited to attend the Exercise Physiology Clinic at Murdoch University for the collection of preliminary measurements and baseline data following attainment of written informed consent. Thereafter, participants from both the T2DM group and Control Group (Healthy but overweight individuals with no T2DM) will be randomly allocated into one of the two intervention training groups (pmEX and amEX) to begin their 12-week exercise training intervention. Mid-intervention assessments will occur during Week 6 to assess: (i) glycemic control and; (ii) aerobic fitness. At least 24 hours after the last training session in week 12, but no more than 96 hours after the last training session, participants will then complete their final assessment of glycaemic control and aerobic fitness.

Procedures:
Participants will continue their medications at the usual dose, frequency and time while participating in this study. Baseline testing will include body anthropometrics (DEXA, height, weight, waist circumference), aerobic fitness assessment (VO2 peak test; modified Bruce treadmill test protocol), diet history, appetite questionnaires, 14-day sleep and physical activity monitoring (Actigraph and diar), 24 h skin temperature (ibutton, data logger), and validated mood chart. Additionally, participants will attend the laboratory (study day) for assessment of PPG and glucose-regulatory hormonal responses as well as assessment of autonomic function. The study day will involve assessment of two distinct postprandial responses (mixed-meal tolerance tests) comprising the first and second meal of the day (second meal phenomenon; the glucose response to the second meal should be less than the first meal). Measures of glycaemic control (HbA1c; 1,5-anhydroglucitol [1,5-AG]) will be collected from the baseline sample into separate EDTA tubes.

Following the baseline assessments, participants will be randomly assigned into their respective intervention groups (amEX and pmEX) for both the T2DM and Healthy Control groups. Randomisation and allocation will be performed on unique study I.D.'s by an independent investigator using randomly permutated blocks (http://www.randomisation.com) with males and females counterbalanced across groups. This list will be then be forwarded back to the study researcher. Participants from both intervention groups will undertake three supervised 55-65 min exercise-training sessions per week (165-190 min supervised per week) for a total of 12 weeks. The exercise training sessions will be performed in groups of 3-5 individuals at Murdoch University Strength and Conditioning gym under the supervision of a trained exercise physiologist. The testing battery for the baseline (pre-) and post-intervention assessments will be identical. The mid-intervention assessment will include 1,5-AG, fasting glucose and VO2 peak test only .

The supervised exercise intervention will consist of a progressive resistance (2-3 sets x 10/12 repetitions; 4 exercises targeting upper- and lower-body performed in a circuit style) and brisk walking (at 65% VO2 peak for 35-45 min). The intensity and volume of both the aerobic and resistance exercises are prescribed in accordance to the American Heart Association scientific statement. The exact exercises and repetitions performed for the resistance exercises will be determined by the supervising exercise physiologist at every training session depending on the participant's fitness levels. Additionally, for the resistance exercises, once the participants are able to complete 12 repetitions for each set of exercises on 2 consecutive exercise sessions (2-by-2 rule), the prescribed intensity of each execise will increase. This process will be overseen by the exercise physiologist during the training sessions. The amEX (0500-1000) will be performed 30-120 min after "breakfast" (food consumption of >200 Cal), while the evening exercise will be performed 30-120 min after the last meal of the day. Participants in the pmEX group will be asked to refrain from consuming food after the evening exercise session. The training workload (volume and intensity) will be monitored closely by the exercise physiologist at every session. All exercise sessions will be recorded in a logbook with attendance taken as well as sessional RPE for each individual training session over the 12-week period. An interviewer-administered 24 h recall will be captured on five separate occasions beyond the diet history assessment to assess diet-related changes (which may be added to the model as a covariate).

Blood analysis:
A total of 15 blood samples (3ml) will be collected during the study-days. A portion of whole blood (200 micro-litres) will be analysed immediately using a clinical benchtop analyser (GEM3500) for metabolites (glucose, lactate, haematocrit). The remaining blood will be transferred into EDTA-coated tubes pre-treated with 30 micro-litres of dipeptidyl peptidase IV inhibitor and aprotinin (Millipore) for later determination of plasma hormone concentrations of insulin, C-peptide, glucagon, GLP-1, and gastric inhibitory polypeptide (GIP) using a MILLIPLEX magnetic bead–based quantitative multiplex immunoassay with the MAGPIX instrumentation (Millipore). Our group has previously published using these techniques and all facilities are available. Baseline samples from each study day will also be assessed for HbA1c (Clinipath Laboratories) and 1,5-AG (Glycomark).

Intervention code [1]

Treatment: Other

Comparator / control treatment

Healthy individuals without type 2 diabetes mellitus but are overweight (BMI of more than or equal to 27) will be recruited into the control group in the study. Participants from the control group will undergo the same procedures as the T2DM group (i.e. baseline assessments, random allocation in to amEX or pmEX intervention groups and post-intervention assessments).

Control group

Active

Outcomes

Primary outcome [1]

To determine the impact of exercise-timing (morning versus evening) on glycaemic control in individuals enrolled into a 12-week evidence-based multi-modal exercise training program. The measure of glycaemic control will be done through the analysis of HbA1c (glycosylated haemoglobin) levels (%). All blood samples will be sent to an external provider (Clinipath Laboratories) to be assessed.

Timepoint [1]

Prior to the start of the 12-week training intervention during baseline assessment (study day) and at least 24 hours after the last training session in week 12, but no more than 96 hours after the last training session (post-intervention study day)

Secondary outcome [1]

To determine the impact of exercise-timing (morning versus evening) on diurnal glycaemia in individuals enrolled into a 12-week evidence-based multi-modal exercise training program. Diurnal glycaemia will be assessed during baseline and post-intervention assessment (Study Day) through plasma serum using glucose assay kits.

