Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12623000025639
Ethics application status
Approved
Date submitted
27/11/2022
Date registered
11/01/2023
Date last updated
22/04/2024
Date data sharing statement initially provided
11/01/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Uncovering bone-muscle-fat interaction in patients with type 2 diabetes: effects of acute and chronic exercise
Scientific title
Uncovering bone-muscle-fat interaction in patients with type 2 diabetes: effects of acute and chronic exercise
Secondary ID [1] 308476 0
N/A
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Type 2 Diabetes 328313 0
Condition category
Condition code
Metabolic and Endocrine 325357 325357 0 0
Diabetes
Musculoskeletal 325434 325434 0 0
Other muscular and skeletal disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The study involves three main parts. 1) screening and baseline assessments related to bone, muscle and body composition health, 2) acute high intensity interval exercise (HIIE) and 3) chronic exercise training (10-weeks).
For all acute HIIE and exercise training visits, participants will be supervised by an Exercise Physiologists in a 1:1 or 1:2 format. All the assessments and exercise training will be conducted face-to-face at Victoria University. Acute sessions at baseline will be conducted within 7 days of screening, acute sessions following 4 and 10 weeks of exercise training will be conducted after 72 hours of the last exercise training session.
EFFECTS OF ACUTE EXERCISE
We will examine the effects of acute high intensity interval exercise (HIIE) on markers of bone, muscle and fat metabolism as well as changes in markers of metabolic and cardiovascular (CV) risk (glucose, lipids, inflammation etc). This (identical) acute HIIE session will also be performed following 4 and 10 weeks of HIIE training, with each session taking approximately 4 hours. Should the participant decide to complete an OGTT at the end of the 1st acute session, this will take the duration to 7 hours total. Blood sampling will be taken before exercise, immediately following exercise, and up to 180 min post-exercise. Urine samples will be taken before and following exercise. Participants can elect to have none, one (at rest) or six (1 at rest and 1 following each acute exercise session) muscle and adipose tissue biopsies. Muscle will be analysed for protein degradation and protein synthesis pathways. Other novel markers associated with muscle, bone and fat health may also be assessed.
Twenty-four hours prior to the acute HIIE session participants will be asked to refrain from any formal exercise, consume their normal diet and not take caffeine or alcohol. Participants will arrive to our lab between 7-8am after an overnight fast. At the start of each visit, a cannula will be inserted into the antecubital vein. At each testing visit we will take six blood samples (~20 to 25 ml each), one at rest before exercise, and one immediately following exercise, then at 30, 60, 120 and 180 mins post-exercise. The total blood volume taken in one visit is around 140ml. The acute HIIE session incudes 4 sets x 4 minutes of cycling (on a cycle ergometer) at 90-95% of heart rate reserve (HRR) with 2 minutes of active recovery between sets.
Participant will be able to consume water, however, they will be unable to eat until the end of the visit. Participants will also be asked to complete some simple short questionnaires. The Feelings scale, the Depression Anxiety Stress Scale (DASS) and The subjective exercise experience scale (SEES). Participants will also have the option of completing an oral glucose tolerance test (OGTT) following the first acute session.
The OGTT will be completed at baseline, following the 1st acute exercise session (optional) and post-intervention at the Victoria University Exercise Physiology Lab. A cannula will be inserted into the forearm by a qualified and experienced investigator at the beginning of the trial to collect venous blood. Catheters are used when several blood samples are needed from one site over a brief duration such as to be used here. The oral glucose tolerance test will take 2 hours in duration. During this test, participants will consume a glucose beverage (75g of glucose) and serial blood samples (4ml at each interval) will then be taken at regular intervals (every 30 mins: 0mins, 30mins, 60mins, 90mins and 120mins) to monitor blood glucose and insulin concentrations for the determination of insulin sensitivity and glucose tolerance. The total amount of blood drawn will be 20ml. Catheterisation and blood sampling is a well-established and accepted technique routinely performed at Victoria University.
EFFECTS OF 4 and 10-WEEKS HIIT EXERCISE TRAINING
Following the acute exercise, participants will be randomised (using 2:1 ratio of randomisation, sealed envelope) to receive either 10 weeks of exercise training, or 10 weeks of standard clinical care (control). Training will be 3 sessions per week. The format of these sessions will be the same as the acute HIIE session 4 sets x 4 minutes of cycling (on a cycle ergometer) at 90-95% of HRR with 2 minutes of active recovery between sets. Blood pressure and heart rate will be monitored before and after exercise. Both before, mid and after the chronic training period we will administer the third version of Behavioral Regulation in Exercise Questionnaire (BREQ 3) to assess baseline exercise motivation and determine if the applied intervention positively impacts internal or external motivation for exercise participation. The study coordinator will be in close contact with the participant to arrange all training sessions and will maintain a session attendance checklist to monitor adherence to the intervention.
Following 4 and 10-weeks of the intervention (exercise training and control) and between 48 to 72 hours after their acute exercise visits, participants will attend Victoria University for mid intervention (4 week) and post intervention assessments (10 weeks) which will be a repeat of the baseline testing and acute exercise.
Intervention code [1] 324933 0
Lifestyle
Intervention code [2] 325016 0
Treatment: Other
Comparator / control treatment
Participants who will be randomized to the control group (no exercise) will continue with their normal daily routine/or standard clinical care for 10 weeks. If randomised to control, participants will be asked to maintain their normal habitual behaviours and diet. For those randomised to control, following their final testing day, as a courtesy for their participation in the study, we will offer them 4 weeks of exercise training.
Control group
Active

