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Trial registered on ANZCTR


Trial ID
ACTRN12614001197628
Ethics application status
Approved
Date submitted
3/11/2014
Date registered
14/11/2014
Date last updated
1/02/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
Can protein improve glucose tolerance in older adults with type-2 diabetes??
Scientific title
Can protein supplementation combined with a 14 week exercise program improve glucose tolerance in older adults with type-2 diabetes?
Secondary ID [1] 285590 0
none
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Non-insulin dependent type-2 diabetes 293430 0
Condition category
Condition code
Metabolic and Endocrine 293704 293704 0 0
Diabetes

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants will be randomly allocated to 1 of 3 dietary supplementation groups: 1) wool derived protein, 2) whey protein, or 3) placebo. The study duration will be 17 weeks, which includes an initial two testing weeks, 14 weeks of exercise and protein supplementation co-intervention and a final testing week.. For the 2 week familiarisation, all participants will consume the placebo. The supplement will only be consumed during weekdays, to coincide with the exercise sessions.

Supplement: will be delivered in the form of health bars and capsules, to be consumed 2 times per day (post-exercise, 1 hour prior to bedtime), separated by at least 3 hours. The total daily protein dose in each treatment arm will be 40 gram: a) 17 g KDP+23 g whey, b) 40 g whey, or c) placebo - no added protein. The placebo bars will have the supplemental protein energy content replaced with gluten free flour and refined carbohydrate (maltodextrin, glucose) and fat to match energy and minimize protein content.

Exercise: Exercise Physiologists will supervise 5 days/week intermittent high-intensity mixed-mode, group-based exercise program designed to achieve a fixed-rate 2% gain in exercise load/week. Each training session will be approximately 60 minutes in duration, including: a. Warm-up:10 min light cardio machine exercise and stretching b. Days 1, 2, 4, 5: aerobic (stationary cycle) exercise, comprising a mix of continuous exercise and anaerobic intervals (70-90% of peak power and recovery at 40-50% of peak power). Exercise intensity will be standardised by having all sessions conducted on calibrated ergometers c. Day 3: standardised circuit resistance training (10-30% of the exercise 1 repetition maximum) emphasising the legs d. Cool-down: 5-10 minutes of stretching to cool down Subjects will be required to attend a minimum of 60 sessions over the 14 weeks, and will be provided with the opportunity to complete any missed sessions on weekends.

To ensure adherence to exercise the participants will be supervised. The participants will be required to complete a 3-day dietary recall each time they visit the laboratory for testing, and a text message will be sent to remind the participant to consume the evening dose.
Intervention code [1] 290540 0
Treatment: Other
Comparator / control treatment
The control bars will have the supplemental protein energy content replaced with by refined carbohydrate (maltodextrin, glucose) and fat to match energy. The control group will be prescribed identical exercise. The only difference between groups is the allotment of protein or placebo
Control group
Placebo

