Peter Strålfors

Mid Sweden University, Härnösand, Västernorrland, Sweden

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Publications (65)263.63 Total impact

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    ABSTRACT: 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 Map-kinases 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, 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.
    The Journal of biological chemistry. 10/2014;
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    Rikard Johansson, Peter Strålfors, Gunnar Cedersund
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    ABSTRACT: Model rejections lie at the heart of systems biology, since they provide conclusive statements: that the corresponding mechanistic assumptions do not serve as valid explanations for the experimental data. Rejections are usually done using e.g. the chi-square test (X2) or the Durbin-Watson test (DW). Analytical formulas for the corresponding distributions rely on assumptions that typically are not fulfilled. This problem is partly alleviated by the usage of bootstrapping, a computationally heavy approach to calculate an empirical distribution. Bootstrapping also allows for a natural extension to estimation of joint distributions, but this feature has so far been little exploited. We herein show that simplistic combinations of bootstrapped tests, like the max or min of the individual p-values, give inconsistent, i.e. overly conservative or liberal, results. A new two-dimensional (2D) approach based on parametric bootstrapping, on the other hand, is found both consistent and with a higher power than the individual tests, when tested on static and dynamic examples where the truth is known. In the same examples, the most superior test is a 2D X2 vs X2, where the second X2-value comes from an additional help model, and its ability to describe bootstraps from the tested model. This superiority is lost if the help model is too simple, or too flexible. If a useful help model is found, the most powerful approach is the bootstrapped log-likelihood ratio (LHR). We show that this is because the LHR is one-dimensional, because the second dimension comes at a cost, and because LHR has retained most of the crucial information in the 2D distribution. These approaches statistically resolve a previously published rejection example for the first time. We have shown how to, and how not to, combine tests in a bootstrap setting, when the combination is advantageous, and when it is advantageous to include a second model. These results also provide a deeper insight into the original motivation for formulating the LHR, for the more general setting of nonlinear and non-nested models. These insights are valuable in cases when accuracy and power, rather than computational speed, are prioritized.
    BMC Systems Biology 04/2014; 8(1):46. · 2.98 Impact Factor
  • Martin Osth, Anita Ost, Preben Kjolhede, Peter Strålfors
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    ABSTRACT: We have examined the concentration of β-carotene in the fat of isolated abdominal subcutaneous adipocytes obtained from lean (BMI<23 kg/m(2)), non-obese with higher BMI (23≤BMI<28 kg/m(2)), obese (BMI≥28 kg/m(2)), and from a group of obese subjects with type 2 diabetes. The concentration of β-carotene was 50% lower in the adipocytes from the obese and obese/diabetic groups compared with the lean and non-obese groups. Interestingly, the total amount of β-carotene in the adipocyte stores of each subject was constant among all groups. Triacylglycerol constituted 92±1% (by weight) of the adipocyte lipids in the lean group and this was increased to 99±2% in the obese group with diabetes (p<0.05). The concentration of cholesteryl esters was in all cases <0.1 g per 100 g of total lipids, demonstrating that mature human adipocytes have negligible stores of cholesteryl ester. Our findings demonstrate that adipocyte concentrations of β-carotene are reduced in obese subjects. The lower concentrations in adipocytes from subjects with type 2 diabetes apparently reflect subjectś obesity. Our finding that whole-body stores of β-carotene in adipocytes are constant raises new questions regarding what function it serves, as well as the mechanisms for maintaining constant levels in the face of varied adipose tissue mass among individuals over a period of time.
    PLoS ONE 01/2014; 9(1):e85610. · 3.53 Impact Factor
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    ABSTRACT: Epidemiological evidence indicates yet unknown epigenetic mechanisms underlying a propensity for overweight and type 2 diabetes. We analyzed the extent of methylation at lysine 4 and lysine 9 of histone H3 in primary human adipocytes from 43 subjects using modification-specific antibodies. The level of lysine 9 dimethylation was stable, while adipocytes from type 2 diabetic and non-diabetic overweight subjects exhibited about 40% lower levels of lysine 4 dimethylation compared with cells from normal-weight subjects. In contrast, trimethylation at lysine 4 was 40% higher in adipocytes from overweight diabetic subjects compared with normal-weight and overweight non-diabetic subjects. There was no association between level of modification and age of subjects. The findings define genome-wide molecular modifications of histones in adipocytes that are directly associated with overweight and diabetes, and thus suggest a molecular basis for existing epidemiological evidence of epigenetic inheritance.
