Understanding the mechanistic links between nutrition, skeletal muscle and exercise and type 2 diabetic phenotypes in older Indians.

Diabetes is a global epidemic posing immense public health challenges across the world, but particularly in the growing populations of the Indian sub-continent. In India alone the number of people with this disease is over 65 million the annual cost of this disease is now enormous. It is thus already a major health and health-care issue and one which is continuing to grow with the changing demographic towards that of an older population. It is in the older population where the biggest changes and challenges are occurring.

Type 2 diabetes is a metabolic disease typically characterized by insulin resistance and caused primarily by a combination of high energy intake and low energy expenditure. Thus individuals typically are overweight (have a high body mass index) and have low levels of physical activity. In Indians's there is a second population of individuals who have a similar metabolic condition, but are not overweight - termed "metabolically obese". Here, there appears to be fat accumulation in areas not typically associated with adipose deposition. One of these areas is in skeletal muscle. Muscle plays a vital role in metabolic health. It is the biggest store and biggest user of glucose in the body, providing a clear link to physical inactivity. This project seeks to increase our understanding of the mechanisms underpinning these two different types of diabetes in India.

It will do this by identifying the the skeletal muscle metabolic /lipid characteristics of Indians over 55 years who represent the two different metabolic phenotypes (as well as healthy controls) and how this is related to beta cell function and insulin sensitivity, body composition, cardio-respiratory fitness and muscle function.

It will compare the metabolic (metabolomic) and mitochondrial phenotype (respiratory function, proteome, transcriptome) in skeletal muscle in terms of Indians exhibiting the two different metabolic types. It will seek to establish differences in lipid accumulation and cellular phenotypes in muscle-derived cells (myoblasts and fibroblasts) studied in culture (outside the body) obtained from the two different diabetic phenotypes and determine if this relates to altered mitochondrial function.

It will then compare the above with similar measures made on 2nd/3rd generation Indians living in the UK.

Finally, the project will undertake a longitudinal to investigate the effects of an intervention programme, which uses targeted nutritional supplementation combined with both aerobic and strength training exercise to improve mitochondrial, muscle size and metabolic health in the different Indian diabetic phenotypes described above.

The proposed project seeks to understand mechanisms and interactions between nutrition, exercise and skeletal muscle in the two distinct diabetic phenotypes in India - with a focus on those over 55 years. The two phenotypes are that those are "typically" diabetic - characterised by a high BMI and low physical activity and those that have a normal BMI, but have an obese metabolic phenotype. We also intend to compare 2nd / 3rd generation Indians living in the UK.

This work is in particular regard to lipid accumulation in skeletal muscle and to mitochondrial function. We will identify the skeletal muscle metabolic /lipid characteristics of Indians over 55 years who represent the two different metabolic phenotypes (compared to healthy normal BMI controls) and how this is related to beta cell function and insulin sensitivity, body composition, cardiorespiratory fitness and muscle function. We will then compare the metabolic (metabolomic) and mitochondrial phenotype (respiratory function, proteome, transcriptome) in skeletal muscle. In parallel studies we will establish if there are differences in lipid accumulation and cellular phenotypes in muscle derived cells (myoblasts and fibroblasts) obtained from biopsy samples taken from the different populations and studied in culture.

Finally, we will use the methods described above to investigate study the effects of a multimodal programme, which uses targeted nutritional supplementation combined with both aerobic and strength training exercise to improve mitochondrial function and metabolic phenotype in the two different Indian phenotypes.

The number of people with diabetes in India has increased a great deal from 26 million in 1990 to 65 million in 2016, with an increase in crude prevalence from 5.5 to 7.7% in the same time period. Several successful lifestyle modification trials have shown that diet and physical activity management, along with weight loss, result in a lower incidence of diabetes.

However, public health messaging and clinical advice about weight control and lifestyle, need to be nuanced appropriately in India. For example, diabetes and prediabetes occur at a normal or slightly overweight BMI in India, where weight loss might not be the relevant strategy for glycaemic control. In such subjects, weight loss in the absence of appropriate exercise also leads to the loss of skeletal muscle, which is an important sink for postprandial increases in blood glucose. It is also clear from preliminary work by this group of investigators, that ectopic fat accumulation in skeletal muscle is substantial in Indians with prediabetes.

The pathway to impact will be through:

i) the communication and dissemination of the results of this work to relevant science forums.

ii) engaging with specific task forces at the Indian Council of Medical Research (ICMR), and the Department of Biotechnology (DBT), to set out specific recommendations for exercise in existing lifestyle recommendations. The Indian investigators sit on several advisory committees of the ICMR and DBT. At present, recommendations are vague, and usually deal with simple aerobic exercises like walking or running to maintain body weight. Much more specificity is required on the need for a routine of exercise, that includes isometrics.

iii) finding ways to translate our findings (and subsequent recommendations) into daily use by people of all ages. Since the access to exercise equipment is limited in India, we will engage with white collar industries to suggest the installation of appropriate gym equipment and trainers to encourage a safe transition to a more active and exercise-time. We will also define 'at home' ways to engage in isometric exercise, that are safe for middle aged and elderly people. We will work with physiotherapy departments in Bangalore (and eventually in other cities) to bring out booklets and social media pieces on 'how to do' these exercises at home. Fifth, it is important to people who engage in the appropriate exercise to know how they are doing. We will evaluate ways and means (DEXA or bioimpedance) for reasonably economical ways for participants to monitor their own muscle mass, and even segmental fat content. If this can be made a part of routine medical check-ups, that will be very useful in the impact pathway. For that, we will engage with doctors associations, specifically diabetologists.

Overall, we anticipate that our path to impact will be through a mix of 'official' recommendations for lifestyle in the prevention of adult chronic disease, as well as the specific informing of the clinical management of diabetic Indians who are normal or overweight. More importantly, we also hope to evolve more informal guidelines (from nutrition or physiotherapy associations) on how these recommendations can be translated into daily life at low cost. These more informal methods will include the use of social media and audiovisual aids.