Timepoint [1]

Eligibility

Key inclusion criteria

T2DM Group:
Non-smoking, sedentary (defined as the accrual of less than 150 min of exercise per week) individuals who are overweight (body mass index more than or equal to 27 kg/m2) and have an existing diagnosis of T2DM.

Healthy Control Group:
Non-smoking, sedentary (defined as the accrual of less than 150 min of exercise per week) individuals who are overweight (body mass index more than or equal to 27 kg/m2)

Minimum age

18 Years

Maximum age

65 Years

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

Participants will not be eligible if: (i) they are unable to complete exercise or have a condition which is known to be aggravated by exercise (assessed using the Exercise and Sports Science Australia pre-exercise screening tool); (ii) they are on insulin; (iii) have had surgery for weight loss; (iv) they had prior history of heart, lung, kidney, endocrine or liver disease; (v) experienced recent weight loss (4 kg or more) in previous month.

Study design

Purpose of the study

Treatment

Allocation to intervention

Randomised controlled trial

Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)

Following the baseline assessments, participants will be randomly assigned into their respective intervention groups (amEX and pmEX). Randomisation and allocation will be performed on unique study I.D.'s by an independent investigator using randomly permutated blocks (http://www.randomisation.com) with males and females counterbalanced across groups. This list will be then be forwarded back to the study researcher.

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Permutated block randomisation

Masking / blinding

Blinded (masking used)

Who is / are masked / blinded?

The people receiving the treatment/s

Intervention assignment

Parallel

Other design features

Phase

Not Applicable

Type of endpoint/s

Efficacy

Statistical methods / analysis

Data will presented as means +/- SD. Treatment effects will be estimated using linear mixed models (LMM) to assess for any changes over time (pre-, mid-, post-exercise intervention) in the primary outcome variables between the two groups (amEX, pmEX). The hypothesis of interest is the group by time interaction (modeled as fixed effects; random intercept) which will be examined with pairwise comparisons of the estimated marginal means. Statistical significance will be set at less than 0.05.

Based on Bidwell et al. (reference below), a sample size of 13 participants per intervention group (T2DM amEX, T2DM, pmEX, healthy control amEX and healthy control pmEX) will provide 80% power to detect a significant difference in HbA1c levels when the alpha -error probability is set at 0.05. We therefore aim to recruit 60 participants (15 per group to allow 20% attrition).

Reference: Bidwell AJ, Fairchild TJ, Redmond J, Wang L, Keslacy S, Kanaley JA. Physical activity offsets the negative effects of a high fructose diet. Medicine and science in sports and exercise 2014.

Recruitment

Recruitment status

Recruiting

Date of first participant enrolment

Anticipated

1/10/2016

Actual

25/10/2016

Date of last participant enrolment

Anticipated

1/08/2017

Actual

Date of last data collection

Anticipated

31/10/2017

Actual

Sample size

Target

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

Funding & Sponsors

Funding source category [1]

University

Name [1]

Murdoch University

Address [1]

90 South Street, Murdoch, Perth Western Australia 6150

Country [1]

Australia

Primary sponsor type

University

Name

Murdoch University

Address

90 South Street, Murdoch, Perth Western Australia 6150

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Murdoch University Human Research Ethics Committee

Ethics committee address [1]

90 South Street, Murdoch, Perth Western Australia 6150

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

14/08/2015

Approval date [1]

12/10/2015

Ethics approval number [1]

2015/170

Summary

Brief summary

Exercise training leads to clinical improvements in blood glucose control in individuals with T2DM. This improvement in blood glucose control occurs because of improvements in post-meal glucose spikes (reducing time spent in hyperglycaemia by 129 min per day) and not in improvements in fasting glucose. Acute (single observation) studies reveal that exercise performed during the post-meal period (>30 min after meal ingestion) results in significant improvements in the post-meal glucose response compared to exercise performed fasted (or pre-meal consumption), at the same time as minimising the risk of hypoglycaemia. Moreover, exercise has consistently been shown to alter circadian rhythms in humans and within this body of research, the evidence shows that morning and evening exercise differentially regulate the autonomic nervous system. What is currently not known is (i) the impact of exercise-timing (morning versus evening) on daily glucose control and longer-term glucose control in individuals with T2DM; (ii) the potential mechanisms which may explain the improvements observed in glucose control with exercise training. Therefore, the overarching aim of this proposed research is to determine the impact of exercise-timing (morning versus evening) on blood glucose control in individuals enrolled into a 12-week evidence-based combined exercise training program. The secondary aim of this study is to explore the underlying mechanisms associated with the improvements in blood glucose control control. This research builds on previous work from which demonstrates: (i) reduced post-meal glucose and insulin responses when exercise is performed after meal ingestion; (ii) increased glucose responses when exercise is performed in the fasted state before breakfast; (iii) exercise training improves autonomic function in individuals with T2DM. We hypothesise that:

1. Both morning and evening training programs will lead to significant improvements in blood glucose control which will be attributable to improvements in post-meal glucose levels;
2. Morning exercise will improve blood glucose control and post-meal glucose responses to a greater extent than evening exercise, and this will be associated with improvements in autonomic function.

The International Diabetes Federation has stated that, "Postmeal hyperglycaemia is harmful and should be addressed". The project proposed herein will directly address this issue by furthering our understanding of the role of exercise training in improving the post-meal glucose responses and longer-term blood glucose control control.

Trial website

Trial related presentations / publications

Public notes