Mechanisms of Insulin Resistance and Exercise in South Asians

Insulin Resistance Clinical Trial

Official title:

Effects of Exercise Training on Insulin Sensitivity in South Asians at Risk of Diabetes: the Roles of Skeletal Muscle Microvasculature and Mitochondrial Metabolism

Clinical Trial Details — Status: Suspended

Administrative data

• NCT number: NCT04007926
• Other study ID #: 265320
• Status: Suspended
• Phase: N/A
• Start date: August 2021
• Est. completion date: January 2025

Study information

• Verified date: October 2020
• Source: University of Glasgow
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Suspended
• Enrollment: 66
• Est. completion date: January 2025
• Est. primary completion date: March 2023
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 30 Years to 65 Years

Eligibility

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

Related Conditions & MeSH terms

• Insulin Resistance

Intervention

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.
• 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.

Locations

Country	Name	City	State
United Kingdom	University of Glasgow	Glasgow

Sponsors (2)

Lead Sponsor	Collaborator
University of Glasgow	Medical Research Council

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Whole-body Insulin sensitivity	Change in whole-body insulin sensitivity measured by hyperinsulinaemic-euglycaemic clamp.	Change between baseline and 12 weeks.
Secondary	Insulin-stimulated GLUT4 translocation	Change in insulin-stimulated GLUT4 translocation in muscle biopsies from vastus lateralis using immunofluorescence microscopy	Change between baseline and 12 weeks.
Secondary	Microvascular blood volume	Change in fold-increase in insulin stimulated quadriceps muscle blood volume measured using contrast enhanced ultrasound.	Change between baseline and 12 weeks.
Secondary	Muscle mitochondrial function	Change in mitochondrial function (oxygen consumption rate) in isolated skeletal muscle mitochondria from the vastus lateralis measured using respirometry	Change between baseline and 12 weeks.
Secondary	Lipid droplet content in skeletal muscle	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	Change between baseline and 12 weeks.
Secondary	Lipid droplet proximity to mitochondria in skeletal muscle	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	Change between baseline and 12 weeks.
Secondary	Microvascular density in skeletal muscle	Change in fibre-type specific capillarisation in muscle biopsies from vastus lateralis	Change between baseline and 12 weeks.
Secondary	Change in enzymes controlling insulin-mediated increases in perfusion in skeletal muscle	Change in endothelial specific protein content and phosphorylation of key microvascular enzymes in muscle biopsies from vastus lateralis assessed using quantitative immunofluorescence.	Change between baseline and 12 weeks.
Secondary	Maximal oxygen uptake	Change in maximal oxygen uptake consumption assessed using continuous incremental uphill walking protocol until volitional exhaustion.	Change between baseline and 12 weeks.
Secondary	Muscle maximal voluntary contraction	Change in knee extensor muscles maximal voluntary contraction	Change between baseline and 12 weeks.
Secondary	Lower body muscle strength	Change in 1-RM (one maximal repetition) (kg) for leg press.	Change between baseline and 12 weeks.
Secondary	Upper body muscle strength	Change in 1-RM (one maximal repetition) (kg) for chest press.	Change between baseline and 12 weeks.
Secondary	Grip strength	Change in grip strength (kg).	Change between baseline and 12 weeks.
Secondary	Fat mass	Change in fat mass measured with bioelectrical impedance analysis (BIA).	Change between baseline and 12 weeks.
Secondary	Fat-free mass	Change in fat-free mass measured with bioelectrical impedance analysis (BIA).	Change between baseline and 12 weeks.
Secondary	Weight	Change in weight (kg).	Change between baseline and 12 weeks.
Secondary	Waist circumference	Change in waist circumference (cm)	Change between baseline and 12 weeks.