liu.seSearch for publications in DiVA
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Mass and Information Feedbacks through Receptor Endocytosis Govern Insulin Signaling as Revealed Using a Parameter-free Modeling Framework
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Electrical Engineering, Automatic Control. Linköping University, The Institute of Technology.
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
Show others and affiliations
2010 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 285, no 26, 20171-20179 p.Article in journal (Refereed) Published
Abstract [en]

Insulin and other hormones control target cells through a network of signal-mediating molecules. Such networks are extremely complex due to multiple feedback loops in combination with redundancy, shared signal mediators, and cross-talk between signal pathways. We present a novel framework that integrates experimental work and mathematical modeling to quantitatively characterize the role and relation between coexisting submechanisms in complex signaling networks. The approach is independent of knowing or uniquely estimating model parameters because it only relies on (i) rejections and (ii) core predictions (uniquely identified properties in unidentifiable models). The power of our approach is demonstrated through numerous iterations between experiments, model-based data analyses, and theoretical predictions to characterize the relative role of co-existing feedbacks governing insulin signaling. We examined phosphorylation of the insulin receptor and insulin receptor substrate-1 and endocytosis of the receptor in response to various different experimental perturbations in primary human adipocytes. The analysis revealed that receptor endocytosis is necessary for two identified feedback mechanisms involving mass and information transfer, respectively. Experimental findings indicate that interfering with the feedback may substantially increase overall signaling strength, suggesting novel therapeutic targets for insulin resistance and type 2 diabetes. Because the central observations are present in other signaling networks, our results may indicate a general mechanism in hormonal control.

Place, publisher, year, edition, pages
American Society for Biochemistry and Molecular Biology, 2010. Vol. 285, no 26, 20171-20179 p.
Keyword [en]
Insulin, Signal-mediating molecules, Framework
National Category
Medical and Health Sciences Control Engineering
Identifiers
URN: urn:nbn:se:liu:diva-58292DOI: 10.1074/jbc.M110.106849ISI: 000279012000052OAI: oai:DiVA.org:liu-58292DiVA: diva2:337903
Available from: 2010-08-10 Created: 2010-08-09 Last updated: 2017-12-12
In thesis
1. Insulin Signaling in Human Adipocytes a Systems Biology Approach
Open this publication in new window or tab >>Insulin Signaling in Human Adipocytes a Systems Biology Approach
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Obesity and a sedentary life style are associated with type 2 diabetes, a disease starting with insulin resistance in the adipose tissue, which spreads to the whole body. Despite large research efforts to understand the insulin signaling system, there is little knowledge of the mechanisms behind insulin resistance and type 2 diabetes developments. We have herein focused on the insulin signaling in adipocytes, elucidating mechanisms for early signaling. We have also modeled isolated adipocytes and data from the in vivo, whole bodysituation, concurrently. We also mapped and quantitatively described differences in the insulin signaling of adipocytes from type 2 diabetics and non-diabetics.

In paper I we show that neither insulin degradation, receptor internalization, nor feedback signals can as separate explanations cause the overshoot in tyrosine phosphorylation of IRS1, while an endocytosis-dependent feedback mechanism explains all available data.

In paper II we show that it is not possible to scale up the experimentally determined glucose uptake by isolated human adipocytes to match the glucose uptake profile of the whole adipose tissue in vivo. Other insulin effects need to be accounted for.

In paper III we show that attenuation of the positive feedback to serine 307 phosphorylation of IRS1 can explain the insulin resistance in the insulin signaling in adipocytes seen in type 2 diabetes. However, to fully explain both the signaling and the glucose uptake, a reduction in the amount of Glut4 is also needed.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2012. 82 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1331
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-85001 (URN)978-91-7519-789-0 (ISBN)
Public defence
2012-11-30, Berzelius, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2012-10-30 Created: 2012-10-30 Last updated: 2012-10-30Bibliographically approved

Open Access in DiVA

fulltext(6486 kB)300 downloads
File information
File name FULLTEXT01.pdfFile size 6486 kBChecksum SHA-512
9fb65adbef906c4cce6fc0e6111981e4ee6a68333b248e5487c695ce5e98017ac76860735f558a72a567209edd12959089109aded40ebe8d664bbf4e486be8e6
Type fulltextMimetype application/pdf

Other links

Publisher's full text

Authority records BETA

Brannmark, CeciliaGlad, TorkelCedersund, GunnarStrålfors, Peter

Search in DiVA

By author/editor
Brannmark, CeciliaGlad, TorkelCedersund, GunnarStrålfors, Peter
By organisation
Cell BiologyFaculty of Health SciencesAutomatic ControlThe Institute of Technology
In the same journal
Journal of Biological Chemistry
Medical and Health SciencesControl Engineering

Search outside of DiVA

GoogleGoogle Scholar
Total: 300 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

doi
urn-nbn

Altmetric score

doi
urn-nbn
Total: 307 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf