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PLoS One. 2017 Feb 8;12(2):e0171781. doi: 10.1371/journal.pone.0171781. eCollection 2017.

Interpretation of metabolic memory phenomenon using a physiological systems model: What drives oxidative stress following glucose normalization?

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M&S decisions LLC, Moscow, Russia.
Quantitative Clinical Pharmacology, Early Clinical Development, Innovative Medicines, AstraZeneca Pharmaceuticals, Boston, Massachusetts, United States of America.


Hyperglycemia is generally associated with oxidative stress, which plays a key role in diabetes-related complications. A complex, quantitative relationship has been established between glucose levels and oxidative stress, both in vitro and in vivo. For example, oxidative stress is known to persist after glucose normalization, a phenomenon described as metabolic memory. Also, uncontrolled glucose levels appear to be more detrimental to patients with diabetes (non-constant glucose levels) vs. patients with high, constant glucose levels. The objective of the current study was to delineate the mechanisms underlying such behaviors, using a mechanistic physiological systems modeling approach that captures and integrates essential underlying pathophysiological processes. The proposed model was based on a system of ordinary differential equations. It describes the interplay between reactive oxygen species production potential (ROS), ROS-induced cell alterations, and subsequent adaptation mechanisms. Model parameters were calibrated using different sources of experimental information, including ROS production in cell cultures exposed to various concentration profiles of constant and oscillating glucose levels. The model adequately reproduced the ROS excess generation after glucose normalization. Such behavior appeared to be driven by positive feedback regulations between ROS and ROS-induced cell alterations. The further oxidative stress-related detrimental effect as induced by unstable glucose levels can be explained by inability of cells to adapt to dynamic environment. Cell adaptation to instable high glucose declines during glucose normalization phases, and further glucose increase promotes similar or higher oxidative stress. In contrast, gradual ROS production potential decrease, driven by adaptation, is observed in cells exposed to constant high glucose.

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Conflict of interest statement

AstraZeneca and M&S Decisions LLC did not provide any data, patients and products for this study. The research is unfunded and based on published information and data. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

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