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Physiologically Based Simulations of Deuterated Glucose for Quantifying Cell Turnover in Humans.

Lahoz-Beneytez, J; Schaller, S; Macallan, D; Eissing, T; Niederalt, C; Asquith, B (2017) Physiologically Based Simulations of Deuterated Glucose for Quantifying Cell Turnover in Humans. Frontiers in Immunology, 8: 474. https://doi.org/10.3389/fimmu.2017.00474
SGUL Authors: Macallan, Derek Clive

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Abstract

In vivo [6,6-(2)H2]-glucose labeling is a state-of-the-art technique for quantifying cell proliferation and cell disappearance in humans. However, there are discrepancies between estimates of T cell proliferation reported in short (1-day) versus long (7-day) (2)H2-glucose studies and very-long (9-week) (2)H2O studies. It has been suggested that these discrepancies arise from underestimation of true glucose exposure from intermittent blood sampling in the 1-day study. Label availability in glucose studies is normally approximated by a "square pulse" (Sq pulse). Since the body glucose pool is small and turns over rapidly, the availability of labeled glucose can be subject to large fluctuations and the Sq pulse approximation may be very inaccurate. Here, we model the pharmacokinetics of exogenous labeled glucose using a physiologically based pharmacokinetic (PBPK) model to assess the impact of a more complete description of label availability as a function of time on estimates of CD4+ and CD8+ T cell proliferation and disappearance. The model enabled us to predict the exposure to labeled glucose during the fasting and de-labeling phases, to capture the fluctuations of labeled glucose availability caused by the intake of food or high-glucose beverages, and to recalculate the proliferation and death rates of immune cells. The PBPK model was used to reanalyze experimental data from three previously published studies using different labeling protocols. Although using the PBPK enrichment profile decreased the 1-day proliferation estimates by about 4 and 7% for CD4 and CD8+ T cells, respectively, differences with the 7-day and 9-week studies remained significant. We conclude that the approximations underlying the "square pulse" approach-recently suggested as the most plausible hypothesis-only explain a component of the discrepancy in published T cell proliferation rate estimates.

Item Type: Article
Additional Information: Copyright © 2017 Lahoz-Beneytez, Schaller, Macallan, Eissing, Niederalt and Asquith. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Keywords: T cell kinetics, cell turnover, deuterium labeling, mathematical modeling, systems biology, T cell kinetics, cell turnover, deuterium labeling, mathematical modeling, systems biology
SGUL Research Institute / Research Centre: Academic Structure > Infection and Immunity Research Institute (INII)
Journal or Publication Title: Frontiers in Immunology
Language: eng
Dates:
DateEvent
25 April 2017Published
5 April 2017Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
317040 (QuanTI)European Union Seventh Framework Programme (FP7/2007- 2013)UNSPECIFIED
103865Wellcome Trusthttp://dx.doi.org/10.13039/100004440
J007439Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
G1001052Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
15012Leukemia and Lymphoma ResearchUNSPECIFIED
PubMed ID: 28487698
Go to PubMed abstract
URI: http://openaccess.sgul.ac.uk/id/eprint/108859
Publisher's version: https://doi.org/10.3389/fimmu.2017.00474

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