C-13 NMR of intermediary metabolism: Implications for systemic physiology

The study of intermediary metabolism in biomolecules has been given new dir ections by recent experiments in human muscle and brain by C-13 NMR. Labele d substrates, generally glucose, have enabled the fluxes to be determined i n vivo, whereas the naturally abundant C-13 has enabled concentrations to b e measured. In muscle the glycogen synthesis pathway has been measured and the flux control determined by metabolic control analysis of data, which sh ows 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 p hysiological point of view the most surprising result was that the heavily regulated allosteric enzyme, glycogen synthase, does not control flux but i s 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 cel lular activities. In human and rat brains C-13 NMR measurements of the flow of labeled glucos e into glutamate and glutamine simultaneously determine the rate of glucose oxidation and glutamate neurotransmitter cycling and reveal a 1:1 stoichio metry between the two fluxes. Implications for the interpretation of functi onal imaging studies and for psychology are discussed. These results demonstrate how intermediary metabolism serves to connect bio chemistry with systemic physiology when measured and analyzed by in vivo NM R methods.