PhD defence S. (Shamma) Almuraikhy

Validation and therapeutic targeting of novel biomarkers of insulin resistance in non-obese subjects

This thesis investigates the molecular mechanisms underlying the effects of exercise on insulin sensitivity in non-obese individuals at risk of developing type 2 diabetes (T2D). The high prevalence of insulin resistance and T2D, even among non-obese populations, become a major global health challenge. Exercise is an effective non-pharmaceutical intervention for improving insulin sensitivity and reducing T2D risk. However, the underlying molecular pathways mediating these protective effects are not fully understood.The research utilizes metabolomics data from elite athletes and Biobank to compare exercise-induced metabolic alterations between active and sedentary healthy individuals with varying insulin sensitivity status. Key findings include distinct metabolic signatures associated with leukocyte telomere length in elite soccer players, lower circulating complement levels in high endurance athletes indicating reduced inflammation, and differential effects of physical activity on lipid versus glucose metabolism pathways in insulin-resistant individuals.The thesis identifies metabolic biomarkers and pathways related to fatty acid oxidation, oxidative stress, and inflammation that are modulated by exercise and associated with insulin sensitivity in non-obese subjects. An 8-week aerobic exercise intervention in young women demonstrated improvements in insulin sensitivity accompanied by increases in antioxidant metabolites like bilirubin degradation products. A combined exercise and fasting intervention revealed increased telomere length, suggesting benefits for cellular aging.Overall, the research provides insights into the potential of exercise to reverse insulin resistance before disease onset through regulation of specific metabolic pathways. The findings have implications for developing targeted exercise prescriptions and preventive interventions for metabolic disorders in at-risk non-obese populations.