Mechanisms of Insulin Resistance and Exercise in South Asians

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

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.

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.

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