Outcomes
Primary outcome [1] 293511 0
Whole-body glucose disposal rate during hyperinsulinemic euglycaemic clamp
Timepoint [1] 293511 0
Weeks 2 and 16
Secondary outcome [1] 311206 0
GLUT4 density and sarcolemmal translocation using differential centrifugation and immunoblot or ELISA, immunoflurochemistry. Skeletal muscle tissue harvested will be from the vastus lateralis.
Timepoint [1] 311206 0
Weeks 2 and 16
Secondary outcome [2] 311207 0
Insulin-stimulated skeletal muscle (vastus lateralis) mircovascular blood flow, assessed using near-infrared spectroscopy during the hyperinsulinemic euglycaemic clamp
Timepoint [2] 311207 0
Weeks 2 and 16
Secondary outcome [3] 311208 0
Mitochondrial capacity of the vastus lateralis muscle, assessed using near-infrared spectroscopy
Timepoint [3] 311208 0
Weeks 2 and 16
Secondary outcome [4] 311209 0
contraction-mediated skeletal muscle (vastus lateralis) microvascular blood flow, assessed using near-infrared spectroscopy during leg-kicking exercise
Timepoint [4] 311209 0
Weeks 2 and 16
Secondary outcome [5] 311210 0
Blood cholesterol, triglycerides, fasting glucose/insulin, Hb1Ac, alkaline phosphatase, total protein
Timepoint [5] 311210 0
Weeks 2, 5, 8, 12, 17
Secondary outcome [6] 311211 0
Metabolomics (urine)
Timepoint [6] 311211 0
Weeks 2, 5, 8, 12, 17
Secondary outcome [7] 311212 0
Daily physical activity, assessed over 7 day using accelerometry
Timepoint [7] 311212 0
Weeks 1 and 15
Secondary outcome [8] 311213 0
Functional health and well-being via psychometric assessment using
SF36 and DASS
Timepoint [8] 311213 0
Weeks 2 and 16
Secondary outcome [9] 311214 0
Body composition, using anthropometry and bio-impedance analysis
Timepoint [9] 311214 0
Weeks 2, 5, 8, 12, 17
Secondary outcome [10] 311319 0
Sleep behaviour, assessed over 7 day using accelerometry
Timepoint [10] 311319 0
Weeks 2 and 16
Secondary outcome [11] 311321 0
Skeletal muscle capillary density by light microscopy. Skeletal muscle tissue harvested will be from the vastus lateralis.
Timepoint [11] 311321 0
Weeks 2 and 16
Secondary outcome [12] 311322 0
Mitochondrial metabolic function will be gauged via citrate synthase and cytochrome oxidase IV activity using ELISA. Skeletal muscle tissue harvested will be from the vastus lateralis.
Timepoint [12] 311322 0
Weeks 2 and 16
Secondary outcome [13] 311323 0
Tissue fibrosis plasticity by endomyosium/myofibril area using light microscopy. Skeletal muscle tissue harvested will be from the vastus lateralis.
Timepoint [13] 311323 0
Weeks 2 and 16
Secondary outcome [14] 311324 0
phosphorylation status of insulin signalling pathway (PI3K, AS160 on multiple phosphorylation sites) using immunoblot and immunoflurochemistry. Skeletal muscle tissue harvested will be from the vastus lateralis.
Timepoint [14] 311324 0
Weeks 2 and 16
Secondary outcome [15] 311326 0
gene and protein expression using RT-PCR, transcriptome, proteome and associated molecular methods. Skeletal muscle tissue harvested will be from the vastus lateralis.
Timepoint [15] 311326 0
Weeks 2 and 16
Secondary outcome [16] 311327 0
anti-oxidant biology (e.g. glutathione, glutathione peroxidase pathways) using biochemical methods. Skeletal muscle tissue harvested will be from the vastus lateralis.
Timepoint [16] 311327 0
Weeks 2 and 16
Secondary outcome [17] 321333 0
Carotid arterial stiffness. Measured using B-mode ultrasound
Timepoint [17] 321333 0
Weeks 2, 5, 8, 12, 17
Secondary outcome [18] 321334 0
maximal oxygen uptake via indirect calorimetry using an incremental cycle test to exhaustion
Timepoint [18] 321334 0
Weeks 2 and 16
Secondary outcome [19] 321335 0
isokinetic leg strength on a Biodex dynamometer
Timepoint [19] 321335 0
Weeks 2 and 16
Secondary outcome [20] 321336 0
isometric leg strength on a Biodex dynamometer
Timepoint [20] 321336 0
Weeks 2 and 16
Secondary outcome [21] 321337 0
dynamic leg strength. Tested as 1RM on a leg press
Timepoint [21] 321337 0
Weeks 2 and 16

Eligibility
Key inclusion criteria
Thirty-six men and women with non-insulin dependent Type-2 diabetics (diagnosed for a minimum of 1 year), aged 35-70, BMI 25-40, HbA1c >48 mmol/mol, stable weight and not having participated in regular exercise in the past 6 months
Minimum age
35 Years
Maximum age
70 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion criteria will include; use of beta-blockers, moderate to severe retinopathy, nephropathy and neuropathy, history of cerebrovascular or cardiovascular diseases, current smoker or having smoked 6 months prior.

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)
Participants will be recruited through advertising and through medical centres in Wellington NZ, based upon database records identifying them as meeting the eligibility criteria. After baseline testing, a researcher not involved in the study will randomly allocate participants to treatment and control groups.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Each sex will be allocated into the 3 conditions by way of minimisation to reduce the differences between the group means in: baseline glucose clearance rate being the primary clinical defining parameter; peak power on a cycle ergometer as the secondary and fasting baseline glucose concentration as the third parameter.

