Improving flexibility in substrate metabolism: a pharmacological and lifestyle approach

Overweight increases the risk of cancer, non-alcoholic fatty liver disease, cardiovascular disease, and the development of diabetes type 2. These metabolic diseases are characterised by less pronounced carbohydrate and fat oxidation fluctuations over 24 hours. This thesis focuses on a better understanding of 24-hour substrate metabolism and investigates whether pharmacological and lifestyle interventions that stimulate a more pronounced overnight fast can improve metabolic health. First of all, it was demonstrated that treatment with a pharmacological compound, an SGLT2 inhibitor, increased 24-hour and nocturnal fat oxidation and reduced carbohydrate oxidation in individuals with prediabetes. Second, it was demonstrated that acutely prolonging the overnight fast by 6.5 hours in individuals with non-alcoholic fatty liver disease and age matched controls, resulted in higher nocturnal fat oxidation and lower nocturnal carbohydrate oxidation. Third, repeatedly prolonging the overnight fast in individuals with type 2 diabetes lowered 24-hour carbohydrate oxidation, but did not result in higher fat oxidation. However, fasting and 24-hour glucose levels improved. In conclusion, it was shown that individuals with overweight or obesity have a disturbed 24-hour substrate metabolism, and that this can be improved by pharmacological and lifestyle interventions, eliciting a more pronounced overnight fast.