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Multilevel-Modeling, Core Predictions, and the Concept of Final Conclusions

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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.

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References

  1. Backer JM, Kahn CR, White MF (1989) Tyrosine phosphorylation of the insulin receptor during insulin-stimulated internalization in rat hepatoma cells. J Biol Chem 264:1694–1701

    PubMed  CAS  Google Scholar 

  2. Bodenlenz M, Schaupp LA, Druml T, Sommer R, Wutte A, Schaller HC, Sinner F, Wach P, Pieber TR (2005) Measurement of interstitial insulin in human adipose and muscle tissue under moderate hyperinsulinemia by means of direct interstitial access. Am J Physiol Endocrinol Metab 289:E296–E300

    Article  PubMed  CAS  Google Scholar 

  3. Brännmark C, Palmér R, Cedersund G, Strålfors P, Glad ST (2010) Mass and information feedbacks through receptor endocytosis govern insulin signaling as revealed using a parameter-free modeling framework. J Biol Chem 285:20171–20179

    Article  PubMed  Google Scholar 

  4. Cedersund G, Roll J, Ulfhielm E, Danielsson A, Tidefelt H, Strålfors P (2008) Model-based hypothesis testing of key mechanisms in initial phase of insulin signaling. PLoS Comput Biol 4:e1000096

    Article  PubMed  Google Scholar 

  5. Cedersund G, Roll J (2009) Systems biology: model based evaluation and comparison of potential explanations for given biological data. FEBS J 276:903–922

    Article  PubMed  CAS  Google Scholar 

  6. Corin RE, Donner DB (1982) Insulin receptors convert to a higher affinity state subsequent to hormone binding. A two-state model for the insulin receptor. J Biol Chem 257:104–110

    CAS  Google Scholar 

  7. De Meyts P (1994) The structural basis of insulin and insulin-like growth factor-I receptor binding and negative co-operativity, and its relevance to mitogenic versus metabolic signalling. Diabetologia 37:S135–S148

    Article  PubMed  Google Scholar 

  8. Gerich JE (2000) Physiology of glucose homeostasis. Diabetes Obes Metab 2:345–350

    Article  PubMed  CAS  Google Scholar 

  9. Gerozissis K (2008) Brain insulin, energy and glucose homeostasis; genes, environment and metabolic pathologies. Eur J Pharmacol 585:38–49

    Article  PubMed  CAS  Google Scholar 

  10. Giri, L, Mutalik VK, Venkatesh KV (2004) A steady state analysis indicates that negative feedback regulation of PTP1B by Akt elicits bistability in insulin-stimulated GLUT4 translocation. Theor Biol Med Model 1:2–17

    Article  PubMed  Google Scholar 

  11. Göbel B, Langemann D, Oltmanns KM, Kerstin M, Chung M (2010) Compact energy metabolism model: brain controlled energy supply. J Theor Biol 264:1214–1224

    Article  PubMed  Google Scholar 

  12. Gustavsson J, Parpal S, Karlsson M, Ramsing C, Thorn H, Borg M, Lindroth M, Peterson KH, Magnusson, K-E, Strålfors P (1999) Localization of the insulin receptor in caveolae of adipocyte plasma membrane. FASEB J 13:1961–1971

    PubMed  CAS  Google Scholar 

  13. Hammond BJ, Tikerpae J, Smith GD (1997) An evaluation of the cross-linking model for the interaction of insulin with its receptor Am J Physiol 272:E1136–E1144

    CAS  Google Scholar 

  14. Herman MA, Kahn BB (2006) Glucose transport and sensing in the maintenance of glucose homeostasis and metabolic harmony. J Clin Invest 116:1767–1775

    Article  PubMed  CAS  Google Scholar 

  15. Hori SS, Kurland IJ, DiStefano JJ (2006) Role of endosomal trafficking dynamics on the regulation of hepatic insulin receptor activity: models for Fao cells. Ann Biomed Eng 34: 879–892

    Article  PubMed  Google Scholar 

  16. Jeneson JAL, Westerhoff HV, Kushmerick MJ (2000) A metabolic control analysis of kinetic controls in ATP free energy metabolism in contracting skeletal muscle. Am J Physiol Cell Physiol 279:C813–C832

    PubMed  CAS  Google Scholar 

  17. Kiselyov VV, Versteyhe S, Gauguin L, De Meyts P (2009) Harmonic oscillator model of the insulin and IGF1 receptors’ allosteric binding and activation. Mol Syst Biol 5, Art. No. 243