    Clinical epigenetics. 09/2013; 5(1):15.
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    ABSTRACT: 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, using systems wide and internally consistent data from human adipocytes. Based on quantitative steady-state and dynamic time-course data on signaling intermediaries, normally and in diabetes, we developed a dynamic mathematical model of insulin signaling. The model structure and parameters are identical in the normal and diabetic states of the model, except for three parameters that change in diabetes: (i) reduced concentration of insulin receptor and (ii) of insulin-regulated glucose transporter GLUT4, and (iii) changed feedback from mammalian target of rapamycin in complex with raptor (mTORC1). Modeling reveals that at the core of insulin resistance in human adipocytes is attenuation of a positive feedback from mTORC1 to the insulin receptor substrate-1 (IRS1), which explains reduced sensitivity and signal strength throughout the signaling network. Model simulations with inhibition of mTORC1 are comparable to experimental data on inhibition of mTORC1 using rapamycin in human adipocytes. We demonstrate the potential of the model for identification of drug targets, e.g. increasing the feedback restores insulin signaling, both at the cellular level and, using a multi-level model, at the whole-body level. Our findings suggest that insulin resistance in an expanded adipose tissue results from cell growth restriction to prevent cell necrosis.
    Journal of Biological Chemistry 02/2013; · 4.65 Impact Factor
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    ABSTRACT: The insulin receptor substrate-1 (IRS1) is phosphorylated on serine 307 (human sequence, corresponding to murine serine 302) in response to insulin as part of a feedback loop that controls IRS1 phosphorylation on tyrosine residues by the insulin receptor. This in turn directly affects downstream signaling and is in human adipocytes implicated in the pathogenesis of insulin resistance and type 2 diabetes. The phosphorylation is inhibited by rapamycin, a specific inhibitor of mammalian target of rapamycin (mTOR) in complex with raptor (mTORC1). The mTORC1-downstream p70 ribosomal protein S6 kinase (S6K1), which is activated by insulin, can phosphorylate IRS1 at serine 307 in vitro and is considered the physiological protein kinase. Because the IRS1 serine 307-kinase catalyzes a critical step in the control of insulin signaling and constitutes a potential target for treatment of insulin resistance, it is important to know whether S6K1 is the physiological serine 307-kinase or not. We report that, by several criteria, S6K1 does not phosphorylate IRS1 at serine 307 in response to insulin in intact human primary adipocytes: (i) The time-courses for phosphorylation of S6K1 and its phosphorylation of S6 are not compatible with the phosphorylation of IRS1 at serine 307; (ii) A dominant-negative construct of S6K1 inhibits the phosphorylation of S6, without effect on the phosphorylation of IRS1 at serine 307; (iii) The specific inhibitor of S6K1 PF-4708671 inhibits the phosphorylation of S6, without effect on phosphorylation of IRS1 at serine 307. mTOR-immunoprecipitates from insulin-stimulated adipocytes contains an unidentified protein kinase specific for phosphorylation of IRS1 at serine 307, but it is not mTOR or S6K1.
    PLoS ONE 01/2013; 8(4):e59725. · 3.53 Impact Factor
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    ABSTRACT: In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
    Autophagy 04/2012; 8(4):445. · 12.04 Impact Factor
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    Autophagy 04/2012; 8(4):1-100. · 12.04 Impact Factor
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    [Show abstract] [Hide abstract]
    ABSTRACT: In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
    Autophagy 04/2012; 8(4):445-544. · 12.04 Impact Factor
  • Elin Nyman, Gunnar Cedersund, Peter Strålfors
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    ABSTRACT: Signaling pathways that only a few years ago appeared simple and understandable, albeit far from complete, have evolved into very complex multi-layered networks of cellular control mechanisms, which in turn are integrated in a similarly complex whole-body level of control mechanisms. This complexity sets limits for classical biochemical reasoning, such that a correct and complete analysis of experimental data while taking the full complexity into account is not possible. In this Opinion we propose that mathematical modeling can be used as a tool in insulin signaling research, and we demonstrate how recent developments in modeling - and the integration of modeling in the experimental process - provide new possibilities to approach and decipher complex biological systems more efficiently.
