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A Hierarchical Whole-body Modeling Approach Elucidates the Link between in Vitro Insulin Signaling and in Vivo Glucose Homeostasis
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 Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
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2011 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 286, no 29, 26028-26041 p.Article in journal (Refereed) Published
Abstract [en]

Type 2 diabetes is a metabolic disease that profoundly affects energy homeostasis. The disease involves failure at several levels and subsystems and is characterized by insulin resistance in target cells and tissues (i.e. by impaired intracellular insulin signaling). We have previously used an iterative experimental-theoretical approach to unravel the early insulin signaling events in primary human adipocytes. That study, like most insulin signaling studies, is based on in vitro experimental examination of cells, and the in vivo relevance of such studies for human beings has not been systematically examined. Herein, we develop a hierarchical model of the adipose tissue, which links intracellular insulin control of glucose transport in human primary adipocytes with whole-body glucose homeostasis. An iterative approach between experiments and minimal modeling allowed us to conclude that it is not possible to scale up the experimentally determined glucose uptake by the isolated adipocytes to match the glucose uptake profile of the adipose tissue in vivo. However, a model that additionally includes insulin effects on blood flow in the adipose tissue and GLUT4 translocation due to cell handling can explain all data, but neither of these additions is sufficient independently. We also extend the minimal model to include hierarchical dynamic links to more detailed models (both to our own models and to those by others), which act as submodules that can be turned on or off. The resulting multilevel hierarchical model can merge detailed results on different subsystems into a coherent understanding of whole-body glucose homeostasis. This hierarchical modeling can potentially create bridges between other experimental model systems and the in vivo human situation and offers a framework for systematic evaluation of the physiological relevance of in vitro obtained molecular/cellular experimental data.

Place, publisher, year, edition, pages
American Society for Biochemistry and Molecular Biology , 2011. Vol. 286, no 29, 26028-26041 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-70109DOI: 10.1074/jbc.M110.188987ISI: 000293073000061OAI: oai:DiVA.org:liu-70109DiVA: diva2:435544
Note

This research was originally published in: Elin Nyman, Cecilia Brännmark, Robert Palmér, Jan Brugård, Fredrik Nyström, Peter Strålfors and Gunnar Cedersund, A Hierarchical Whole-body Modeling Approach Elucidates the Link between in Vitro Insulin Signaling and in Vivo Glucose Homeostasis, 2011, Journal of Biological Chemistry, (286), 29, 26028-26041. http://dx.doi.org/10.1074/jbc.M110.188987 © the American Society for Biochemistry and Molecular Biology http://www.asbmb.org/

Available from: 2013-04-11 Created: 2011-08-19 Last updated: 2017-12-08Bibliographically approved
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
2. Insulin signaling dynamics in human adipocytes: Mathematical modeling reveals mechanisms of insulin resistance in type 2 diabetes
Open this publication in new window or tab >>Insulin signaling dynamics in human adipocytes: Mathematical modeling reveals mechanisms of insulin resistance in type 2 diabetes
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Type 2 diabetes is characterized by raised blood glucose levels caused by an insufficient insulin control of glucose homeostasis. This lack of control is expressed both through insufficient release of insulin by the pancreatic beta-cells, and through insulin resistance in the insulin-responding tissues. We find insulin resistance of the adipose tissue particularly interesting since it appears to influence other insulin-responding tissues, such as muscle and liver, to also become insulin resistant.

The insulin signaling network is highly complex with cross-interacting intermediaries, positive and negative feedbacks, etc. To facilitate the mechanistic understanding of this network, we obtain dynamic, information-rich data and use model-based analysis as a tool to formally test different hypotheses that arise from the experimental observations. With dynamic mathematical models, we are able to combine knowledge and experimental data into mechanistic hypotheses, and draw conclusions such as rejection of hypotheses and prediction of outcomes of new experiments.

We aim for an increased understanding of adipocyte insulin signaling and the underlying mechanisms of the insulin resistance that we observe in adipocytes from subjects diagnosed with type 2 diabetes. We also aim for a complete picture of the insulin signaling network in primary human adipocytes from normal and diabetic subjects with a link to relevant clinical parameters: plasma glucose and insulin. Such a complete picture of insulin signaling has not been presented before. Not for adipocytes and not for other types of cells.

In this thesis, I present the development of the first comprehensive insulin signaling model that can simulate both normal and diabetic data from adipocytes – and that is linked to a whole-body glucose-insulin model. In the linking process we conclude that at least two glucose uptake parameters differ between the in vivo and in vitro conditions (Paper I). We also perform a model analysis of the early insulin signaling dynamics in rat adipocytes and conclude that internalization is important for an apparent reversed order of phosphorylation seen in these cells (Paper II). In the development of the first version of the comprehensive insulin signaling model, we introduce a key parameter for the diabetic state – an attenuated feedback (Paper III). We finally continue to build on the comprehensive model and include signaling to nuclear transcription via ERK and report substantial crosstalk in the insulin signaling network (Paper IV).

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2014. 67 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1389
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-104725 (URN)10.3384/diss.diva-104725 (DOI)978-91-7519-430-1 (ISBN)
Public defence
2014-03-28, Eken, Campus US, Linköpings universitet, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2014-02-24 Created: 2014-02-24 Last updated: 2014-05-06Bibliographically approved

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Nyman, ElinBrännmark, CeciliaPalmér, RobertNyström, FredrikStrålfors, PeterCedersund, Gunnar

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