Insulin Receptor Binding Kinetics: Modeling and Simulation Studies

Wanant, Sumanas; Quon, Michael J.

doi:10.1006/jtbi.2000.2069

Cited by 48 publications

(54 citation statements)

References 47 publications

(32 reference statements)

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“…Insulin signaling is initiated by insulin binding to the insulin receptor (IR), 3 which has been modeled to some extent (2)(3)(4)(5). These modeling efforts have considered nonlinear behaviors, such as cooperativity (4) and the effects of more than one insulin molecule binding to the IR (5).…”

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confidence: 99%

“…These modeling efforts have considered nonlinear behaviors, such as cooperativity (4) and the effects of more than one insulin molecule binding to the IR (5). Binding of insulin leads to rapid autophosphorylation and endocytosis of the insulin-autophosphorylated insulin-IR complex and an increased receptor tyrosine protein kinase activity toward downstream signal mediators, such as the insulin receptor substrate-1 (IRS1).…”

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confidence: 99%

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A Hierarchical Whole-body Modeling Approach Elucidates the Link between in Vitro Insulin Signaling and in Vivo Glucose Homeostasis

Nyman

Brännmark

Palmer

et al. 2011

Journal of Biological Chemistry

123

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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.

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confidence: 99%

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confidence: 99%

A Hierarchical Whole-body Modeling Approach Elucidates the Link between in Vitro Insulin Signaling and in Vivo Glucose Homeostasis

Nyman

Brännmark

Palmer

et al. 2011

Journal of Biological Chemistry

123

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“…The data have been analyzed using mathematical modeling approaches and the important finding are: i) several insulin molecules can bind to each receptor [19,[30][31][32][33], ii) IR contains heterogeneous binding sites with different affinities for insulin [19,[29][30][31][34][35][36], and iii) these different affinities can be explained by a specific interaction between the two α-subunits after insulin binding [19,30,31,36]. Presently, the only mathematical model that can simulate all complex characteristics in insulin binding data is a comprehensive model by Kiselyov et al [19] that is based on advanced biochemical structural information about IR.…”

Section: Figure 7: the Insulin Receptormentioning

confidence: 99%

“…In this first detailed model of the metabolic part of insulin signaling, Sedaghat et al combined previous models of insulin-IR binding and IR recycling [33,44] with models of GLUT4 regulation [75,76] and knowledge about mechanisms and intermediates involved in downstream signaling to control of glucose uptake, i.e. phosphorylation of PI3K and PKB, and GLUT4 translocation [142].…”

Section: Detailed Mathematical Models Of the Insulin Signaling Networkmentioning

confidence: 99%

Insulin signaling dynamics in human adipocytes : Mathematical modeling reveals mechanisms of insulin resistance in type 2 diabetes

Nyman¹

2014

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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). Populärvetenskaplig sammanfattningTyp 2-diabetes är en vanligt förekommande sjukdom där kroppens vävnader förlorar sin känslighet mot hormonet insulin. Insulinets uppgift är att hålla en jämn blodsockernivå dygnet runt. Insulin utsöndras i samband med måltider och påverkar muskel-och fettvävnader att ta upp socker och levern att sluta producera socker. Det är viktigt att hålla en jämn blodsockernivå eftersom låga nivåer kan vara direkt dödligt och höga nivåer är skadligt för blodkärlen, vilket i sin tur kan led...

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“…One submodel adds an insulin receptor recycling model to a previously published model of insulin-receptor binding (Wanant and Quon [2000] …”

Section: Modelmentioning

confidence: 99%

Systems Analysis of the Insulin Signaling Pathway

Kwei

Sanft

Petzold

et al. 2008

IFAC Proceedings Volumes

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Insulin Receptor Binding Kinetics: Modeling and Simulation Studies

Cited by 48 publications

References 47 publications

A Hierarchical Whole-body Modeling Approach Elucidates the Link between in Vitro Insulin Signaling and in Vivo Glucose Homeostasis

A Hierarchical Whole-body Modeling Approach Elucidates the Link between in Vitro Insulin Signaling and in Vivo Glucose Homeostasis

Insulin signaling dynamics in human adipocytes : Mathematical modeling reveals mechanisms of insulin resistance in type 2 diabetes

Systems Analysis of the Insulin Signaling Pathway

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