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Johansson, Cecilia
Alternative names
Publications (10 of 13) Show all publications
Nyman, E., Rohini Rajan, M., Fagerholm, S., Brännmark, C., Cedersund, G. & Strålfors, P. (2014). A Single Mechanism Can Explain Network-wide Insulin Resistance in Adipocytes from Obese Patients with Type 2 Diabetes. Journal of Biological Chemistry, 289(48), 33215-33230
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, p. 33215-33230Article 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: 2017-12-05
Nyman, E., Rohini Rajan, M., Fagerholm, S., Brännmark, C., Cedersund, G. & Strålfors, P. (2014). 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
Brännmark, C., Nyman, E., Fagerholm, S., Bergenholm, L., Ekstrand, E.-M., Cedersund, G. & Strålfors, P. (2013). Insulin Signaling in Type 2 Diabetes: Experimental and Modeling Analyses Reveal Mechanisms of Insulin Resistance in Human Adipocytes. Journal of Biological Chemistry, 288(14), 9867-9880
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, p. 9867-9880Article 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
Brännmark, C. (2012). Insulin Signaling in Human Adipocytes a Systems Biology Approach. (Doctoral dissertation). Linköping: Linköping University Electronic Press
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. p. 82
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
Nyman, E., Brännmark, C., Palmér, R., Brugård, J., Nyström, F., Strålfors, P. & Cedersund, G. (2011). A Hierarchical Whole-body Modeling Approach Elucidates the Link between in Vitro Insulin Signaling and in Vivo Glucose Homeostasis. Journal of Biological Chemistry, 286(29), 26028-26041
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, p. 26028-26041Article 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
Bäck, K., Brännmark, C., Strålfors, P. & Arnqvist, H. (2011). Differential effects of IGF-I, IGF-II and insulin in human preadipocytes and adipocytes - Role of insulin and IGF-I receptors. Molecular and Cellular Endocrinology, 339(02-jan), 130-135
Open this publication in new window or tab >>Differential effects of IGF-I, IGF-II and insulin in human preadipocytes and adipocytes - Role of insulin and IGF-I receptors
2011 (English)In: Molecular and Cellular Endocrinology, ISSN 0303-7207, E-ISSN 1872-8057, Vol. 339, no 02-jan, p. 130-135Article in journal (Refereed) Published
Abstract [en]

We compared insulin and IGF effects in adipocytes expressing IR (insulin receptors), and preadipocytes expressing IR and IGF-IR (IGF-I receptors). Treatment of adipocytes with insulin, IGF-II or IGF-I resulted in phosphorylation of IR. Order of potency was insulin greater thanIGF-IIgreater than IGF-I. In preadipocytes IR, IGF-IR and insulin/IGF-I hybrid receptors (HR) were detected. Treatment of preadipocytes with IGF-I and IGF-II 10(-8) M resulted in activation of IGF-IR and IR whereas insulin was more potent in activating IR, with no effect on IGF-IR. In adipocytes glucose transport was 100-fold more sensitive to insulin than to IGFs and the maximal effect was higher with insulin. In preadipocytes glucose accumulation and DNA synthesis was equally sensitive to insulin and IGFs but the maximal effect was higher with IGF-I. In conclusion, insulin and IGF-I activate their cognate receptors and IGF-I also HR. IGF-II activates IR, IGF-IR and HR. Insulin and IGF-I are partial agonists to each others receptors.

Place, publisher, year, edition, pages
Elsevier Science B.V., Amsterdam., 2011
Keywords
Growth factors; Hybrid receptors; Receptor activation; DNA synthesis; Glucose metabolism
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-69862 (URN)10.1016/j.mce.2011.04.005 (DOI)000292580100016 ()
Available from: 2011-08-10 Created: 2011-08-08 Last updated: 2017-12-08
Usman Ali, S., Asif, M., Fulati, A., Nur, O., Willander, M., Brännmark, C., . . . Danielsson, B. (2011). Intracellular K(+) Determination With a Potentiometric Microelectrode Based on ZnO Nanowires. IEEE transactions on nanotechnology, 10(4), 913-919
Open this publication in new window or tab >>Intracellular K(+) Determination With a Potentiometric Microelectrode Based on ZnO Nanowires
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2011 (English)In: IEEE transactions on nanotechnology, ISSN 1536-125X, E-ISSN 1941-0085, Vol. 10, no 4, p. 913-919Article in journal (Refereed) Published
Abstract [en]

The fabrication and application of an intracellular K(+)-selective microelectrode is demonstrated. ZnO nanowires with a diameter of 100-180 nm and a length of approximately 1.5. m are grown on a borosilicate glass microcapillary. The ZnO nanowires were coated by a K(+)-ionophore-containing membrane. The K(+)-selective microelectrode exhibited a K(+)-dependent potentiometric response versus an Ag/AgCl reference microelectrode that was linear over a large concentration range (25 . M-125 mM) with a minimum detection limit of 1 . M. The measured K(+) concentrations in human adipocytes and in frog oocytes were consistent with values of K(+) concentrations reported in the literature. The sensor has several advantages including ease of fabrication, ease of insertion into the cells, low cost, and high selectivity features that make this type of sensor suitable to characterize physiologically relevant ions within single living cells.

