Kinetic Model of 2-Deoxyglucose Metabolism Using Brain Slices

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Abstract
A six-compartment, nine-parameter kinetic model of 2-deoxyglucose (2DG) metabolism, which includes bidirectional tissue transport, phosphorylation, two-step dephosphorylation, phosphoisomerization, and conjugation to UDP and macromolecules, has been derived. Data for analysis were obtained from 540- and 1,000-μm-thick hippocampal and hypothalamic brain slices, which were incubated in buffer containing [14C]2DG, frozen, extracted with perchlorate, and separated on anion-exchange columns. Solutions of the equations of the model were fit to the data by means of nonlinear least-squares analysis. These studies suggest that dephosphorylation is adequately described by a single reaction so that the model reduces to eight parameters. The in vitro rate constants for transport, phosphorylation, and dephosphorylation are very similar to prior in vivo results. The phosphoisomerization rate constant is similar to dephosphorylation, so glycosylated macromolecules slowly accumulate and gradually assume larger relative importance as other compounds disappear more rapidly. Rate constants for 540-μm slices from hypothalamus and hippocampus are similar, while 1,000-μm slices have smaller tissue transport constants and larger phosphorylation constants. The rate equation for glucose utilization of this model is relatively insensitive to uncertainties regarding the rate constants. Including later metabolic components in kinetic models improves the calculations of glucose utilization with long isotope exposures.

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