PloS one, 2014-07, Vol.9 (7), p.e102319-e102319
2014
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- Autor(en) / Beteiligte
- Titel
- Multi-tissue computational modeling analyzes pathophysiology of type 2 diabetes in MKR mice
- Ist Teil von
- PloS one, 2014-07, Vol.9 (7), p.e102319-e102319
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2014
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- Computational models using metabolic reconstructions for in silico simulation of metabolic disorders such as type 2 diabetes mellitus (T2DM) can provide a better understanding of disease pathophysiology and avoid high experimentation costs. There is a limited amount of computational work, using metabolic reconstructions, performed in this field for the better understanding of T2DM. In this study, a new algorithm for generating tissue-specific metabolic models is presented, along with the resulting multi-confidence level (MCL) multi-tissue model. The effect of T2DM on liver, muscle, and fat in MKR mice was first studied by microarray analysis and subsequently the changes in gene expression of frank T2DM MKR mice versus healthy mice were applied to the multi-tissue model to test the effect. Using the first multi-tissue genome-scale model of all metabolic pathways in T2DM, we found out that branched-chain amino acids' degradation and fatty acids oxidation pathway is downregulated in T2DM MKR mice. Microarray data showed low expression of genes in MKR mice versus healthy mice in the degradation of branched-chain amino acids and fatty-acid oxidation pathways. In addition, the flux balance analysis using the MCL multi-tissue model showed that the degradation pathways of branched-chain amino acid and fatty acid oxidation were significantly downregulated in MKR mice versus healthy mice. Validation of the model was performed using data derived from the literature regarding T2DM. Microarray data was used in conjunction with the model to predict fluxes of various other metabolic pathways in the T2DM mouse model and alterations in a number of pathways were detected. The Type 2 Diabetes MCL multi-tissue model may explain the high level of branched-chain amino acids and free fatty acids in plasma of Type 2 Diabetic subjects from a metabolic fluxes perspective.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1932-6203eISSN: 1932-6203DOI: 10.1371/journal.pone.0102319Titel-ID: cdi_plos_journals_1545527921
- Format
- –
- Schlagworte
- Adipose Tissue - metabolism, Algorithms, Amino acids, Amino Acids - metabolism, Animal models, Animals, Biochemistry, Biology, Biology and Life Sciences, Bone diseases, Branched chain amino acids, Chain branching, Chains, Computation, Computer and Information Sciences, Computer applications, Computer Simulation, Confidence intervals, Degradation, Diabetes, Diabetes mellitus, Diabetes mellitus (non-insulin dependent), Diabetes Mellitus, Type 2 - physiopathology, Disease control, Disease Models, Animal, DNA microarrays, Endocrinology, Engineering and Technology, Enzymes, Experimentation, Fatty acids, Fatty Acids - metabolism, Fluxes, Gene expression, Gene Expression Regulation - physiology, Genomes, Insulin resistance, Kidney diseases, Kinases, Laboratories, Liver, Liver - metabolism, Mathematical models, Medicine and Health Sciences, Metabolic disorders, Metabolic Flux Analysis, Metabolic Networks and Pathways - physiology, Metabolic pathways, Metabolites, Mice, Mice, Transgenic, Microarray Analysis, Model testing, Models, Biological, Muscle, Skeletal - metabolism, Muscles, Musculoskeletal system, Mutation, Missense - genetics, Obesity, Oxidation, Pathways, Physical Sciences, Physiology, Plasma, Proteins, Receptors, Somatomedin - genetics, Research and Analysis Methods, Type 2 diabetes