The process will be completed using an Excel spreadsheet (not using sealed envelopes).
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint(s)
Statistical methods / analysis
The between group effect of treatment will be analysed using mixed linear models via the Proc Mixed utility in SAS (SAS, Cary, NC). Fixed effects within the models will be group (treatment) and time. Random effects (covariance matrix) will be subject, treatment; additional random effects may be added following evaluation of other sources of variability. The baseline values will be added as a covariate to adjust for between-subject variability. Parametric data will be log-transformed prior to analysis, which allows for changes to be expressed as percents and manages heteroscedasticity to adjust residuals to normally-distributed data. Clinical inference and inference to mechanisms outcomes will be via the method of magnitude-based inference.

Sample size estimate was based upon the primary outcome, glucose infusion rate (GIR = glucose disposal rate or the measure of insulin sensitivity). The rationale and calculations are as follows: the test-retest measures for GIR values reported by Defronzo et al and equations for statistical superiority reported in Zhong. The minimum meaningful effect size was set at 23%, a statistically significant outcome following 3 months of diabetic medication. GIR has not been measured following chronic amino acid supplementation, but improvements in HbA1c, fasting and postprandial blood glucose that were seen in T2DM participants following 8 weeks of supplementation, exceeded improvements documented in another study comparing the effect of 3 months treatment with hypoglycaemic medication in poorly controlled diabetes. In that study GIR improved by 23%. To achieve power of 0.80, statistical significance p<.05, and a minimum effect of 23% each group requires 12 participants, which accounts for potential drop-outs.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Current
Final
Recruitment outside Australia
Country [1] 6448 0
New Zealand
State/province [1] 6448 0
Wellington

Funding & Sponsors
Funding source category [1] 290183 0
Government body
Name [1] 290183 0
Ministry of Business Innovation and Employment
Address [1] 290183 0
15 Stout Street, Wellington 6011
PO Box 1473, Wellington 6140
Country [1] 290183 0
New Zealand
Primary sponsor type
University
Name
Massey University
Address
63 Wallace St
Mt Cook, Wellington
6021
Country
New Zealand
Secondary sponsor category [1] 288895 0
None
Name [1] 288895 0
Address [1] 288895 0
Country [1] 288895 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 291893 0
Health and Disability Ethics Committee
Ethics committee address [1] 291893 0
Ministry of Health
No 1 The Terrace
PO Box 5013
Wellington Central 6011
Ethics committee country [1] 291893 0
New Zealand
Date submitted for ethics approval [1] 291893 0
13/11/2014
Approval date [1] 291893 0
15/12/2014
Ethics approval number [1] 291893 0
14/CEN/194

Summary
Brief summary
There has been a recent growing interest in the use of protein supplementation in type 2 diabetes (T2DM) therapy. Dietary amino acids are potent stimulators of vascular and skeletal muscle adaptations that have been associated with improved cardiovascular health and metabolic flexibility. Previous studies have typically derived these dietary amino acids from dairy sources; alternatively, keratin- derived protein (KDP) is uniquely rich in the amino acid cysteine and has high levels of selenium — both key components in glutathione, a critical agent in cellular antioxidant processes. Preliminary findings suggest that KDP supplementation may aid the attenuation of oxidative stress in diseased (e.g. T2DM) skeletal muscle leading to attenuation in muscle-degradative stress and fibrosis. Therefore, the current study will determine whether chronic KDP supplementation enhances the effects of 12 weeks exercise training on systemic glucose disposal and insulin signalling in middle-aged adults with T2DM. The findings may provide a new simple and practical direction for improving diabetic rehabilitation.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 52478 0
Dr Lee Stoner
Address 52478 0
School of Sport and Exercise, College of Health, Massey University 63 Wallace St Mt Cook, Wellington, 6021
Country 52478 0
New Zealand
Phone 52478 0
+6421817878
Fax 52478 0
Email 52478 0
dr.l.stoner@gmail.com
Contact person for public queries
Name 52479 0
Dr Martin Gram
Address 52479 0
School of Sport and Exercise, College of Health, Massey University 63 Wallace St Mt Cook, Wellington, 6021
Country 52479 0
New Zealand
Phone 52479 0
+64221692343
Fax 52479 0
Email 52479 0
m.gram@massey.ac.nz
Contact person for scientific queries
Name 52480 0
Dr Martin Gram
Address 52480 0
School of Sport and Exercise, College of Health, Massey University 63 Wallace St Mt Cook, Wellington, 6021
Country 52480 0
New Zealand
Phone 52480 0
+64221692343
Fax 52480 0
Email 52480 0
m.gram@massey.ac.nz