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Unraveling Mechanisms of Insulin Resistance in Type 2 Diabetes in Human Aidpocytes: Role of extracelluar signal kinase 1/2 (ERK1/2) and farkhead box protein 01 (FOX01)
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Type 2 Diabetes is characterized by hyperglycemia primarily caused due to insulin resistance in insulin responsive tissues and insufficient production of insulin by the β-cells. Insulin resistance appears to develop first in the expanding adipose tissue during caloric surplus and affects other tissues like liver and muscle by ectopic fat accumulation. In spite of significant research in field of insulin signaling, very little has been known about the mechanisms that lead to insulin resistance and T2D.

We aim for network-wide knowledge of insulin signaling in human adipocytes and to identify mechanisms that can induce insulin resistance in diabetic individuals. We have herein focused on the transcriptional control of insulin via ERK and FOXO1, and have used mathematical modelling to gain a systems-level understanding of insulin signaling network.

Through the work in this thesis, we present for the first time a dynamic comprehensive model for insulin signaling for the adipocytes, for both metabolic and transcriptional control, and that can simulate data from both normal and diabetic individuals. We described insulin regulation of ERK phosphorylation and showed that both its insulin sensitivity and maxima  response to insulin was curtailed in adipocytes from diabetic individuals (Paper I). Our findings indicate that insulin regulated ERK pathway exerts control on transcription not only through phosphorylation of Elk-1 but also through phosphorylation of FOXO1 and exerts translational control via phosphorylation of ribosomal protein S6 (Paper I, II). Furthermore, we showed that insulin-induced FOXO1 phosphorylation or its insulin sensitivity was not impaired in diabetic individuals, although FOXO1 protein level was reduced by 45% in adipocytes from patients with type 2 diabetes. Comprehensive analysis of the detailed insulin signaling model showed that attenuation of the feedback from mTORC1 to IRS1-Ser307 explained dominant part of the insulin resistance seen in adipocytes from diabetic individuals (Paper II). More interestingly, inhibition of FOXO1 with a dominant negative construct of FOXO1, mimicked the diabetic state in the adipocytes, with the similarity extending to both insulin signaling as well as the reduced protein levels, as seen in the diabetic adipocytes. We also show that mTORC1 and FOXO1 maintain each other’s expression/activity in the human adipocytes (Paper II, III). Our findings thus demonstrate that the interplay between mTORC1 and FOXO1 maintains normal insulin signaling in the human adipocytes.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2016. , 93 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1541
National Category
Endocrinology and Diabetes Cell and Molecular Biology Cell Biology Physiology Other Clinical Medicine
Identifiers
URN: urn:nbn:se:liu:diva-131421DOI: 10.3384/doss.diva-131421ISBN: 9789176856772 (Print)OAI: oai:DiVA.org:liu-131421DiVA: diva2:971905
Public defence
2016-10-27, Berzeliussalen, Campus US, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2016-09-19 Created: 2016-09-19 Last updated: 2016-09-19Bibliographically approved
List of papers
1. A Single Mechanism Can Explain Network-wide Insulin Resistance in Adipocytes from Obese Patients with Type 2 Diabetes
Open this publication in new window or tab >>A Single Mechanism Can Explain Network-wide Insulin Resistance in Adipocytes from Obese Patients with Type 2 Diabetes
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2014 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 289, no 48, 33215-33230 p.Article in journal (Refereed) Published
Abstract [en]

The response to insulin is impaired in type 2 diabetes. Much information is available about insulin signaling, but understanding of the cellular mechanisms causing impaired signaling and insulin resistance is hampered by fragmented data, mainly obtained from different cell lines and animals. We have collected quantitative and systems-wide dynamic data on insulin signaling in primary adipocytes and compared cells isolated from healthy and diabetic individuals. Mathematical modeling and experimental verification identified mechanisms of insulin control of the MAPKs ERK1/2. We found that in human adipocytes, insulin stimulates phosphorylation of the ribosomal protein S6 and hence protein synthesis about equally via ERK1/2 and mTORC1. Using mathematical modeling, we examined the signaling network as a whole and show that a single mechanism can explain the insulin resistance of type 2 diabetes throughout the network, involving signaling both through IRS1, PKB, and mTOR and via ERK1/2 to the nuclear transcription factor Elk1. The most important part of the insulin resistance mechanism is an attenuated feedback from the protein kinase mTORC1 to IRS1, which spreads signal attenuation to all parts of the insulin signaling network. Experimental inhibition of mTORC1 using rapamycin in adipocytes from non-diabetic individuals induced and thus confirmed the predicted network-wide insulin resistance.

Place, publisher, year, edition, pages
American Society for Biochemistry and Molecular Biology, 2014
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-113198 (URN)10.1074/jbc.M114.608927 (DOI)000345636600015 ()25320095 (PubMedID)
Note

Funding Agencies|Swedish Diabetes Fund; University of Linkoping; Swedish Research Council

Available from: 2015-01-13 Created: 2015-01-12 Last updated: 2016-09-19
2. Systems-wide Experimental and Modeling Analysis of Insulin Signaling through Forkhead Box Protein O1 (FOXO1) in Human Adipocytes, Normally and in Type 2 Diabetes
Open this publication in new window or tab >>Systems-wide Experimental and Modeling Analysis of Insulin Signaling through Forkhead Box Protein O1 (FOXO1) in Human Adipocytes, Normally and in Type 2 Diabetes
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2016 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 291, no 30, 15806-15819 p.Article in journal (Refereed) Published
Abstract [en]

Insulin resistance is a major aspect of type 2 diabetes (T2D), which results from impaired insulin signaling in target cells. Signaling to regulate forkhead box protein O1 (FOXO1) may be the most important mechanism for insulin to control transcription. Despite this, little is known about how insulin regulates FOXO1 and how FOXO1 may contribute to insulin resistance in adipocytes, which are the most critical cell type in the development of insulin resistance. We report a detailed mechanistic analysis of insulin control of FOXO1 in human adipocytes obtained from non-diabetic subjects and from patients with T2D. We show that FOXO1 is mainly phosphorylated through mTORC2-mediated phosphorylation of protein kinase B at Ser(473) and that this mechanism is unperturbed in T2D. We also demonstrate a cross-talk from the MAPK branch of insulin signaling to stimulate phosphorylation of FOXO1. The cellular abundance and consequently activity of FOXO1 are halved in T2D. Interestingly, inhibition of mTORC1 with rapamycin reduces the abundance of FOXO1 to the levels in T2D. This suggests that the reduction of the concentration of FOXO1 is a consequence of attenuation of mTORC1, which defines much of the diabetic state in human adipocytes. We integrate insulin control of FOXO1 in a network-wide mathematical model of insulin signaling dynamics based on compatible data from human adipocytes. The diabetic state is network-wide explained by attenuation of an mTORC1-to-insulin receptor substrate-1 (IRS1) feedback and reduced abundances of insulin receptor, GLUT4, AS160, ribosomal protein S6, and FOXO1. The model demonstrates that attenuation of the mTORC1-to-IRS1 feedback is a major mechanism of insulin resistance in the diabetic state.

Place, publisher, year, edition, pages
Rockville, Maryland: American Society for Biochemistry and Molecular Biology, 2016
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:liu:diva-130998 (URN)10.1074/jbc.M116.715763 (DOI)000380584200033 ()27226562 (PubMedID)
Note

Funding agencies|Swedish Diabetes Fund, University of Linköping; Swedish Research Council; AstraZeneca

Available from: 2016-09-02 Created: 2016-09-02 Last updated: 2016-09-19Bibliographically approved

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