Place, publisher, year, edition, pages
IEEE, 2011
Keywords
Frog oocytes; human adipocytes; intracellular potassium ions; ionophore membrane; nanotechnology; potentiometric nanosensor; ZnO nanowires
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-69803 (URN)10.1109/TNANO.2010.2089696 (DOI)000292966400038 ()
Note

©2011 IEEE. Personal use of this material is permitted. However, permission to reprint/republish this material for advertising or promotional purposes or for creating new collective works for resale or redistribution to servers or lists, or to reuse any copyrighted component of this work in other works must be obtained from the IEEE. Syed Usman Ali, Muhammad Asif, Alimujiang Fulati, Omer Nur, Magnus Willander, Cecilia Brännmark, Peter Strålfors, Ulrika Englund, Fredrik Elinder and Bengt Danielsson, Intracellular K(+) Determination With a Potentiometric Microelectrode Based on ZnO Nanowires, 2011, IEEE transactions on nanotechnology, (10), 4, 913-919. http://dx.doi.org/10.1109/TNANO.2010.2089696

Available from: 2011-08-10 Created: 2011-08-08 Last updated: 2018-01-25
Fulati, A., Usman Ali, S. M., Asif, M. H., Hassan Alvi, N. U., Willander, M., Brännmark, C., . . . Danielsson, B. (2010). An intracellular glucose biosensor based on nanoflake ZnO. Sensors and actuators. B, Chemical, 150(2), 673-680
Open this publication in new window or tab >>An intracellular glucose biosensor based on nanoflake ZnO
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2010 (English)In: Sensors and actuators. B, Chemical, ISSN 0925-4005, E-ISSN 1873-3077, Vol. 150, no 2, p. 673-680Article in journal (Other academic) Published
Abstract [en]

In this study, an improved potentiometric intracellular glucose biosensor was fabricated with immobilization of glucose oxidase on a ZnO nanoporous material. The ZnO nanoporous material with a wall thickness around 200 nm was grown on the tip of a borosilicate glass capillary and used as a selective intracellular glucose sensor for the measurement of glucose concentrations in human adipocytes and frog oocytes. The results showed a fast response within 4 s and a linear glucosedependent electrochemical response over a wide range of glucose concentration (500 nM-10 mM). The measurements of intracellular glucose concentrations with our biosensor were consistent with the values of intracellular glucose concentrations reported in the literature. The sensor also demonstrated its capability by detecting an increase in the intracellular glucose concentration induced by insulin. We found that the ZnO nanoporous material provides sensitivity as high as 1.8 times higher than that obtained using ZnO nanorods under the same conditions. Moreover, the fabrication method in our experiment is simple and the excellent performance of the developed nanosensor in sensitivity, stability, selectivity, reproducibility and anti-interference was achieved. All these advantageous features of this intracellular glucose biosensor based on functionalised ZnO nanoporous material compared to ZnO nanorods demonstrate a promising way of enhancing glucose biosensor performance to measure reliable intracellular glucose concentrations within single living cells.

Place, publisher, year, edition, pages
Elsevier, 2010
Keywords
Glucose oxidase (GOD), Intracellular, Potentiometric biosensor, Nanoflake ZnO, Nafion membrane
National Category
Natural Sciences
Identifiers
urn:nbn:se:liu:diva-57294 (URN)10.1016/j.snb.2010.08.021 (DOI)000284339800026 ()
Note

Original Publication:Alimujiang Fulati, Syed M. Usman Ali, Muhammad H. Asif, Naveed Ul Hassan Alvi, Magnus Willander, Cecilia Brännmark, Peter Strålfors, Sara I. Börjesson and Fredrik Elinder, An intracellular glucose biosensor based on nanoflake ZnO, 2010, Sensors and actuators. B, Chemical, (150), 2, 673-680.http://dx.doi.org/10.1016/j.snb.2010.08.021Copyright: Elsevier Science B.V., Amsterdam.http://www.elsevier.com/