Outcomes
Primary outcome [1] 333214 0
Changes in bone remodelling markers. Assessed as a composite primary outcome by: osteocalcin, C-terminal telopeptide of type 1 collagenand lipocalin 2
Timepoint [1] 333214 0
Baseline and immediately following the 30min acute HIE session 0mins, 30mins, 60mins, 120mins (primary endpoint) and 180 mins post exercise and for the chronic training the timepoints are baseline and 4 and 10 weeks post exercise training
Primary outcome [2] 333215 0
Changes in insulin sensitivity. Assessed as a composite primary outcome by: fasting blood glucose, oral glucose tolerance test (OGTT), Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) and HbA1c
Timepoint [2] 333215 0
Baseline and immediately following the 30min acute HIE session 0mins, 30mins, 60mins, 120mins (primary endpoint) and 180 mins post exercise, and for the chronic training the timepoints are baseline and 4 and 10 weeks post exercise training (or control)
Primary outcome [3] 333216 0
Changes in sex hormone levels. Assessed as a composite primary outcome by: testosterone, estradiol, sex hormone binding globulin, follicular stimulating hormone, luteinising hormone.

Analysed through blood
Blood sampling and analysis procedure:
Blood Sampling: All blood samples will be collected into EDTA and SST vacutainers for the appropriate collection of red blood cells, serum and plasma. Following 10 mins clotting time, samples will be centrifuged for 10 mins at 4C and immediately transferred to long-term storage at -80C in 1-2 mL aliquots for later analysis. To analyse, blood samples will undergo quantification of an array of relevant assay protocols to assess biomarkers such as hormones (androgens: total testosterone, dihydrotestosterone(DHT), estradiol, sex hormone binding globulin (SHBG), luteinizing hormone (LH), follicular stimulating hormone (FSH), cortisol, parathyroid hormone), or those related to glucose tolerance, muscle and metabolic metabolism, bone remodelling and cardiometabolic risk factors.
Blood Analyses: Blood samples will undergo quantification of an array of biomarkers related to bone remodelling, muscle and metabolic metabolism and cardiometabolic risk factors. Some of these analyses will include hormones (testosterone, estradiol, LH, FSH, SHBG, cortisol), lipids, glucose and insulin, inflammation markers and potentially other cardiovascular or health markers. Other factors involved in the bone-muscle-adipose crosstalk or, involved in bone, muscle or cardiovascular health will also be considered. These analyses may occur within our research group, with our collaborators or with future collaborators. However, all samples are coded, and identifiable information will not be shared.
Timepoint [3] 333216 0
Baseline and immediately following the 30min acute HIE session 0mins, 30mins, 60mins, 120mins (primary endpoint) and 180 mins post exercise, and for the chronic training the timepoints are baseline and 4 and 10 weeks post exercise training
Secondary outcome [1] 416190 0
Changes in muscle tissue health. Assessed as a composite primary outcome by: proteins associated with muscle hypertrophy/degradation (mammalian target of rapamycin (mTOR), Ak strain transforming (Akt), extracellular signal-regulated kinase 1/2 (ERK1/2)).
Timepoint [1] 416190 0
baseline and following 4 and 10 weeks of exercise training (or control)
Secondary outcome [2] 416191 0
Vascular stiffness, assessed via applanation tonometry (sphygmocor)
Timepoint [2] 416191 0
baseline and following 4 and 10 weeks of exercise training (or control)
Secondary outcome [3] 416192 0
Body composition assessed via Dual-energy X-ray absorptiometry (DXA). This will be a composite assessment of: whole body composition, bone mineral density as well as percentage of lean body mass and fat mass.
Timepoint [3] 416192 0
baseline and following 4 and 10 weeks of exercise training (or control)
Secondary outcome [4] 416193 0
Change in physical performance test score (combined score including performance in timed up and go, gait velocity, stair climbing, stair descending) from baseline to after chronic exercise training.
