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Mechanisms of Insulin Resistance and Exercise in South Asians

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ClinicalTrials.gov Identifier: NCT04007926
Recruitment Status : Suspended (COVID-19)
First Posted : July 5, 2019
Last Update Posted : October 8, 2020
Sponsor:
Collaborator:
Medical Research Council
Information provided by (Responsible Party):
Professor Jason Gill, University of Glasgow

Tracking Information
First Submitted Date  ICMJE June 28, 2019
First Posted Date  ICMJE July 5, 2019
Last Update Posted Date October 8, 2020
Estimated Study Start Date  ICMJE August 2021
Estimated Primary Completion Date March 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 2, 2019)
Whole-body Insulin sensitivity [ Time Frame: Change between baseline and 12 weeks. ]
Change in whole-body insulin sensitivity measured by hyperinsulinaemic-euglycaemic clamp.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 24, 2019)
  • Insulin-stimulated GLUT4 translocation [ Time Frame: Change between baseline and 12 weeks. ]
    Change in insulin-stimulated GLUT4 translocation in muscle biopsies from vastus lateralis using immunofluorescence microscopy
  • Microvascular blood volume [ Time Frame: Change between baseline and 12 weeks. ]
    Change in fold-increase in insulin stimulated quadriceps muscle blood volume measured using contrast enhanced ultrasound.
  • Muscle mitochondrial function [ Time Frame: Change between baseline and 12 weeks. ]
    Change in mitochondrial function (oxygen consumption rate) in isolated skeletal muscle mitochondria from the vastus lateralis measured using respirometry
  • Lipid droplet content in skeletal muscle [ Time Frame: Change between baseline and 12 weeks. ]
    Change in fibre type-specific (type 1 and type 2) and subcellular-specific (subsarcolemmal and intermyofibrillar) lipid droplet content in muscle biopsies from vastus lateralis using immunofluorescence microscopy
  • Lipid droplet proximity to mitochondria in skeletal muscle [ Time Frame: Change between baseline and 12 weeks. ]
    Change in proportion of lipid droplets in contact with mitochondria in subsarcolemmal and intermyofibrillar compartments of type 1 and type 2 muscle fibres in muscle biopsies from vastus lateralis using immunofluorescence microscopy
  • Microvascular density in skeletal muscle [ Time Frame: Change between baseline and 12 weeks. ]
    Change in fibre-type specific capillarisation in muscle biopsies from vastus lateralis
  • Change in enzymes controlling insulin-mediated increases in perfusion in skeletal muscle [ Time Frame: Change between baseline and 12 weeks. ]
    Change in endothelial specific protein content and phosphorylation of key microvascular enzymes in muscle biopsies from vastus lateralis assessed using quantitative immunofluorescence.
  • Maximal oxygen uptake [ Time Frame: Change between baseline and 12 weeks. ]
    Change in maximal oxygen uptake consumption assessed using continuous incremental uphill walking protocol until volitional exhaustion.
  • Muscle maximal voluntary contraction [ Time Frame: Change between baseline and 12 weeks. ]
    Change in knee extensor muscles maximal voluntary contraction
  • Lower body muscle strength [ Time Frame: Change between baseline and 12 weeks. ]
    Change in 1-RM (one maximal repetition) (kg) for leg press.
  • Upper body muscle strength [ Time Frame: Change between baseline and 12 weeks. ]
    Change in 1-RM (one maximal repetition) (kg) for chest press.
  • Grip strength [ Time Frame: Change between baseline and 12 weeks. ]
    Change in grip strength (kg).
  • Fat mass [ Time Frame: Change between baseline and 12 weeks. ]
    Change in fat mass measured with bioelectrical impedance analysis (BIA).
  • Fat-free mass [ Time Frame: Change between baseline and 12 weeks. ]
    Change in fat-free mass measured with bioelectrical impedance analysis (BIA).
  • Weight [ Time Frame: Change between baseline and 12 weeks. ]
    Change in weight (kg).
  • Waist circumference [ Time Frame: Change between baseline and 12 weeks. ]
    Change in waist circumference (cm)
Original Secondary Outcome Measures  ICMJE
 (submitted: July 2, 2019)
  • Insulin-stimulated GLUT4 translocation [ Time Frame: Change between baseline and 12 weeks. ]
    Change in insulin-stimulated GLUT4 translocation in muscle biopsies from vastus lateralis using immunofluorescence microscopy
  • Microvascular blood volume [ Time Frame: Change between baseline and 12 weeks. ]
    Change in fold-increase in insulin stimulated quadriceps muscle blood volume measured using contrast enhanced ultrasound.