    Trends in Endocrinology and Metabolism 03/2012; 23(3):107-15. · 8.90 Impact Factor
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    ABSTRACT: 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. Database The mathematical model described here has been submitted to the Online Cellular Systems Modelling Database and can be accessed at http://jjj.biochem.sun.ac.za/database/nyman/index.html free of charge.
    FEBS Journal 01/2012; · 4.25 Impact Factor
  • Peter Strålfors
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    ABSTRACT: Much data in the scientific literature demonstrate a fundamental involvement of caveolae in insulin action, although particular aspects remain matters of debate. The insulin receptor and part of the downstream signalling mediators are localized in or recruited to caveolae. Moreover, as part of the signalling, insulin receptors are rapidly endocytosed by caveolae in response to the hormone. The insulin regulated glucose transporter GLUT4 appears to localize to caveolae after insulin-stimulated translocation to the plasma membrane, while the endocytosis of GLUT4 may involve a clathrin-mediated process. Insulin resistance due to dysfunction of insulin signalling in target tissues is a primary cornerstone of Type 2 diabetes. Lack of caveolae makes animals and human beings insulin resistant, but there is presently no evidence that caveolae play a role in the pathogenesis of insulin resistance in obesity and Type 2 diabetes.
    Advances in experimental medicine and biology 01/2012; 729:111-26. · 1.83 Impact Factor
  • Elin Nyman, Peter Strålfors, Gunnar Cedersund
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    ABSTRACT: External control of tissues and cells, by hormones, nerves, and other stimuli, involves the transduction of signals from ligand-activated receptors to control of rate-limiting enzymes or proteins that affect key steps in metabolism, gene transcription or other processes within the cells. The signal transduction is carried out by a network of interacting signal mediators, i.e. proteins and small molecule transducers. Such signaling transduction networks display a high degree of complexity, which is due to the presence of feed-forward and feedback loops, both negative and positive, and to the fact that interactions change over time and according to intracellular location. In combination with multiple layers of control, redundancy, shared signal mediators, shared signal paths, and cross-talk between signals, this leads to a complexity that poses new challenges to progress in dissecting and understanding cellular control. Furthermore, many diseases, such as cancer, insulin resistance, and type 2 diabetes, are associated with malfunctioning in the complex signaling networks.
    10/2011: pages 311-328;
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    ABSTRACT: The fabrication and application of an intracellular K<sup>+</sup> -selective microelectrode is demonstrated. ZnO nanowires with a diameter of 100-180 nm and a length of approximately 1.5 μm are grown on a borosilicate glass microcapillary. The ZnO nanowires were coated by a K<sup>+</sup> -ionophore-containing membrane. The K<sup>+</sup>-selective microelectrode exhibited a K<sup>+</sup>-dependent potentiometric response versus an Ag/AgCl reference microelectrode that was linear over a large concentration range (25 μM-125 mM) with a minimum detection limit of 1 μM. The measured K<sup>+</sup> concentrations in human adipocytes and in frog oocytes were consistent with values of K<sup>+</sup> 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.
    IEEE Transactions on Nanotechnology 08/2011; · 1.80 Impact Factor
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    ABSTRACT: 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>IGF-II>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 other's receptors.
    Molecular and Cellular Endocrinology 06/2011; 339(1-2):130-5. · 4.04 Impact Factor
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    ABSTRACT: 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.
    Journal of Biological Chemistry 05/2011; 286(29):26028-41. · 4.65 Impact Factor
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    Asa Jufvas, Peter Strålfors, Alexander V Vener
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    ABSTRACT: Epigenetic changes related to human disease cannot be fully addressed by studies of cells from cultures or from other mammals. We isolated human fat cells from subcutaneous abdominal fat tissue of female subjects and extracted histones from either purified nuclei or intact cells. Direct acid extraction of whole adipocytes was more efficient, yielding about 100 µg of protein with histone content of 60%-70% from 10 mL of fat cells. Differential proteolysis of the protein extracts by trypsin or ArgC-protease followed by nanoLC/MS/MS with alternating CID/ETD peptide sequencing identified 19 histone variants. Four variants were found at the protein level for the first time; particularly HIST2H4B was identified besides the only H4 isoform earlier known to be expressed in humans. Three of the found H2A potentially organize small nucleosomes in transcriptionally