Simultaneous measurement of glucose transport and utilization in the human brain

Abstract

Glucose is the primary fuel for brain function, and determining the kinetics of cerebral glucose transport and utilization is critical for quantifying cerebral energy metabolism. The kinetic parameters of cerebral glucose transport, K(M)(t) and V(max)(t), in humans have so far been obtained by measuring steady-state brain glucose levels by proton ((1)H) NMR as a function of plasma glucose levels and fitting steady-state models to these data. Extraction of the kinetic parameters for cerebral glucose transport necessitated assuming a constant cerebral metabolic rate of glucose (CMR(glc)) obtained from other tracer studies, such as (13)C NMR. Here we present new methodology to simultaneously obtain kinetic parameters for glucose transport and utilization in the human brain by fitting both dynamic and steady-state (1)H NMR data with a reversible, non-steady-state Michaelis-Menten model. Dynamic data were obtained by measuring brain and plasma glucose time courses during glucose infusions to raise and maintain plasma concentration at ∼17 mmol/l for ∼2 h in five healthy volunteers. Steady-state brain vs. plasma glucose concentrations were taken from literature and the steady-state portions of data from the five volunteers. In addition to providing simultaneous measurements of glucose transport and utilization and obviating assumptions for constant CMR(glc), this methodology does not necessitate infusions of expensive or radioactive tracers. Using this new methodology, we found that the maximum transport capacity for glucose through the blood-brain barrier was nearly twofold higher than maximum cerebral glucose utilization. The glucose transport and utilization parameters were consistent with previously published values for human brain.

Fig. 1.

The reversible Michaelis-Menten models utilized to extract kinetic parameters for cerebral glucose transport and utilization. The extracted kinetic parameters are shown in dotted boxes. BBB, blood-brain barrier; BCB, blood-cerebrospinal fluid (CSF) barrier; V_in^t, blood-to-brain glucose transport rate; V_out^t, brain-to-blood glucose transport rate; V_max^t, maximal glucose transport rate through the BBB; K_M^t, the glucose concentration for half-maximal transport through the BBB; V_max,BCB^t, maximal glucose transport rate through the BCB; K_M,BCB^t, the glucose concentration for half-maximal transport through the BCB; k_d, transport coefficient for diffusion between CSF and brain tissue; V_max^util, maximal brain glucose utilization rate; K_M^util, brain glucose concentration for half-maximal utilization; CMR_glc, cerebral metabolic rate of glucose utilization.

Fig. 2.

¹H MR spectra acquired at 4 T from 1 volunteer before (baseline) and during infusion of glucose (Glc) at selected time points. The voxel position is shown on a T₂-weighted image. The increase of the 3.44- and the 5.23-ppm glucose resonances over time is visible in the spectra. Spectra were acquired with a stimulated echo acquisition mode sequence [repetition time (TR) = 4.5 s, echo time (TE) = 5 ms] and weighted with a Gaussian function prior to Fourier transformation. No baseline correction was applied. The residual water peak was removed. Each spectrum consists of 32 transients; i.e., they were acquired over 2.5 min.

Fig. 3.

Plasma and brain glucose concentrations in each of the 5 healthy volunteers. Also shown are the best fits of the non-steady-state, reversible Michaelis-Menten model (model no. 1) to the time courses of brain glucose concentrations. ●Plasma (left) and brain (right) glucose concentrations.

Fig. 4.

Steady-state brain vs. plasma glucose concentrations from literature (6, 19) and the current study. Also shown is the best fit of the steady-state, reversible Michaelis-Menten model to these steady-state data.

Fig. 5.

A: average glucose concentrations obtained in CSF and plasma in response to a bolus intravenous glucose infusion in 5 healthy volunteers from literature; error bars are SD (13). The line represents the best fit of model no. 2 (Fig. 1) for glucose transport through the BCB. B: time course of plasma glucose concentration in subject no. 5 together with CSF glucose concentration predicted based on model no. 2 and values of BCB transport determined in A.