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A systems biology analysis connects insulin receptor signaling with glucose transporter translocation in rat adipocytes
Linköpings universitet, Institutionen för medicinsk teknik. Linköpings universitet, Tekniska fakulteten.
Linköpings universitet, Institutionen för medicinsk teknik, Avdelningen för medicinsk teknik. Linköpings universitet, Tekniska fakulteten. AstraZeneca RandD, Sweden.
Linköpings universitet, Institutionen för medicinsk teknik, Avdelningen för medicinsk teknik. Linköpings universitet, Tekniska fakulteten. Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten.
Lund University, Sweden.
2017 (Engelska)Ingår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 292, nr 27, s. 11206-11217Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

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 (amp;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.

Ort, förlag, år, upplaga, sidor
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC , 2017. Vol. 292, nr 27, s. 11206-11217
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Biofysik
Identifikatorer
URN: urn:nbn:se:liu:diva-139565DOI: 10.1074/jbc.M117.787515ISI: 000405119600007PubMedID: 28495883OAI: oai:DiVA.org:liu-139565DiVA, id: diva2:1130087
Anmärkning

Funding Agencies|Swedish Research Council [2013-3542]; AstraZeneca; Diabetes Foundation; Craaford Foundation; Royal Physiographic Society in Lund

Tillgänglig från: 2017-08-08 Skapad: 2017-08-08 Senast uppdaterad: 2018-04-03

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Nyman, ElinCedersund, Gunnar
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Institutionen för medicinsk teknikTekniska fakultetenAvdelningen för medicinsk teknikInstitutionen för klinisk och experimentell medicinMedicinska fakulteten
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