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Lewis Sheiner


2019
Stockholm, Sweden



2018
Montreux, Switzerland

2017
Budapest, Hungary

2016
Lisboa, Portugal

2015
Hersonissos, Crete, Greece

2014
Alicante, Spain

2013
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2012
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2011
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2010
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2009
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2008
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2007
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2006
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2005
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2004
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2003
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2002
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2001
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2000
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1999
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1998
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1997
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1996
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1995
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1994
Greenford, UK

1993
Paris, France

1992
Basel, Switzerland



Printable version

PAGE. Abstracts of the Annual Meeting of the Population Approach Group in Europe.
ISSN 1871-6032

Reference:
PAGE 25 (2016) Abstr 5760 [www.page-meeting.org/?abstract=5760]


PDF poster/presentation:
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Poster: Drug/Disease modeling - Endocrine


IV-52 Veronika Voronova 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 [1]. 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 [1], 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. 



References:
[1] Quagliaro L, Piconi L, Assaloni R. Intermittent High Glucose Enhances Apoptosis Related to Oxidative Stress in Human Umbilical Vein Endothelial Cells: The Role of Protein Kinase C and NAD(P)H-Oxidase Activation. Diabetes. 52:2795-2804, 2003