Andreas Vigelsø - Age-related metabolic inflexibility studied after 72 hours’ fasting
Age is a major risk factor for insulin resistance, and thus, type 2 diabetes. The development of insulin resistance has been associated with metabolic inflexibility (MI), yet the underlying mechanisms are complex and not well understood. MI is defined and observed as an inability to favor lipid metabolism during fasting and exercise, and conversely, to suppress lipid oxidation and increase glucose uptake, storage, and oxidation under insulin-stimulated conditions (feeding).
Therefore, the age-related changes in the muscle metabolism that regulate muscle substrate choice are of major importance to understand the development of MI. Prolonged fasting (> 48 hours) induces an extreme physiological condition that challenges substrate oxidation and storage (e.g. increases plasma catecholamines, whole-body lipolysis, plasma fatty acids, intramuscular triglyceride levels, ketone body synthesis, and lipid oxidation) that may explain attenuated glucose uptake and oxidation by peripheral tissues (i.e. insulin resistance).
Thus, prolonged fasting is an excellent model to address molecular limitations that may explain MI as e.g. impairments in 5' AMP-activated protein kinase (AMPK) activity, mitochondrial function, and intramuscular triglyceride (IMTG) regulation. Therefore, the aim is to use prolonged fasting combined with acute exercise to study differences in MI between young and older men, and thereby, provide insight that will improve our understanding of the underlying mechanisms leading to type 2 diabetes. Thus, my hypothesis is that older men have an impaired response to fasting, feeding, and exercise as a sign of metabolic inflexibility compared to young men.
Twelve young and 12 older men that are representative for their age-group will be fasting for 72 hours, and after that fed a carbohydrate meal that will increase plasma insulin and lead to a shift towards glucose oxidation and inhibition of whole-body lipolysis. Before and after fasting and after the meal the participants will have their resting fasting metabolic rate measured and perform 60 min cycling exercise at 55 % of VO2max. Before and immediately after each exercise bout a muscle biopsy will be obtained from vastus lateralis. The biopsies will be analyzed for substrates (IMTG and glycogen), AMPK activity, and IMTG regulating proteins.