PMID- 25029527
OWN - NLM
STAT- MEDLINE
DCOM- 20151117
LR  - 20211021
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 9
IP  - 7
DP  - 2014
TI  - Multi-tissue computational modeling analyzes pathophysiology of type 2 diabetes 
      in MKR mice.
PG  - e102319
LID - 10.1371/journal.pone.0102319 [doi]
LID - e102319
AB  - 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.
FAU - Kumar, Amit
AU  - Kumar A
AD  - Department of Chemical and Biomolecular Engineering, Johns Hopkins University, 
      Baltimore, Maryland, United States of America; Biotechnology Core Laboratory, 
      National Institute of Diabetes and Digestive and Kidney Diseases, National 
      Institute of Health, Bethesda, Maryland, United States of America.
FAU - Harrelson, Thomas
AU  - Harrelson T
AD  - Department of Chemical and Biomolecular Engineering, Johns Hopkins University, 
      Baltimore, Maryland, United States of America.
FAU - Lewis, Nathan E
AU  - Lewis NE
AD  - Department of Biology, Brigham Young University, Provo, Utah, United States of 
      America.
FAU - Gallagher, Emily J
AU  - Gallagher EJ
AD  - Division of Endocrinology, Diabetes and Bone Disease and the Diabetes, Obesity, 
      Metabolism Institute, Icahn School of Medicine at Sinai, New York, New York, 
      United States of America.
FAU - LeRoith, Derek
AU  - LeRoith D
AD  - Division of Endocrinology, Diabetes and Bone Disease and the Diabetes, Obesity, 
      Metabolism Institute, Icahn School of Medicine at Sinai, New York, New York, 
      United States of America.
FAU - Shiloach, Joseph
AU  - Shiloach J
AD  - Biotechnology Core Laboratory, National Institute of Diabetes and Digestive and 
      Kidney Diseases, National Institute of Health, Bethesda, Maryland, United States 
      of America.
FAU - Betenbaugh, Michael J
AU  - Betenbaugh MJ
AD  - Department of Chemical and Biomolecular Engineering, Johns Hopkins University, 
      Baltimore, Maryland, United States of America.
LA  - eng
GR  - P30 DK079637/DK/NIDDK NIH HHS/United States
GR  - ImNIH/Intramural NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Intramural
DEP - 20140716
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Amino Acids)
RN  - 0 (Fatty Acids)
RN  - 0 (IGF1R protein, human)
RN  - 0 (Receptors, Somatomedin)
RN  - EC 2.7.10.1 (Receptor, IGF Type 1)
SB  - IM
MH  - Adipose Tissue/metabolism
MH  - *Algorithms
MH  - Amino Acids/metabolism
MH  - Animals
MH  - Computer Simulation
MH  - Diabetes Mellitus, Type 2/*physiopathology
MH  - *Disease Models, Animal
MH  - Fatty Acids/metabolism
MH  - Gene Expression Regulation/*physiology
MH  - Liver/metabolism
MH  - Metabolic Flux Analysis
MH  - Metabolic Networks and Pathways/*physiology
MH  - Mice
MH  - Mice, Transgenic
MH  - Microarray Analysis
MH  - *Models, Biological
MH  - Muscle, Skeletal/metabolism
MH  - Mutation, Missense/genetics
MH  - Receptor, IGF Type 1
MH  - Receptors, Somatomedin/*genetics
PMC - PMC4100879
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2014/07/17 06:00
MHDA- 2015/11/18 06:00
PMCR- 2014/07/16
CRDT- 2014/07/17 06:00
PHST- 2013/08/19 00:00 [received]
PHST- 2014/06/18 00:00 [accepted]
PHST- 2014/07/17 06:00 [entrez]
PHST- 2014/07/17 06:00 [pubmed]
PHST- 2015/11/18 06:00 [medline]
PHST- 2014/07/16 00:00 [pmc-release]
AID - PONE-D-13-34087 [pii]
AID - 10.1371/journal.pone.0102319 [doi]
PST - epublish
SO  - PLoS One. 2014 Jul 16;9(7):e102319. doi: 10.1371/journal.pone.0102319. 
      eCollection 2014.