active chromatin, while two H2AFY variants inactivate X chromosome in female cells. HIST1H2BA and three of the identified H1 variants had earlier been described only as oocyte or testis specific histones. H2AFX and H2AFY revealed differential and variable N-terminal processing. Out of 78 histone modifications by acetylation/trimethylation, methylation, dimethylation, phosphorylation and ubiquitination, identified from six subjects, 68 were found for the first time. Only 23 of these modifications were detected in two or more subjects, while all the others were individual specific. The direct acid extraction of adipocytes allows for personal epigenetic analyses of human fat tissue, for profiling of histone modifications related to obesity, diabetes and metabolic syndrome, as well as for selection of individual medical treatments.
    PLoS ONE 01/2011; 6(1):e15960. · 3.53 Impact Factor
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    ABSTRACT: Insulin and other hormones control target cells through a network of signal-mediating molecules. Such networks are extremely complex due to multiple feedback loops in combination with redundancy, shared signal mediators, and cross-talk between signal pathways. We present a novel framework that integrates experimental work and mathematical modeling to quantitatively characterize the role and relation between co-existing submechanisms in complex signaling networks. The approach is independent of knowing or uniquely estimating model parameters because it only relies on (i) rejections and (ii) core predictions (uniquely identified properties in unidentifiable models). The power of our approach is demonstrated through numerous iterations between experiments, model-based data analyses, and theoretical predictions to characterize the relative role of co-existing feedbacks governing insulin signaling. We examined phosphorylation of the insulin receptor and insulin receptor substrate-1 and endocytosis of the receptor in response to various different experimental perturbations in primary human adipocytes. The analysis revealed that receptor endocytosis is necessary for two identified feedback mechanisms involving mass and information transfer, respectively. Experimental findings indicate that interfering with the feedback may substantially increase overall signaling strength, suggesting novel therapeutic targets for insulin resistance and type 2 diabetes. Because the central observations are present in other signaling networks, our results may indicate a general mechanism in hormonal control.
    Journal of Biological Chemistry 06/2010; 285(26):20171-9. · 4.65 Impact Factor
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    ABSTRACT: 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 microm 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 microM). 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.
    Biosensors & Bioelectronics 03/2010; 25(10):2205-11. · 6.45 Impact Factor
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    ABSTRACT: Type 2 diabetes (T2D) is strongly linked to obesity and an adipose tissue unresponsive to insulin. The insulin resistance is due to defective insulin signaling, but details remain largely unknown. We examined insulin signaling in adipocytes from T2D patients, and contrary to findings in animal studies, we observed attenuation of insulin activation of mammalian target of rapamycin (mTOR) in complex with raptor (mTORC1). As a consequence, mTORC1 downstream effects were also affected in T2D: feedback signaling by insulin to signal-mediator insulin receptor substrate-1 (IRS1) was attenuated, mitochondria were impaired and autophagy was strongly upregulated. There was concomitant autophagic destruction of mitochondria and lipofuscin particles, and a dependence on autophagy for ATP production. Conversely, mitochondrial dysfunction attenuated insulin activation of mTORC1, enhanced autophagy and attenuated feedback to IRS1. The overactive autophagy was associated with large numbers of cytosolic lipid droplets, a subset with colocalization of perlipin and the autophagy protein LC3/atg8, which can contribute to excessive fatty acid release. Patients with diagnoses of T2D and overweight were consecutively recruited from elective surgery, whereas controls did not have T2D. Results were validated in a cohort of patients without diabetes who exhibited a wide range of insulin sensitivities. Because mitochondrial dysfunction, inflammation, endoplasmic-reticulum stress and hypoxia all inactivate mTORC1, our results may suggest a unifying mechanism for the pathogenesis of insulin resistance in T2D, although the underlying causes might differ.
    Molecular Medicine 03/2010; 16(7-8):235-46. · 4.47 Impact Factor

Publication Stats

2k Citations
263.63 Total Impact Points

Institutions

  • 2013
    • Mid Sweden University
      Härnösand, Västernorrland, Sweden
  • 1994–2013
    • Linköping University
      • • Department of Clinical and Experimental Medicine (IKE)
      • • Faculty of Health Sciences
      Linköping, OEstergoetland, Sweden
  • 2012
    • University of Michigan
      • Life Sciences Institute
      Ann Arbor, MI, United States