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The insulin-signaling network in human adipocytes, normally and in diabetes: role of signaling through ERK1/2
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
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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.

Place, publisher, year, edition, pages
2014.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-104724OAI: oai:DiVA.org:liu-104724DiVA: diva2:698669
Available from: 2014-02-24 Created: 2014-02-24 Last updated: 2014-02-24Bibliographically approved
In thesis
1. 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)
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Supervisors
Available from: 2014-02-24 Created: 2014-02-24 Last updated: 2014-05-06Bibliographically approved

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Nyman, ElinRohini Rajan, MeenuFagerholm, SiriBrännmark, CeciliaCedersund, GunnarStrålfors, Peter

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