Steady-state brain glucose transport kinetics re-evaluated with a four-state conformational model

Abstract

Glucose supply from blood to brain occurs through facilitative transporter proteins. A near linear relation between brain and plasma glucose has been experimentally determined and described by a reversible model of enzyme kinetics. A conformational four-state exchange model accounting for trans-acceleration and asymmetry of the carrier was included in a recently developed multi-compartmental model of glucose transport. Based on this model, we demonstrate that brain glucose (G_brain) as function of plasma glucose (G_plasma) can be described by a single analytical equation namely comprising three kinetic compartments: blood, endothelial cells and brain. Transport was described by four parameters: apparent half saturation constant K_t, apparent maximum rate constant T_max, glucose consumption rate CMR_glc, and the iso-inhibition constant K_ii that suggests G_brain as inhibitor of the isomerisation of the unloaded carrier. Previous published data, where G_brain was quantified as a function of plasma glucose by either biochemical methods or NMR spectroscopy, were used to determine the aforementioned kinetic parameters. Glucose transport was characterized by K_t ranging from 1.5 to 3.5 mM, T_max/CMR_glc from 4.6 to 5.6, and K_ii from 51 to 149 mM. It was noteworthy that K_t was on the order of a few mM, as previously determined from the reversible model. The conformational four-state exchange model of glucose transport into the brain includes both efflux and transport inhibition by G_brain, predicting that G_brain eventually approaches a maximum concentration. However, since K_ii largely exceeds G_plasma, iso-inhibition is unlikely to be of substantial importance for plasma glucose below 25 mM. As a consequence, the reversible model can account for most experimental observations under euglycaemia and moderate cases of hypo- and hyperglycaemia.