    Google Scholar 

  18. Man CD, Rizza RA, Cobelli C (2007) Meal simulation model of the glucose-insulin system. IEEE Trans Biomed Eng 54:1740–1749

    Article  PubMed  Google Scholar 

  19. Marsh JW, Westley J, Steiner DF (1984) Insulin-receptor interactions. Presence of a positive cooperative effect. J Biol Chem 259:6641–6649

    CAS  Google Scholar 

  20. Martin TJ, May JM (1986) Testing models of insulin binding in rat adipocytes using network thermodynamic computer simulations. J Recept Res 6:323–336

    PubMed  CAS  Google Scholar 

  21. Muoio DM, Newgard CB (2008) Mechanisms of disease: molecular and metabolic mechanisms of insulin resistance and beta-cell failure in type 2 diabetes. Nat Rev Mol Cell Biol 9:193–205

    Article  PubMed  CAS  Google Scholar 

  22. Nyman E, Brännmark C, Palmér R, Brugård J, Nystrom FH, Strålfors P, Cedersund G (2011) A hierarchical whole body modeling approach elucidates the link between in vitro insulin signaling and in vivo glucose homeostasis. J Biol Chem (in press)

    Google Scholar 

  23. Pedersen MG (2010) A biophysical model of electrical activity in human beta-cells. Biophys J 99:3200–3207

    Article  PubMed  CAS  Google Scholar 

  24. Quon MJ, Campfield LA (1991) A mathematical model and computer simulation study of insulin receptor regulation. J Theor Biol 150:59–72

    Article  PubMed  CAS  Google Scholar 

  25. Regittnig W, Ellmerer M, Fauler G, Sendlhofer G, Trajanoski,Z, Leis HJ, Schaupp L, Wach P, Pieber TR (2003) Assessment of transcapillary glucose exchange in human skeletal muscle and adipose tissue. Am J Physiol Endocrinol Metab 285:E241–E251

    PubMed  CAS  Google Scholar 

  26. Saltiel AR, Kahn CR (2001) Insulin signalling and the regulation of glucose and lipid metabolism. Nature 414:799–806

    Article  PubMed  CAS  Google Scholar 

  27. Schaffer L (1994) A model for insulin binding to the insulin receptor. Eur J Biochem 221: 1127–1132

    Article  PubMed  CAS  Google Scholar 

  28. Sedaghat AR, Sherman A, Quon MJ (2002) A mathematical model of metabolic insulin signaling pathways. Am J Physiol Endocrinol Metab 283:E1084–E1101

    PubMed  CAS  Google Scholar 

  29. Standaert ML, Pollet RJ (1984) Equilibrium model for insulin-induced receptor down-regulation. Regulation of insulin receptors in differentiated BC3H-1 myocytes. J Biol Chem 259:2346–2354

    PubMed  CAS  Google Scholar 

  30. Sturis J, Polonsky KS, Mosekilde E, Van Cauter E (1991) Computer model for mechanisms underlying ultradian oscillations of insulin and glucose. Am J Physiol 260:E801–E809

    PubMed  CAS  Google Scholar 

  31. Taniguchi CM, Emanuelli B, Kahn CR (2006) Critical nodes in signalling pathways: insights into insulin action. Nat Rev Mol Cell Biol 7:85–96

    Article  PubMed  CAS  Google Scholar 

  32. Tolic IM, Mosekilde E, Sturis J (2000) Modeling the insulin-glucose feedback system: the significance of pulsatile insulin secretion. J Theor Biol 207:361–375

    Article  PubMed  CAS  Google Scholar 

  33. Van Belle TL, Coppieters KT, Von Herrath MG (2011) Type 1 diabetes: etiology, immunology, and therapeutic strategies. Physiol Rev 91:79–118

    Article  PubMed  Google Scholar 

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Correspondence to Peter Strålfors or Gunnar Cedersund .

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Nyman, E., Strålfors, P., Cedersund, G. (2011). Multilevel-Modeling, Core Predictions, and the Concept of Final Conclusions. In: Mosekilde, E., Sosnovtseva, O., Rostami-Hodjegan, A. (eds) Biosimulation in Biomedical Research, Health Care and Drug Development. Springer, Vienna. https://doi.org/10.1007/978-3-7091-0418-7_14

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