Participants will complete a Physical Performance Test (PPT), adapted from Levinger et al. The PPT includes four functional mobility tasks; 1) gait velocity; 2) timed up and go; 3) stair climbing power (SCP) and 4) stair ascending and descending. All tests will be scored in time (seconds) and completed three times. The fastest times will be recorded for each test. Gait velocity will be measured using 3 different protocols with reduced physical function determined as <80 cm/sec:
1. Protocol one: Participants walk at their normal pace over a 4m track;
2. Protocol two: Participants walk at their normal pace over an 8m track, with metres 2-6 being recorded (seconds) to exclude acceleration and deceleration;
3. Protocol three: Participants will be instructed to walk as fast as they can without running over an 8m track. Metres 2-6 will be recorded to exclude acceleration and deceleration.
The timed up and go test: A simple performance-based assessment, requiring minimal equipment including; standard arm chair (~46cm), 3-meter walkway with floor mark and stopwatch (time, seconds). It is performed as time (seconds) taken to rise from a seated position, walk 3 meters, turn, walk back to the chair and then sit.
The SCP: Will consist of a rapid ascent of 10 stairs, where;
SCP = body weight (kg) x 9.8ms-2 x step height (m) x number of steps x time -1 (s-1)
The stair descent: Will be time to safely descend 10 stairs. The rest between the ascent and descent will be 45 s. Participants will undergo four attempts on each task and the best time recorded for each. The PPT score will be the sum of the fastest times recorded for each test.
Timepoint [4] 416193 0
baseline and following 4 and 10 weeks of exercise training (or control)
Secondary outcome [5] 416194 0
Change in aerobic capacity (VO2Peak) from baseline to after chronic exercise training:
Participants will complete three graded exercise tests (GXTs), one at each baseline visit and one during post assessments (weeks 4 and 10) for the determination of peak oxygen consumption (VO2Peak). As participants are not familiar with the GXT before starting the exercise training program, the first GXT shows high variability, which leads to unreliable baseline fitness estimates. A second GXT before starting the training program would provide much more stable results that can be used to personalise the exercise intensity of each participant reliably. VO2Peak will be assessed on a cycle ergometer with the initial intensity beginning at 10-30 Watts and increasing by 10-30W×min-1 according to participant ability. Participants will be monitored by 12-lead electrocardiogram (ECG; Mortara, X-Scribe II, Milwaukee, WI). VO2 for each 15-s interval will be measured by gas exchange analysis (BreezeEx, version 3.02, Medical Graphics Corp.) with routine calibration of gas concentrations and flow prior to each test. The test will be terminated according to participants’ self-reported fatigue perception reaching a pre-determined level (using the Borg scale, Rating of Perceived Exertion equals 17) or clinical signs or symptoms. Blood pressure will be monitored at baseline, regular intervals (each stage) and post exercise using a manual sphygmomanometer, and heart rate will be monitored via the 12-lead ECG.
Timepoint [5] 416194 0
baseline and following 4 and 10 weeks of exercise training (or control)
Secondary outcome [6] 417032 0
Participants will perform a one maximal repetition (1RM) test on a leg press. This will be performed twice with the first visit serving as familiarisation. 1RM is defined as the heaviest weight lifted once, with proper technique and without compensatory movements
Timepoint [6] 417032 0
baseline and following 4 and 10 weeks of exercise training (or control)
Secondary outcome [7] 417033 0
Changes in grip strength
Grip strength will be measured using a hand dynamometer (TTM Advanced, HMG Direct, Australia). A result of <20 kg for females and <30 kgs for males will identify low muscle strength. Participants will undergo three tests on both hands, with the highest measure being recorded.
Timepoint [7] 417033 0
Baseline and following 4 and 10 weeks exercise training (or control)
Secondary outcome [8] 417036 0
Changes in muscle and fat tissue quality

