UNDERSTANDING THE MECHANISM OF INSULIN RESISTANCE IN SKELETAL MUSCLE TISSUE IN A MULTI-ETHNIC POPULATION

Abstract

Type 2 diabetes (T2D) is a complex disease with insulin resistance (IR) as one of the key pathophysiologic defects. In this thesis, I used an integrative-omics approach to investigate the molecular basis underlying differences in IR due to ethnicities and weight loss.

From the study on ethnic differences, a network of 46 genes were downregulated in Malays, suggesting dysregulation of cellular respiration in skeletal muscle (SM). Four differentially expressed gene clusters were enriched for genes found in GWAS of metabolic traits and disease.

From the weight loss study, differential co-expression in insulin signalling pathway could explain the decrease in SM IR following weight loss. The FTO locus was also associated with a change in AKT interacting protein gene expression in the skeletal muscle tissue, potentially affecting insulin signalling via the activation of AKT.

These studies identified extensive gene expression changes in SM between ethnicities and highlights specific findings that may explain the IR changes due to ethnic differences and weight loss.