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.

Participants assigned to the control arm of the study will be asked to maintain their normal dietary and exercise habits.

Participants randomised to the aerobic exercise intervention will undertake a 12-week aerobic exercise training programme.

Participants randomised to the resistance exercise intervention will undertake a 12-week aerobic exercise training 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.

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.

Change in insulin-stimulated GLUT4 translocation in muscle biopsies from vastus lateralis using immunofluorescence microscopy

Change in fold-increase in insulin stimulated quadriceps muscle blood volume measured using contrast enhanced ultrasound.

Change in mitochondrial function (oxygen consumption rate) in isolated skeletal muscle mitochondria from the vastus lateralis measured using respirometry

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 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 in endothelial specific protein content and phosphorylation of key microvascular enzymes in muscle biopsies from vastus lateralis assessed using quantitative immunofluorescence.

Change in maximal oxygen uptake consumption assessed using continuous incremental uphill walking protocol until volitional exhaustion.

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

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. Erratum In: Lancet Diabetes Endocrinol. 2021 Jan;9(1):e1.