Assessed by tissue biopsies:
Biopsy procedure
If the participant consents to a muscle biopsy, the muscle sample/s (1 or 6) will be taken from the vastus lateralis under local anaesthesia by an experienced medical practitioner using a percutaneous needle biopsy technique, modified to include suction. Excised tissue will be snap-frozen in liquid nitrogen and stored at -80?C for later analysis. Proteins involved in muscle degradation and hypertrophy (i.e. anabolic and catabolic pathways; ubiquitin-proteasome, autophagy-lysosome and caspase-3-mediated proteolytic pathways) as well as glucose uptake will be assessed, as we previously performed .
Timepoint [8] 417036 0
Baseline and immediately following the 30min acute HIE session 0mins, 30mins, 60mins, 120mins (primary endpoint) and 180 mins post exercise, and for the chronic training the timepoints are baseline and 4 and 10 weeks post exercise training

Eligibility
Key inclusion criteria
Males and females aged over 18years with type 2 diabetes. Postmenopausal Females will be required to be a minimum of 12 months post menopause.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Potential participants will be excluded from the study if they:
- have had any fractures in the previous 3 months, or have commenced antiresorptive medication or any other new osteoporotic treatment within the last three months.
- uncontrolled diabetes, HbA1c >10%
- have any blood or marrow disorders
- have any bone malignancies or tumours
- are taking warfarin or vitamin K supplementation or restriction
- have a body mass index equal to or greater than 40kg/m2
- are professionally active (compete at a high level: national or international sporting competitions)
- are a current smoker, or have ceased smoking in the last 12 months
- have begun any new medications, new physical activity or dietary regimens (food intake) in the last 3 months
- are known to have a high blood pressure (more than 160/100 mmHg) or have been diagnosed with chronic heart failure new york heart association class III or IV or coronary artery disease
- are taking hormone replacement therapy (HRT)
- are taking glucocorticoids or other medications that alter bone metabolism

Additional criteria include:
- are unable to give informed consent independently, we will not include any persons who are unable to give independent informed consent for safety reasons, particularly as we take some invasive measures.
- pregnancy, the effects of maximal exercise whilst during pregnancy remain unclear. For safety precautions we will not include pregnant women.
- unable to understand English, this could potentially be a safety concern if unable to communicate during some of the maximal exertion testing visits, and for the acute exercise bout.

