13C NMR of intermediary metabolism: implications for systemic physiology

The study of intermediary metabolism in biomolecules has been given new directions by recent experiments in human muscle and brain by 13C NMR. Labeled substrates, generally glucose, have enabled the fluxes to be determined in vivo, whereas the naturally abundant 13C has enabled concentrations to be measured. In muscle the glycogen synthesis pathway has been measured and the flux control determined by metabolic control analysis of data, which shows that this pathway is mainly responsible for insulin-stimulated glucose disposal and that a deficiency in the glucose transporter in the pathway is responsible for hyperglycemia in non-insulin-dependent diabetics. From a physiological point of view the most surprising result was that the heavily regulated allosteric enzyme, glycogen synthase, does not control flux but is needed to maintain homeostasis during flux changes. This novel role for a phosphorylated allosteric enzyme is proposed to be a general phenomenon in metabolic and signaling pathways, which physiologically link different cellular activities. In human and rat brains 13C NMR measurements of the flow of labeled glucose into glutamate and glutamine simultaneously determine the rate of glucose oxidation and glutamate neurotransmitter cycling and reveal a 1:1 stoichiometry between the two fluxes. Implications for the interpretation of functional imaging studies and for psychology are discussed. These results demonstrate how intermediary metabolism serves to connect biochemistry with systemic physiology when measured and analyzed by in vivo NMR methods.