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Insulin signaling dynamics in human adipocytes: Mathematical modeling reveals mechanisms of insulin resistance in type 2 diabetes
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
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: urn:nbn:se:liu:diva-104725DOI: 10.3384/diss.diva-104725ISBN: 978-91-7519-430-1 (print)OAI: oai:DiVA.org:liu-104725DiVA: diva2:698675
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
List of papers
1. A Hierarchical Whole-body Modeling Approach Elucidates the Link between in Vitro Insulin Signaling and in Vivo Glucose Homeostasis
Open this publication in new window or tab >>A Hierarchical Whole-body Modeling Approach Elucidates the Link between in Vitro Insulin Signaling and in Vivo Glucose Homeostasis
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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
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-70109 (URN)10.1074/jbc.M110.188987 (DOI)000293073000061 ()
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
2. Mechanistic explanations for counter-intuitive phosphorylation dynamics of the insulin receptor and insulin receptor substrate-1 in response to insulin in murine adipocytes
Open this publication in new window or tab >>Mechanistic explanations for counter-intuitive phosphorylation dynamics of the insulin receptor and insulin receptor substrate-1 in response to insulin in murine adipocytes
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2012 (English)In: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 279, no 6, 987-999 p.Article in journal (Refereed) Published
Abstract [en]

Insulin signaling through insulin receptor (IR) and insulin receptor substrate-1 (IRS1) is important for insulin control of target cells. We have previously demonstrated a rapid and simultaneous overshoot behavior in the phosphorylation dynamics of IR and IRS1 in human adipocytes. Herein, we demonstrate that in murine adipocytes a similar overshoot behavior is not simultaneous for IR and IRS1. The peak of IRS1 phosphorylation, which is a direct consequence of the phosphorylation and the activation of IR, occurs earlier than the peak of IR phosphorylation. We used a conclusive modeling framework to unravel the mechanisms behind this counter-intuitive order of phosphorylation. Through a number of rejections, we demonstrate that two fundamentally different mechanisms may create the reversed order of peaks: (i) two pools of phosphorylated IR, where a large pool of internalized IR peaks late, but phosphorylation of IRS1 is governed by a small plasma membrane-localized pool of IR with an early peak, or (ii) inhibition of the IR-catalyzed phosphorylation of IRS1 by negative feedback. Although (i) may explain the reversed order, this two-pool hypothesis alone requires extensive internalization of IR, which is not supported by experimental data. However, with the additional assumption of limiting concentrations of IRS1, (i) can explain all data. Also, (ii) can explain all available data. Our findings illustrate how modeling can potentiate reasoning, to help draw nontrivial conclusions regarding competing mechanisms in signaling networks. Our work also reveals new differences between human and murine insulin signaling.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2012
Keyword
conclusive mathematical modeling, core prediction, insulin signaling, mechanistic explanation, rat adipocytes
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-76963 (URN)10.1111/j.1742-4658.2012.08488.x (DOI)000301336800009 ()
Note
Funding Agencies|European Commission Network of Excellence Biosim||Ostergotland County Council||Novo Nordisk Foundation||Lions||Swedish Diabetes Association||Swedish Research Council||Available from: 2012-04-27 Created: 2012-04-27 Last updated: 2017-12-07
3. Insulin Signaling in Type 2 Diabetes: Experimental and Modeling Analyses Reveal Mechanisms of Insulin Resistance in Human Adipocytes
Open this publication in new window or tab >>Insulin Signaling in Type 2 Diabetes: Experimental and Modeling Analyses Reveal Mechanisms of Insulin Resistance in Human Adipocytes
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2013 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 288, no 14, 9867-9880 p.Article in journal (Refereed) Published
Abstract [en]

Type 2 diabetes originates in an expanding adipose tissue that for unknown reasons becomes insulin resistant. Insulin resistance reflects impairments in insulin signaling, but mechanisms involved are unclear because current research is fragmented. We report a systems-level mechanistic understanding of insulin resistance in humans. We developed a dynamic mathematical model of insulin signaling – normally and in diabetes – based on quantitative steady-state and dynamic time-course data on signaling intermediaries in human mature adipocytes. At the core of insulin resistance is attenuation of a positive feedback from mammalian target of rapamycin in complex with raptor (mTORC1) to the insulin receptor substrate-1 (IRS1), which explains reduced sensitivity and signal strength throughout the signaling network. We demonstrate the potential of the model for identification of drug targets, e.g. increasing the feedback restores insulin signaling. Our findings suggest that insulin resistance in an expanded adipose tissue results from cell growth restriction to prevent cell necrosis.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-84999 (URN)10.1074/jbc.M112.432062 (DOI)000317114000027 ()
Available from: 2012-10-30 Created: 2012-10-30 Last updated: 2017-12-07Bibliographically approved
4. The insulin-signaling network in human adipocytes, normally and in diabetes: role of signaling through ERK1/2
Open this publication in new window or tab >>The insulin-signaling network in human adipocytes, normally and in diabetes: role of signaling through ERK1/2
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2014 (English)Manuscript (preprint) (Other academic)
Abstract [en]

Insulin acutely controls metabolism in adipocytes, but also nuclear transcription through the “mitogenic” signaling pathway mediated by Map-kinases ERK1/2 (ERK). The cellular metabolic response to insulin is attenuated in insulin resistance and type 2 diabetes, but whether this involves also signaling through ERK is unclear. Based on experimental data from primary mature human adipocytes from diabetic and nondiabetic individuals, we demonstrate a network-wide, model-based analysis of insulin signaling through ERK to phosphorylation of transcription factor Elk1 integrated with signaling for “metabolic” control. We use minimal modeling to analyze the idiosyncratic phosphorylation dynamics of ERK, i.e. a slow phosphorylation response that returns to basal in response to insulin, and conclude that sequestration of ERK is the simplest explanation to data. We also demonstrate a significant cross-talk between ERK and mTORC1 signaling to ribosomal protein S6 for control of protein synthesis. A reduced sensitivity and reduced maximal phosphorylation of ERK in response to insulin in the diabetic state can be explained by the same mechanisms that generate insulin resistance in the control of metabolism.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-104724 (URN)
Available from: 2014-02-24 Created: 2014-02-24 Last updated: 2014-02-24Bibliographically approved

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