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)
A 2:1 ratio of notes for exercise training group vs control group will be inserted into concealed envelop. 2 notes for control and 4 notes for exercise training will be used to ensure the 2:1 ratio of exercise intervention to control group allocation for every 6 participants.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Permuted randomisation. The person responsible for the randomisation, will not be involved in the project. Randomisation will be stratified by age group (adult, middle aged and older adults) and by sex (female and male) to ensure similar number of males and females in each group (training or control).
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Not Applicable
Type of endpoint/s
Statistical methods / analysis
Statistical analyses will be performed using Statistical Package for the Social Sciences (SPSS Inc. Chicago, IL, USA, version 22).
Independent t-tests will be conducted to examine baseline differences between males and females as well as middle-aged and older adults. Spearman rho correlations will be used to assess the relationship between bone and sex hormone concentrations as well as other outcome measures. Spearman partial correlations will be used for additional adjustments of age and body mass index (BMI) as they are strong influencers of hormone levels. All data will be reported as mean ± standard error of mean (SEM) and all statistical analyses will be conducted at the 95% level of significance (p=0.05). General linear model ANOVA and a repeated Measure ANOVA will be used for comparison of multiple time points within and between interventions. A multi- linear regression model will be used to determine associations between selected measurements.

The sample size (n) required to reach a significant level of 0.05 with a power of 80% has been calculated a priori using G*Power analysis (g*power 3.1.9.2; two-tailed dependent t-test, alpha = 0.05, 95% power, within-person correlation of r = 0.5). 34 participants per group would be required using the more conservative effect size (0.7), equalling 68 participants in total to detect significant differences in bone and muscle metabolism as well as sex hormone levels following acute and chronic exercise training. Allowing for dropout, we are aiming to recruit 80 participants (40 exercise training, 40 control).

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/01/2023
Actual
1/04/2023
Date of last participant enrolment
Anticipated
31/12/2024
Actual
Date of last data collection
Anticipated
31/12/2024
Actual
Sample size
Target
80
Accrual to date
10
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 23642 0
Austin Health - Austin Hospital - Heidelberg
Recruitment postcode(s) [1] 39062 0
3084 - Heidelberg
Recruitment postcode(s) [2] 39063 0
3011 - Footscray

Funding & Sponsors
Funding source category [1] 312718 0
University
Name [1] 312718 0
Victoria University
Country [1] 312718 0
Australia
Primary sponsor type
University
Name
Victoria University
Address
Victoria University,
PO Box 14428,
Melbourne, VIC 8001
Australia
Country
Australia
Secondary sponsor category [1] 314339 0
None
Name [1] 314339 0
N/A
Address [1] 314339 0
N/A
Country [1] 314339 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 312019 0
Victoria University Human Research Ethics Committee
Ethics committee address [1] 312019 0
Ethics committee country [1] 312019 0
Australia
Date submitted for ethics approval [1] 312019 0
17/08/2022
Approval date [1] 312019 0
17/11/2022
Ethics approval number [1] 312019 0
HRE22-164

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 123194 0
Prof Itamar Levinger
Address 123194 0
Institute for Health and Sport (IHES)
Victoria University,
PO Box 14428,
Melbourne, VIC 8001
Australia
Country 123194 0
Australia
Phone 123194 0
+61399195343
Fax 123194 0
Email 123194 0
[email protected]
Contact person for public queries
Name 123195 0
Itamar Levinger
Address 123195 0
Institute for Health and Sport (IHES)
Victoria University,
PO Box 14428,
Melbourne, VIC 8001
Australia
Country 123195 0
Australia
Phone 123195 0
+61399195343
Fax 123195 0
Email 123195 0
[email protected]
Contact person for scientific queries
Name 123196 0
Itamar Levinger
Address 123196 0
Institute for Health and Sport (IHES)
Victoria University,
PO Box 14428,
Melbourne, VIC 8001
Australia
Country 123196 0
Australia
Phone 123196 0
+61399195343
Fax 123196 0
Email 123196 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
All coded data will be shared with an approval from the relevant ethics committee and consent from individuals.
When will data be available (start and end dates)?
Up to 5 years post data collection (1 Jan 2025- 24 Dec 2029)
Available to whom?
Universities and research institutes recognized by the NHMRC
Available for what types of analyses?
To increase sample size of other studies conducted in related areas.
How or where can data be obtained?
The data can be obtained by approaching CI Levinger ([email protected]).


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
17714Study protocol  [email protected]
17715Statistical analysis plan  [email protected]
17716Informed consent form  [email protected]
17717Ethical approval  [email protected]



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