Impaired skeletal muscle fat oxidation as a mechanism for insulin resistance in South Asians

The impending global pandemic of obesity, type 2 diabetes and vascular disease suggests an urgent need for both prevention strategies and effective treatment. Of all the common ethnic groups South Asians, who make up a fifth of the world’s population, have the highest prevalence of both diabetes and vascular disease. The high rates of diabetes, in particular, occur with lower average adiposity levels, suggesting that South Asians are more susceptible to the effects of obesity. Differences in insulin sensitivity and diabetes prevalence between South Asians and Europeans cannot be fully explained by differences in adiposity alone. The aim of this thesis was to investigate whether differences in oxidative capacity and capacity for fatty acid utilisation in South Asians might contribute, using a range of whole-body and skeletal muscle measures. Twenty South Asian men and 20 age and BMI-matched white European men underwent exercise and metabolic testing and muscle biopsy to determine expression of oxidative and lipid metabolism genes and of insulin signalling proteins. In fully adjusted analyses, South Asians, compared to Europeans, exhibited significantly reduced insulin sensitivity; lower VO2max and reduced fat oxidation during submaximal exercise at the same exercise intensities. South Asians exhibited significantly higher skeletal muscle gene expression of CPT1A and FASN and significantly lower skeletal muscle protein expression of PI3K and PKB Ser473 phosphorylation. Fat oxidation during submaximal exercise and VO2max both correlated significantly with insulin sensitivity index and PKB Ser473 phosphorylation, with VO2max or fat oxidation during exercise explaining 10–13% of the variance in insulin sensitivity index, independent of age, adiposity and physical activity. These data suggest that reduced oxidative capacity and capacity for fatty acid utilisation at the whole body level are key features of the insulin resistant phenotype observed in South Asians, but that this is not the consequence of reduced skeletal muscle expression of oxidative and lipid metabolism genes