Investigation of the diabetes-related metabolic memory phenomenon using a quantitative systems pharmacology approach
Veronika Voronova (1), Kirill Zhudenkov (1)
(1) M&S Decisions LLC
Objectives: Hyperglycemia is generally associated with an increased intracellular generation of reactive oxygen species (ROS) and oxidative stress. ROS may, in turn, play a key role in the development of various diabetes-related complications. A quantitative link between glucose plasma levels and oxidative stress shows a complex behavior . First, oxidative stress persists after glucose normalization, and this is defined as metabolic memory. Second, instable glucose is more detrimental for living systems comparing to constant high glucose. The objective of the current study was to explain mechanisms of these observations, using an integrative, quantitative systems pharmacology (QSP) modeling approach.
Methods: The model was based on a system of ordinary differential equations and included the following mechanistic and semi-empirical relationships: (a) increased glucose level stimulates ROS generation and oxidative stress, which triggers a process of continuous adaptation to hyperglycemia; (b) excess ROS promotes the accumulation of metabolic memory, which accelerates glucose effect on ROS generation. Model parameters were verified using published in vitro data , such as ROS generation as measured in endothelial cell cultures placed into constant high (20 or 30 mmol/l) or oscillating (24 h in 5 mmol/l - 24 h in 25 mmol/l) glucose followed by normal glucose (5 mmol/l).
Results: The developed model adequately described data from the literature. It adequately reproduced the metabolic memory phenomenon and predicted excess ROS generation after glucose normalization. This behavior is caused by a system of positive feedback regulations between ROS and cumulative effects of the metabolic memory appearance and adaptation. Additionally, model simulations showed that, in vitro, the appearance of metabolic memory is dependent on the duration of cell exposure to glucose levels.
Conclusions: A QSP model describing glucose effects on ROS generation was developed, based on data published in the literature. The model was used to explore the hypothesis of metabolic memory appearance in response to excess ROS and glucose levels. This model can be further used to probe long-term effects of diabetes progression and development of diabetes-related complications.
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