Modeling of glucose regulation and insulin-signaling pathways

A model of glucose regulation system was combined with a model of insulin-signaling pathways in this study. A feedback loop was added to link the transportation of glucose into cells (by GLUT4 in the insulin-signaling pathways) and the insulin-dependent glucose uptake in the glucose regulation model using the Michaelis-Menten kinetic model. A value of K(m) for GLUT4 was estimated using Genetic Algorithm. The estimated value was found to be 25.3 mM, which was in the range of K(m) values found experimentally from in vivo and in vitro human studies. Based on the results of this study, the combined model enables us to understand the overall dynamics of glucose at the systemic level, monitor the time profile of components in the insulin-signaling pathways at the cellular level and gives a good estimate of the K(m) value of glucose transportation by GLUT4. In conclusion, metabolic modeling such as displayed in this study provides a good predictive method to study the step-by-step reactions in an organism at different levels and should be used in combination with experimental approach to increase our understanding of metabolic disorders such as type 2 diabetes.

[1]  R A Roth,et al.  Correlation between insulin receptor occupancy and tyrosine kinase activity at low insulin concentrations and effect of major histocompatibility complex class I-derived peptide. , 1993, The Journal of pharmacology and experimental therapeutics.

[2]  B. Thorens,et al.  Facilitated glucose transporters in epithelial cells. , 1993, Annual review of physiology.

[3]  M. Birnbaum,et al.  Kinetics of GLUT1 and GLUT4 glucose transporters expressed in Xenopus oocytes. , 1993, The Journal of biological chemistry.

[4]  Jason M Haugh,et al.  A unified model for signal transduction reactions in cellular membranes. , 2002, Biophysical journal.

[5]  Kenneth H Norwich,et al.  Molecular Dynamics in Biosystems , 1977 .

[6]  R. Bergman,et al.  Physiologic evaluation of factors controlling glucose tolerance in man: measurement of insulin sensitivity and beta-cell glucose sensitivity from the response to intravenous glucose. , 1981, The Journal of clinical investigation.

[7]  H. Yki-Järvinen.  Pathogenesis of non-insulin-dependent diabetes mellitus , 1994, The Lancet.

[8]  C. Hales,et al.  Measurement of Insulin Secretion in Type 2 Diabetes: Problems and Pitfalls , 1992, Diabetic medicine : a journal of the British Diabetic Association.

[9]  R. DeFronzo,et al.  Glucose clamp technique: a method for quantifying insulin secretion and resistance. , 1979, The American journal of physiology.

[10]  A. Dornhorst.  Insulinotropic meglitinide analogues , 2001, The Lancet.

[11]  M. A. Henson,et al.  A molecular model for intercellular synchronization in the mammalian circadian clock. , 2007, Biophysical journal.

[12]  B N Kholodenko,et al.  Diffusion control of protein phosphorylation in signal transduction pathways. , 2000, The Biochemical journal.

[13]  H. Landahl,et al.  Comparison of storage- and signal-limited models of pancreatic insulin secretion. , 1980, The American journal of physiology.

[14]  B. Kahn,et al.  Glucose transporters and insulin action--implications for insulin resistance and diabetes mellitus. , 1999, The New England journal of medicine.

[15]  G I Bell,et al.  Molecular Biology of Mammalian Glucose Transporters , 1990, Diabetes Care.

[16]  F. Assimacopoulos-Jeannet,et al.  Hyperinsulinemia increases the amount of GLUT4 mRNA in white adipose tissue and decreases that of muscles: a clue for increased fat depot and insulin resistance. , 1990, Endocrinology.

[17]  L C Gatewood,et al.  Model studies of blood-glucose regulation. , 1965, The Bulletin of mathematical biophysics.

[18]  M Berman,et al.  A model of the kinetics of insulin in man. , 1974, The Journal of clinical investigation.

[19]  E. Cerasi,et al.  A Mathematical Model for the Glucose Induced Insulin Release in Man , 1974, European journal of clinical investigation.

[20]  G. Saidel,et al.  Multi-Scale Computational Model of Fuel Homeostasis During Exercise: Effect of Hormonal Control , 2006, Annals of Biomedical Engineering.

[21]  M. Quon,et al.  Advances in kinetic analysis of insulin-stimulated GLUT-4 translocation in adipose cells. , 1994, The American journal of physiology.

[22]  G I Bell,et al.  Structure and function of mammalian facilitative sugar transporters. , 1993, The Journal of biological chemistry.

[23]  R. Hovorka,et al.  Partitioning glucose distribution/transport, disposal, and endogenous production during IVGTT. , 2002, American journal of physiology. Endocrinology and metabolism.

[24]  V. Bolie,et al.  Coefficients of normal blood glucose regulation. , 1961, Journal of applied physiology.

[25]  G. Segre,et al.  Modeling Blood Glucose and Insulin Kinetics in Normal, Diabetic and Obese Subjects , 1973, Diabetes.

[26]  Claudio Cobelli,et al.  An integrated mathematical model of the dynamics of blood glucose and its hormonal control , 1982 .

[27]  W. C. Mello,et al.  Circulation Research an Official Journal of the American Heart Association Brief Reviews Intercellular Communication in Cardiac Muscle Intercellular Junction and the Electrical Coupling of Heart Cells , 2022 .

