Non-invasive markers of muscular metabolic flexibility

Metabolic flexibility is the ability of an organism to adapt to changes in metabolic demand due to the nutrient availability or activity. Impairment of metabolic flexibility is one of the hallmarks of prevalent metabolic diseases insulin resistance and type-2-diabetes mellitus. The failure to switch from lipid oxidation in fasting state to carbohydrate consumption can be assessed on whole body scale by indirect calorimetry, but these effects are only the summ of processes in specific human tissues. Based on our previous findings and the available literature, we suppose that we can non- invasively detect and characterize dynamic markers of metabolic inflexibility by in vivo novel state- of-the art high field magnetic resonance measurements within skeletal muscle. We assume that the acetylcarnitine concentration will be significantly lower while nicotinamide adenine dinucleotide phosphate concentrations will be higher in otherwise healthy but impaired glucose tolerant individuals and type 2 diabetes patients compared to normally active, healthy volunteers. Furthermore, we hypothesize that the measurement of dynamic changes induced by acute physical exercise and/or oral glucose intake might be able to record subtle differences in acetylcarnitine and NAD(P) metabolism between type-2-diabetes mellitus patients, volunteers with impaired glucose tolerance and healthy volunteers. The understanding and assessment of these processes can be used in further clinical research, medical diagnosis, and the assessment of effects of different pharmacologic or life-style interventions in population prone to diabetes mellitus and reveal potential targets for therapy of metabolic disease. Furthermore, the study will yield technical developments for simultaneous MRS-based detection of different metabolites which could became novel non-invasive markers of metabolic flexibility.

Metabolic flexibility is the ability of an organism to adapt to changes in metabolic demand due to the nutrient availability or activity. Impairment of metabolic flexibility is one of the hallmarks of prevalent metabolic diseases insulin resistance and type-2-diabetes mellitus. The failure to switch from lipid oxidation in fasting state to carbohydrate consumption can be assessed on whole body scale by indirect calorimetry, but these effects are only the sum of processes in specific human tissues. In this project we aimed at the dynamic measurement of skeletal muscle acetylcarnitine and nicotinamide adenine dinucleotide phosphate concentration by advanced interleaved methods of multinuclear MRS during acute exercise challenge or nutrient oversupply. We could establish this highly specific measurement and demonstrate its value for the phenotyping lean/active and obese/sedentary volunteers. We could also show, that the dynamic changes in acetylcarnitine relate to well established measures of mitochondrial capacity. Thus, we suggest this broadly applicable measure as a novel marker non-invasive marker of metabolic flexibility. To validate this hypotheses, we have initiated the measurements on volunteers with insulin resistance and type 2 diabetes mellitus in the final stage of the project. The understanding and assessment of these processes can be used in further clinical research, medical diagnosis, and the assessment of effects of different pharmacologic or life-style interventions in population prone to diabetes mellitus and reveal potential targets for therapy of metabolic disease.