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A model-based analysis of the multi-tissue interplay underlying blood glucose regulation in diabetes

Author(s):

Wadehn, Frederico
Conference/Journal:

Master Thesis, FS 13 (10240)
Abstract:

Diabetes is a metabolic disorder affecting over 300 million people world-wide, with a prevalence varying strongly between different populations. Several studies have pointed out that impairments in cellular metabolism, both in-born and acquired, play a significant role in the origination of diabetes. Discovery of diabetes associated genetic predispositions and enzyme deficiencies, with the help of mechanistic in silico models, would provide new means for early stage diagnosis and could foster the development of anti-diabetic drugs, by indicating novel drug targets. On a whole-body level, physiologically based pharmacokinetic-pharmacodynamic (PBPK-PD) models, describing the complex interplay of regulating hormones like insulin and glucagon in blood glucose regulation, have been used successfully in current research. These ODE-based PBPK-PD models for distribution of regulating hormones and metabolism of glucose, describe cellular processes only on an abstract phenomenological level. To study impaired cellular metabolism in diabetes, genome-scale metabolic networks are increasingly being used in modern diabetes research. These cellular models however, have been limited to stationary analysis of intracellular processes. The approach in this thesis was to build a multi-scale multi-tissue model for blood glucose regulation in diabetes patients, by integrating three genome scale metabolic networks for adipocytes, hepatocytes and myocytes into a whole-body PBPK-PD model for blood glucose regulation. The multi-scale model was then used to assess the effect of diabetes related gene-defects and drug-induced enzyme inhibitions on blood glucose levels. Furthermore, flux span analysis with models for diabetic adipocytes, hepatocytes and myocytes was used to identify the activation of suboptimal metabolic pathways in impaired metabolic networks. Altogether the developed multi-scale diabetes model provides a platform to study interrelations between cellular metabolism and whole-body blood glucose regulation in diabetes.

Year:

2014
Type of Publication:

(12)Diploma/Master Thesis
Supervisor:

H. Koeppl

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% Autogenerated BibTeX entry
@PhdThesis { WadFre:2014:IFA_4674
}
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