Available from: 2010-06-16 Created: 2010-06-16 Last updated: 2018-01-25Bibliographically approved
Öst, A., Svensson, K., Ruishalme, I., Brännmark, C., Franck, N., Krook, H., . . . Strålfors, P. (2010). Attenuated mTOR signaling and enhanced autophagy in adipocytes from obese patients with type 2 diabetes. Molecular medicine (Cambridge, Mass. Print), 16(07-Aug), 235-246
Open this publication in new window or tab >>Attenuated mTOR signaling and enhanced autophagy in adipocytes from obese patients with type 2 diabetes
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2010 (English)In: Molecular medicine (Cambridge, Mass. Print), ISSN 1076-1551, E-ISSN 1528-3658, Vol. 16, no 07-Aug, p. 235-246Article in journal (Refereed) Published
Abstract [en]

The protein kinase mammalian target of rapamycin (mTOR) mediates insulin control ofprotein synthesis, autophagy, mitochondrial function, and, through feedback signaling tophosphorylation of IRS1 at serine residues, mTOR directly controls insulin signaling. Weshow that in adipocytes from patients with type 2 diabetes (T2D) insulin activation of mTORis attenuated and that the resultant phenotype is compatible with, and can be mimicked by,loss of mTOR activation. In T2D adipocytes mitochondrial function is impaired andautophagy strongly upregulated, with concomitant increased autophagic destruction ofmitochondria and lipofuscin particles, and a dependence on autophagy for ATP production.Conversely, mitochondrial dysfunction attenuates insulin activation of mTOR, enhancesautophagy and attenuates feedback to IRS1. Our findings put mTOR in the driver´s seat of aninsulin resistance that in adipocytes can be fuelled by mitochondrial dysfunction,inflammation, ER-stress, or hypoxia.

Place, publisher, year, edition, pages
Feinstein Institute for Medical Research, 2010
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-20655 (URN)10.2119/molmed.2010.00023 (DOI)000280048100001 ()20386866 (PubMedID)
Available from: 2009-09-16 Created: 2009-09-16 Last updated: 2019-06-28Bibliographically approved
Asif, M. H., Usman Ali, S. M., Nur, O., Willander, M., Brännmark, C., Strålfors, P., . . . Danielsson, B. (2010). Functionalised ZnO-nanorod-based selective electrochemical sensor for intracellular glucose. Biosensors & bioelectronics, 25(10), 2205-2211
Open this publication in new window or tab >>Functionalised ZnO-nanorod-based selective electrochemical sensor for intracellular glucose
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2010 (English)In: Biosensors & bioelectronics, ISSN 0956-5663, E-ISSN 1873-4235, Vol. 25, no 10, p. 2205-2211Article in journal (Refereed) Published
Abstract [en]

In this article, we report a functionalised ZnO-nanorod-based selective electrochemical sensor for intracellular glucose. To adjust the sensor for intracellular glucose measurements, we grew hexagonal ZnO nanorods on the tip of a silver-covered borosilicate glass capillary (0.7 mu m diameter) and coated them with the enzyme glucose oxidase. The enzyme-coated ZnO nanorods exhibited a glucose-dependent electrochemical potential difference versus an Ag/AgCl reference microelectrode. The potential difference was linear over the concentration range of interest (0.5-1000 mu M). The measured glucose concentration in human adipocytes or frog oocytes using our ZnO-nanorod sensor was consistent with values of glucose concentration reported in the literature; furthermore, the sensor was able to show that insulin increased the intracellular glucose concentration. This nanoelectrode device demonstrates a simple technique to measure intracellular glucose concentration.

Place, publisher, year, edition, pages
Elsevier Science B.V., Amsterdam., 2010
Keywords
ZnO nanorods; Functionalisation; Intracellular glucose; Electrochemical sensor
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-58381 (URN)10.1016/j.bios.2010.02.025 (DOI)000278702600004 ()
Note
Original Publication: Muhammad Asif, Syed Usman Ali, Omer Nour, Magnus Willander, Cecilia Brännmark, Peter Strålfors, Ulrika Englund, Fredrik Elinder and Bengt Danielsson, Functionalised ZnO-nanorod-based selective electrochemical sensor for intracellular glucose, 2010, Biosensors & bioelectronics, (25), 10, 2205-2211. http://dx.doi.org/10.1016/j.bios.2010.02.025 Copyright: Elsevier Science B.V., Amsterdam. http://www.elsevier.com/ Available from: 2010-08-13 Created: 2010-08-11 Last updated: 2018-01-25
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