In vivo determination of the kinetic parameters of glucose transport in the human brain using 11C-methyl-d-glucose (CMG) and dynamic positron emission tomography (dPET)

Abstract

A method was developed to measure simultaneously the rate constants for glucose influx and glucose efflux, and the Michaelis-Menten constant (KM) and maximal velocity (Vmax) for glucose transport across the blood-brain barrier (BBB) in any selected brain area. Moreover, on the basis of a mathematical model, the local perfusion rate (LPR) and local unidirectional glucose transport rate (LUGTR) are calculated in terms of parameters of the time-activity curves registered over different brain regions; 11C-methyl-D-glucose (CMG) is used as an indicator. The transaxial distribution of activity in the organism is registered using dynamic positron-emission tomography (dPET). The method was used in 4 normal subjects and 50 patients with ischemic brain disease. In normals, the rate constant for CMG efflux was found to be 0.25 +/- 0.04 min-1 in the cortex and 0.12 +/- 0.02 min-1 in white matter. In the cortex, the KM was found to be 6.42 mumol/g and the Vmax was 2.46 mumol/g per minute. The LUGTR ranged from 0.43 to 0.6 mumol/g per minute in the cortex, and from 0.09 to 0.12 mumol/g per minute in white matter. The LPR was calculated to be 0.80-0.98 ml/g per minute for the cortex and 0.2-0.4 ml/g per minute for white matter. In patients with stroke, the ischemic defects appeared to be larger in CMG scans than in computed x-ray tomography (CT) scans. Prolonged reversible ischemic neurological deficit was associated with a significant fall in the LUGTR but no change in the LPR in the corresponding cerebral cortex. Normal LUGTR and significantly decreased LPR were registered in a patient with progressive occlusion of the middle cerebral artery. In a patient with transient ischemic attacks, a slightly reduced LPR and a disproportionally reduced LUGTR were observed before operation. After extra- and intracranial bypass surgery, the LPR became normal, whereas the LUGTR increased but did not achieve normal values.

Simultaneous Determination of the Rates of the TCA Cycle, Glucose Utilization, α-Ketoglutarate/Glutamate Exchange, and Glutamine Synthesis in Human Brain by NMR

“…The primary effects of glucose trans port on the calculation of V tca are described by the parameter llt1h' Glucose transport kinetic constants of 4.9 mM for Km and 3.6 for V m a x/CMRgl deter mined by l3C NMR (Gruetter et aI., 1992a) with a TCA cycle rate V tca = 0.729 /-lmol min -1 g -1 led to a value of 1.50 min for lltl/2 during a typical [1-l3C]glucose infusion protocol. The glucose trans port kinetics of Vyska et al (1985) and Feinendegen et al (1986) measured using positron emission to mography (PET) in humans yielded similar llt1/z val ues (1.55 and 1.45 min, respectively). The smallest value of lltlh assumed in the test was 0, which cor responded to infinitely fast blood-brain glucose transport.…”

Assessment of insulin sensitivity in vivo in control and diabetic mice with a radioactive tracer of glucose transport: [125I]‐6‐deoxy‐6‐iodo‐D‐glucose

“…6-DIG will be of clinical interest only if it can be used to identify variations in glucose transport in vivo, as demonstrated with 3-OMG. In fact, [ 11 C]-3-OMG has been used with dynamic positron emission tomography (PET) to study variations in glucose transport in cardiology [21] and neurology [22,[38][39][40]. However, more recently, Bonadonna et al have used carbon 14-labelled 3-OMG in vivo to identify insulin resistance in the skeletal muscle of patients with type 2 diabetes [1].…”

Nuclear Imaging of Glucose Transport/Metabolism – An Interesting Tool to Screen Insulin Resistance, Refine Diagnosis of Type 2 Diabetes, Understand Disease Mechanisms, and/or Evaluate New Therapies

“…D: representative tissue to plasma ratios (TPR) of 11 C-3-OMG radioactivity. [ Figure adapted There have been prior in vivo PET investigations in humans using [ 11 C]3-OMG to study glucose transport across the blood-brain barrier (Vyska et al, 1985;Feinendegen et al, 1986;Brooks et al, 1986aBrooks et al, , 1986b. But the use of this tracer was limited by the fact that it is labelled with carbon 11, a short half-life radioisotope (t 1/2 = 20 minutes) produced by cyclotron, which undoubtedly explains why very few studies have been devoted to this compound.…”