  • Muscle mitochondrial function [ Time Frame: Change between baseline and 12 weeks. ]
    Change in mitochondrial function (oxygen consumption rate) in isolated skeletal muscle mitochondria from the vastus lateralis measured using respirometry
  • Lipid droplet content in skeletal muscle [ Time Frame: Change between baseline and 12 weeks. ]
    Change in fibre type-specific (type 1 and type 2) and subcellular-specific (subsarcolemmal and intermyofibrillar) lipid droplet content in muscle biopsies from vastus lateralis using immunofluorescence microscopy
  • Lipid droplet proximity to mitochondria in skeletal muscle [ Time Frame: Change between baseline and 12 weeks. ]
    Change in proportion of lipid droplets in contact with mitochondria in subsarcolemmal and intermyofibrillar compartments of type 1 and type 2 muscle fibres in muscle biopsies from vastus lateralis using immunofluorescence microscopy
  • Microvascular density in skeletal muscle [ Time Frame: Change between baseline and 12 weeks. ]
    Change in fibre-type specific capillarisation in muscle biopsies from vastus lateralis
  • Change in enzymes controlling insulin-mediated increases in perfusion in skeletal muscle [ Time Frame: Change between baseline and 12 weeks. ]
    Change in endothelial specific protein content and phosphorylation of key microvascular enzymes in muscle biopsies from vastus lateralis assessed using quantitative immunofluorescence.
  • Maximal oxygen uptake [ Time Frame: Change between baseline and 12 weeks. ]
    Change in maximal oxygen uptake consumption assessed using continuous incremental uphill walking protocol until volitional exhaustion.
  • Muscle maximal voluntary contraction [ Time Frame: Change between baseline and 12 weeks. ]
    Change in knee extensor muscles maximal voluntary contraction
  • Lower body muscle strength [ Time Frame: Change between baseline and 12 weeks. ]
    Sum of change in 1-RM (one maximal repetition) (kg) for leg press, calf press, leg extension and leg curl.
  • Upper body muscle strength [ Time Frame: Change between baseline and 12 weeks. ]
    Sum of hange in 1-RM (one maximal repetition) (kg) for chest press, shoulder press, lat pull down and seated row.
  • Grip strength [ Time Frame: Change between baseline and 12 weeks. ]
    Change in grip strength (kg).
  • Fat mass [ Time Frame: Change between baseline and 12 weeks. ]
    Change in fat mass measured with bioelectrical impedance analysis (BIA).
  • Fat-free mass [ Time Frame: Change between baseline and 12 weeks. ]
    Change in fat-free mass measured with bioelectrical impedance analysis (BIA).
  • Weight [ Time Frame: Change between baseline and 12 weeks. ]
    Change in weight (kg).
  • Waist circumference [ Time Frame: Change between baseline and 12 weeks. ]
    Change in waist circumference (cm)
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Mechanisms of Insulin Resistance and Exercise in South Asians
Official Title  ICMJE Effects of Exercise Training on Insulin Sensitivity in South Asians at Risk of Diabetes: the Roles of Skeletal Muscle Microvasculature and Mitochondrial Metabolism
Brief Summary This study determines the effect of aerobic and resistance exercise training on whole-body and skeletal muscle insulin sensitivity in south Asians and evaluate the mechanisms which contribute to improvements in insulin sensitivity after exercise training.
Detailed Description South Asians (SA) have 2-4 fold higher risk of type 2 diabetes and develop the disease at lower body weights and younger ages than white Europeans. Lower cardiorespiratory fitness and capacity for muscle fat oxidation contributes substantially to SAs' greater insulin resistance, the extent to which this can be improved by exercise training is unclear. This randomised controlled trial will investigate the effects of a 12-week aerobic or resistance exercise training intervention on insulin sensitivity (hyperinsulinaemic-euglycaemic clamp) in South Asian adults (22 control, 22 aerobic exercise group and 22 resistance exercise group). The study will also explore the mechanisms within skeletal muscle which mediate these changes by evaluating aerobic and resistance exercise-training induced changes: in basal and insulin-stimulated microvascular blood volume (using contrast-enhanced ultrasound); skeletal muscle mitochondrial function; and lipid droplet morphology and spatial interaction with mitochrondria, muscle fibre capillarisation, endothelial content of key enzymes controlling dilation/constriction and GLUT-4 translocation (using confocal immunofluorescence microscopy and transmission electron microscopy methods). Thus, this work will integrate physiological and molecular data to determine the extent to which exercise training can improve insulin sensitivity in SA and the mechanisms underpinning this improvement. This knowledge is important for optimising diabetes prevention interventions in SAs and identification of potential novel therapeutic targets.
Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Randomised controlled trial
Masking: None (Open Label)
Masking Description:
Masking is not possible due to nature of intervention (exercise training programme).
Primary Purpose: Prevention
Condition  ICMJE Insulin Resistance
Intervention  ICMJE
  • Behavioral: Aerobic exercise programme
    Participants will start with 3 x 20 minute exercise sessions in the first week, building up to 5 x 60 minutes of exercise by weeks 9-12 of the intervention, at an intensity of 65-80% of predicted maximum heart rate.
  • Behavioral: Resistance exercise programme
    Participants will undertake two supervised sessions per week. The exercises performed during each session will consist of leg press, calf press, leg extension, leg curl, chest press, shoulder press, lateral pull down and seated row. Exercises will be performed at 60-80% 1RM. In weeks 1-2 participants will perform, during each session, a single set of 5-10 repetitions of each exercise (tiring but comfortably achievable) to ensure they are comfortable with the exercises and are performing these in the correct form. In weeks 3-4 participants will perform, during each session, two sets of each exercise to voluntary muscular failure - defined as not being able to perform single another repetition. In weeks 5-12 this will progress to 3 sets of each exercise to voluntary muscular failure, in each session.
Study Arms  ICMJE
  • No Intervention: Control Group
    Participants assigned to the control arm of the study will be asked to maintain their normal dietary and exercise habits.
  • Experimental: Aerobic exercise group
    Participants randomised to the aerobic exercise intervention will undertake a 12-week aerobic exercise training programme.
    Intervention: Behavioral: Aerobic exercise programme
  • Experimental: Resistance exercise group
    Participants randomised to the resistance exercise intervention will undertake a 12-week aerobic exercise training programme.
    Intervention: Behavioral: Resistance exercise programme
Publications * Marx N, Davies MJ, Grant PJ, Mathieu C, Petrie JR, Cosentino F, Buse JB. Guideline recommendations and the positioning of newer drugs in type 2 diabetes care. Lancet Diabetes Endocrinol. 2021 Jan;9(1):46-52. doi: 10.1016/S2213-8587(20)30343-0. Epub 2020 Nov 4. Review. Erratum in: Lancet Diabetes Endocrinol. 2021 Jan;9(1):e1.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Suspended
Estimated Enrollment  ICMJE
 (submitted: July 2, 2019)
66
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 2025
Estimated Primary Completion Date March 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Male
  • South Asian ethnicity (self-report of both parents of Indian, Pakistani, Bangladeshi or Sri Lankan origin)
  • Age 30-65 years
  • At least 10% 10-year risk of developing type 2 diabetes, determined using the QDiabetes®2018 risk score (http://qdiabetes.org/2018/index.php)

Exclusion Criteria:

  • Female
  • Diabetes (physician diagnosed or HbA1c ≥48 mmol/mol on screening)
  • History of cardiovascular disease
  • Hypertension (taking anti-hypertensives or BP consistently ≥ 150/90 mmHg on screening).
  • Regular participation in vigorous physical activity
  • Regular participation in resistance exercise
  • Current smoking
  • Taking drugs or supplements thought to affect carbohydrate or lipid metabolism
  • Taking drugs affecting blood clotting (e.g. aspirin)
  • Current treatment with anti-obesity drugs
  • Any other significant illness that would prevent full participation in the study
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Ages  ICMJE 30 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04007926
Other Study ID Numbers  ICMJE 265320
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Professor Jason Gill, University of Glasgow
Study Sponsor  ICMJE University of Glasgow
Collaborators  ICMJE Medical Research Council
Investigators  ICMJE
Principal Investigator: Jason Gill, PhD University of Glasgow
PRS Account University of Glasgow
Verification Date October 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP