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Insulin Signaling in Type 2 Diabetes: Experimental and Modeling Analyses Reveal Mechanisms of Insulin Resistance in Human Adipocytes
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.
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
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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.

Place, publisher, year, edition, pages
2013. Vol. 288, no 14, 9867-9880 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-84999DOI: 10.1074/jbc.M112.432062ISI: 000317114000027OAI: oai:DiVA.org:liu-84999DiVA: diva2:563486
Available from: 2012-10-30 Created: 2012-10-30 Last updated: 2017-12-07Bibliographically 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 in primary adipocytes in insulin sensitive and insulin resistant states
Open this publication in new window or tab >>Insulin signaling in primary adipocytes in insulin sensitive and insulin resistant states
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Increasing numbers of people world-wide develops the disease type 2 diabetes. Development of type 2 diabetes is characterized by a shift from an insulin sensitive state to an insulin resistant state in peripheral insulin responding organs, which originates from the development of insulin resistance in the adipose tissue. Insulin resistance in combination with reduced pancreatic insulin secretion lead to overt type 2 diabetes.

In this thesis, the insulin signaling network in primary adipocytes was analyzed. Key proteins and mechanisms were studied to gain deeper knowledge of signaling both in the insulin sensitive state and in the insulin resistant state produced by rapid weight gain as well as in type 2 diabetes.

The surface of the adipocyte is dotted with invaginations in the cell membrane called caveolae that act as important metabolic and signaling platforms in adipocytes, and also harbor the insulin receptor. In paper I we show that insulin stimulation of primary adipocytes results in a rapid phosphorylation of the insulin receptor and caveolin-1, and that internalization of the proteins is mediated by endocytosis of caveolae.

Weight gain due to overfeeding and obesity has been associated with the development of insulin resistance in insulin sensitive tissues such as the adipose tissue. In paper II we show that short-term overfeeding for one month of lean subjects results in an insulin resistant state. At the end of the study, the subjects had developed a mild systemic insulin resistance. Moreover, in isolated subcutaneous adipocytes we found several alterations of the insulin signaling pathway that mimicked alterations found in isolated subcutaneous adipocytes from subjects with type 2 diabetes.

In paper III we present a first dynamic mathematical model of the insulin signaling network in human adipocytes that are based on experimental data acquired in a consistent fashion. The model takes account of insulin signaling in both the healthy, insulin sensitive state and in the insulin resistant state of type 2 diabetes. We show that attenuated mTORC1-mediated positive feedback to control of phosphorylation of IRS1 at Ser307 is an essential component of the insulin resistant state of type 2 diabetes. A future application of the model is the identification and evaluation of drug targets for the treatment of insulin resistance and type 2 diabetes.

In paper IV we examine the protein kinase that catalyzes the insulin stimulated mTORC1- mediated feedback to IRS1. We find that the phosphorylation of IRS1 at Ser307 is not likely to be catalyzed by the kinases S6K1, mTOR or PKB. However, a catalyzing protein kinase for the in vitro phosphorylation of IRS1 at Ser307 was found to be associated with the complex mTORC1.

In conclusion, this thesis provide new insights and characterize mechanisms of the intrinsically complex insulin signaling network of primary adipocytes, both in insulin sensitive and insulin resistant states.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2013. 64 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1369
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-95562 (URN)978-91-7519-577-3 (ISBN)
Public defence
2013-08-30, Berzeliussalen, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2013-07-08 Created: 2013-07-08 Last updated: 2013-10-23Bibliographically approved
3. 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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Brännmark, CeciliaNyman, ElinFagerholm, SiriCedersund, GunnarStrålfors, Peter

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