Mechanisms of insulin resistance in South Asians (MIRSA): the roles of skeletal muscle microvasculature and mitochondrial metabolism

Type 2 diabetes is a major public health problem with worldwide cases projected to rise from ~400 million, currently, to ~600 million by 2035. The risk of diabetes is not consistent across different ethnic groups with people of South Asian (Indian, Pakistani, Bangladeshi, Sri Lankan) origin, who make up nearly a quarter of the world's population, having 2-4 fold higher rates than white Europeans. South Asians also develop diabetes 5-10 years earlier and at lower body weights than white Europeans. By the age of 70, 30-40% of South Asians have diabetes. A key factor influencing risk of type 2 diabetes is a reduction in the ability of muscle to respond appropriately to insulin to take up glucose (sugar) from the blood. This is termed insulin resistance. There is growing evidence that lower levels of fitness and capacity of muscle to burn fat (compared with white Europeans) contributes to South Asians' insulin resistance and higher diabetes risk, but the extent to which this can be improved by exercise is unclear. The main aim of the current proposal, which combines expertise from world-leading groups across three UK Universities, is to determine the extent to which insulin resistance can be improved by an exercise training intervention in South Asian adults, and to identify specific changes in muscle which are responsible for this improvement.

The current proposal is a randomised controlled trial in which 44 South Asian adults at increased risk of diabetes will be randomly assigned to either a 12-week exercise training intervention or 12-weeks of usual lifestyle (control). We will assess the effects of the intervention on insulin resistance, using the gold-standard method, called a euglycaemic hyperinsulinaemic clamp, which measures how well the hormone insulin enables glucose to be removed from the blood. We will also use state-of-the-art techniques to identify how exercise training improves insulin resistance in South Asians by measuring effects of the exercise intervention on: the ability of muscle to burn fat within organelles within muscle called mitochondria, on the number of small blood vessels within the muscle structure (called the microvasculature), and the ability of these small blood vessels to relax. This knowledge will help to optimise lifestyle-based diabetes prevention interventions in South Asians, as well as helping to identify potential new treatment approaches.

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. In this randomised controlled trial, we will investigate the effects of a 12-week exercise training intervention on insulin sensitivity (hyperinsulinaemic-euglycaemic clamp) in South Asian adults (22 intervention, 22 control). We will also explore the mechanisms within skeletal muscle which mediate these changes by evaluating exercise-training induced changes: in basal and insulin-stimulated microvascular blood volume (using contrast-enhanced ultrasound); skeletal muscle mitochondrial function (Seahorse); 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 novel 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.

The aims of the current proposal are to investigate the extent to which insulin sensitivity can be improved by exercise training in South Asians at increased risk of diabetes, and the mechanisms within skeletal muscle underpinning these changes. Successfully achieving these aims will produce a number of major impacts on human health and have practical importance within both academia and industry:

1) We will determine the extent to which insulin resistance can be reduced in South Asians with an achievable exercise-training intervention. Demonstration of the efficacy of such an intervention will facilitate communication to South Asians about why they are at increased risk of diabetes and how exercise can benefit them. This work could lead to the development of larger-scale, longer-term pragmatic exercise training interventions to improve insulin sensitivity and reduce diabetes risk in South Asians. In particular, the findings will facilitate future randomised controlled trials using exercise training to improve insulin sensitivity and reduce diabetes risk in South Asians before the onset of impaired glucose tolerance (when current interventions are less effective in South Asians, than in other ethnic groups). This will be of benefit to South Asians at risk of diabetes, healthcare providers, and the academic community.

2) It will increase basic science knowledge of the mechanisms by which exercise training improves insulin sensitivity in South Asians. This will benefit academics researching insulin resistance and pathogenesis of diabetes and will also help with the optimisation of lifestyle-based interventions to improve insulin sensitivity and reduce diabetes risk. These mechanistic insights also have wider potential benefits. Whilst it is likely that exercise training will substantially improve insulin sensitivity in South Asians, we are aware that many South Asians at risk of diabetes may not engage with participating in such interventions. Thus, understanding the mechanisms by which exercise training improves insulin sensitivity in South Asians opens up the potential for development pharmacological therapies to mimic these effects. This will benefit pharmaceutical companies, and academics/clinicians with an interest in the development of pharmacological therapies for diabetes prevention and treatment.

The ultimate beneficiary would be South Asians at increased risk of diabetes, and healthcare providers responsible for their treatment. Improved therapies for diabetes prevention will contribute to reduced incidence of diabetes and associated complications. This will improve quality of life and reduce both healthcare and wider societal costs associated with diabetes in South Asian populations.