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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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
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
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
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
Cedersund G, Roll J (2009) Systems biology: model based evaluation and comparison of potential explanations for given biological data. FEBS J 276:903–922
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
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
Gerich JE (2000) Physiology of glucose homeostasis. Diabetes Obes Metab 2:345–350
Gerozissis K (2008) Brain insulin, energy and glucose homeostasis; genes, environment and metabolic pathologies. Eur J Pharmacol 585:38–49
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
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
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
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
Herman MA, Kahn BB (2006) Glucose transport and sensing in the maintenance of glucose homeostasis and metabolic harmony. J Clin Invest 116:1767–1775
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
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
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
Man CD, Rizza RA, Cobelli C (2007) Meal simulation model of the glucose-insulin system. IEEE Trans Biomed Eng 54:1740–1749
Marsh JW, Westley J, Steiner DF (1984) Insulin-receptor interactions. Presence of a positive cooperative effect. J Biol Chem 259:6641–6649
Martin TJ, May JM (1986) Testing models of insulin binding in rat adipocytes using network thermodynamic computer simulations. J Recept Res 6:323–336
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
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)
Pedersen MG (2010) A biophysical model of electrical activity in human beta-cells. Biophys J 99:3200–3207
Quon MJ, Campfield LA (1991) A mathematical model and computer simulation study of insulin receptor regulation. J Theor Biol 150:59–72
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
Saltiel AR, Kahn CR (2001) Insulin signalling and the regulation of glucose and lipid metabolism. Nature 414:799–806
Schaffer L (1994) A model for insulin binding to the insulin receptor. Eur J Biochem 221: 1127–1132
Sedaghat AR, Sherman A, Quon MJ (2002) A mathematical model of metabolic insulin signaling pathways. Am J Physiol Endocrinol Metab 283:E1084–E1101
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
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
Taniguchi CM, Emanuelli B, Kahn CR (2006) Critical nodes in signalling pathways: insights into insulin action. Nat Rev Mol Cell Biol 7:85–96
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
Van Belle TL, Coppieters KT, Von Herrath MG (2011) Type 1 diabetes: etiology, immunology, and therapeutic strategies. Physiol Rev 91:79–118
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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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