Advanced

A systems biology analysis connects insulin receptor signaling with glucose transporter translocation in rat adipocytes

Bergqvist, Niclas; Nyman, Elin; Cedersund, Gunnar and Stenkula, Karin G. LU (2017) In Journal of Biological Chemistry 292(27). p.11206-11217
Abstract

Type 2 diabetes is characterized by insulin resistance, which arises from malfunctions in the intracellular insulin signaling network. Knowledge of the insulin signaling network is fragmented, and because of the complexity of this network, little consensus has emerged for the structure and importance of the different branches of the network. To help overcome this complexity, systems biology mathematical models have been generated for predicting both the activation of the insulin receptor (IR) and the redistribution of glucose transporter 4 (GLUT4) to the plasma membrane. Although the insulin signal transduction between IR and GLUT4 has been thoroughly studied with modeling and time-resolved data in human cells, comparable analyses in... (More)

Type 2 diabetes is characterized by insulin resistance, which arises from malfunctions in the intracellular insulin signaling network. Knowledge of the insulin signaling network is fragmented, and because of the complexity of this network, little consensus has emerged for the structure and importance of the different branches of the network. To help overcome this complexity, systems biology mathematical models have been generated for predicting both the activation of the insulin receptor (IR) and the redistribution of glucose transporter 4 (GLUT4) to the plasma membrane. Although the insulin signal transduction between IR and GLUT4 has been thoroughly studied with modeling and time-resolved data in human cells, comparable analyses in cells from commonly used model organisms such as rats and mice are lacking. Here, we combined existing data and models for rat adipocytes with new data collected for the signaling network between IR and GLUT4 to create a model also for their interconnections. To describe all data (>140 data points), the model needed three distinct pathways from IR to GLUT4: (i) via protein kinase B (PKB) and Akt substrate of 160 kDa (AS160), (ii) via an AS160-independent pathway from PKB, and (iii) via an additional pathway from IR, e.g. affecting the membrane constitution. The developed combined model could describe data not used for training the model and was used to generate predictions of the relative contributions of the pathways from IR to translocation of GLUT4. The combined model provides a systems-level understanding of insulin signaling in rat adipocytes, which, when combined with corresponding models for human adipocytes, may contribute to model-based drug development for diabetes.

(Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
adipocyte, cell signaling, glucose transporter type 4 (GLUT4), insulin, insulin signaling, mathematical modeling, mechanistic modeling
in
Journal of Biological Chemistry
volume
292
issue
27
pages
12 pages
publisher
ASBMB
external identifiers
  • scopus:85026192268
  • wos:000405119600007
ISSN
1083-351X
DOI
10.1074/jbc.M117.787515
language
English
LU publication?
yes
id
1489c62e-13bc-46bb-a2c8-c9f485109d47
date added to LUP
2017-08-04 10:45:00
date last changed
2017-09-18 11:40:57
@article{1489c62e-13bc-46bb-a2c8-c9f485109d47,
  abstract     = {<p>Type 2 diabetes is characterized by insulin resistance, which arises from malfunctions in the intracellular insulin signaling network. Knowledge of the insulin signaling network is fragmented, and because of the complexity of this network, little consensus has emerged for the structure and importance of the different branches of the network. To help overcome this complexity, systems biology mathematical models have been generated for predicting both the activation of the insulin receptor (IR) and the redistribution of glucose transporter 4 (GLUT4) to the plasma membrane. Although the insulin signal transduction between IR and GLUT4 has been thoroughly studied with modeling and time-resolved data in human cells, comparable analyses in cells from commonly used model organisms such as rats and mice are lacking. Here, we combined existing data and models for rat adipocytes with new data collected for the signaling network between IR and GLUT4 to create a model also for their interconnections. To describe all data (&gt;140 data points), the model needed three distinct pathways from IR to GLUT4: (i) via protein kinase B (PKB) and Akt substrate of 160 kDa (AS160), (ii) via an AS160-independent pathway from PKB, and (iii) via an additional pathway from IR, e.g. affecting the membrane constitution. The developed combined model could describe data not used for training the model and was used to generate predictions of the relative contributions of the pathways from IR to translocation of GLUT4. The combined model provides a systems-level understanding of insulin signaling in rat adipocytes, which, when combined with corresponding models for human adipocytes, may contribute to model-based drug development for diabetes.</p>},
  author       = {Bergqvist, Niclas and Nyman, Elin and Cedersund, Gunnar and Stenkula, Karin G.},
  issn         = {1083-351X},
  keyword      = {adipocyte,cell signaling,glucose transporter type 4 (GLUT4),insulin,insulin signaling,mathematical modeling,mechanistic modeling},
  language     = {eng},
  month        = {07},
  number       = {27},
  pages        = {11206--11217},
  publisher    = {ASBMB},
  series       = {Journal of Biological Chemistry},
  title        = {A systems biology analysis connects insulin receptor signaling with glucose transporter translocation in rat adipocytes},
  url          = {http://dx.doi.org/10.1074/jbc.M117.787515},
  volume       = {292},
  year         = {2017},
}