[28]  R. Roussel,et al.  13C/31P NMR studies of glucose transport in human skeletal muscle. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[29]  V. Grill,et al.  Low insulin response: a marker of prediabetes. , 1988, Advances in experimental medicine and biology.

[30]  Terry Martin,et al.  A Fuzzy Model of Glucose Regulation , 2005, Journal of Medical Systems.

[31]  M. Quon,et al.  A mathematical model and computer simulation study of insulin receptor regulation. , 1991, Journal of theoretical biology.

[32]  M. Quon,et al.  A mathematical model and computer simulation study of insulin sensitive glucose transporter regulation. , 1991, Journal of theoretical biology.

[33]  R. DeFronzo.  The Triumvirate: β-Cell, Muscle, Liver: A Collusion Responsible for NIDDM , 1988, Diabetes.

[34]  J. Doyle,et al.  Metabolic syndrome and robustness tradeoffs. , 2004, Diabetes.

[35]  M. Vranic,et al.  Normal hepatic insulin sensitivity in lean, mild noninsulin-dependent diabetic patients. , 1996, The Journal of clinical endocrinology and metabolism.

[36]  G M Steil,et al.  Dynamics of Glucose Production and Uptake Are More Closely Related to Insulin in Hindlimb Lymph Than in Thoracic Duct Lymph , 1994, Diabetes.

[37]  Robert V Farese,et al.  Insulin Activates Protein Kinases C-ζ and C-λ by an Autophosphorylation-dependent Mechanism and Stimulates Their Translocation to GLUT4 Vesicles and Other Membrane Fractions in Rat Adipocytes* , 1999, The Journal of Biological Chemistry.

[38]  R. Paffenbarger,et al.  Physical activity and reduced occurrence of non-insulin-dependent diabetes mellitus. , 1991, The New England journal of medicine.

[39]  Erol Cerasi,et al.  Modeling phasic insulin release: immediate and time-dependent effects of glucose. , 2002, Diabetes.

[40]  Lee,et al.  Pathogenesis of non-insulin-dependent (type II) diabetes mellitus (NIDDM) - genetic predisposition and metabolic abnormalities. , 1999, Advanced drug delivery reviews.

[41]  M Berman,et al.  Insulin control of glucose metabolism in man: a new kinetic analysis. , 1975, The Journal of clinical investigation.

[42]  Wilfred Peter Charette.  Control systems theory applied to metabolic homeostatic systems and the derivation and identification of mathematical models. , 1969 .

[43]  Robert S Parker,et al.  Dynamic modeling of free fatty acid, glucose, and insulin: an extended "minimal model". , 2006, Diabetes technology & therapeutics.

[44]  Y. Z. Ider,et al.  Quantitative estimation of insulin sensitivity. , 1979, The American journal of physiology.

[45]  C Cobelli,et al.  Estimation of insulin sensitivity and glucose clearance from minimal model: new insights from labeled IVGTT. , 1986, The American journal of physiology.

[46]  G. Grodsky,et al.  Dynamics of insulin secretion by the perfused rat pancreas. , 1968, Endocrinology.

[47]  E. Cerasi,et al.  PLASMA-INSULIN RESPONSE TO SUSTAINED HYPERGLYCEMIA INDUCED BY GLUCOSE INFUSION IN HUMAN SUBJECTS. , 1963, Lancet.

[48]  C. Cobelli,et al.  Validation of mathematical models of complex endocrine-metabolic systems. A case study on a model of glucose regulation , 1983, Medical and Biological Engineering and Computing.

[49]  K. Narayan,et al.  Preventing Non-Insulin-Dependent Diabetes , 1995, Diabetes.

[50]  L. Schäffer.  A model for insulin binding to the insulin receptor. , 1994, European journal of biochemistry.

[51]  Claudio Cobelli,et al.  Meal Simulation Model of the Glucose-Insulin System , 2007, IEEE Transactions on Biomedical Engineering.

[52]  S. O’Rahilly,et al.  Type 2 (non-insulin-dependent) diabetes mellitus new genetics for old nightmares , 1988, Diabetologia.

[53]  Reinhart Heinrich,et al.  Mathematical models of protein kinase signal transduction. , 2002, Molecular cell.

[54]  L. Lo Leggio,et al.  Insulin-stimulated GLUT4 glucose transporter recycling. A problem in membrane protein subcellular trafficking through multiple pools. , 1994, The Journal of biological chemistry.

[55]  R. Palfreyman,et al.  Kinetic resolution of the separate GLUT1 and GLUT4 glucose transport activities in 3T3-L1 cells. , 1992, The Biochemical journal.

[56]  O. Ezaki,et al.  Exercise Training Increases Glucose Transporter Content in Skeletal Muscles More Efficiently From Aged Obese Rats Than Young Lean Rats , 1992, Diabetes.

[57]  Claudio Cobelli,et al.  Minimal model SGoverestimation and SIunderestimation: improved accuracy by a Bayesian two-compartment model. , 1999, American journal of physiology. Endocrinology and metabolism.

[58]  A. Sherman,et al.  A mathematical model of metabolic insulin signaling pathways. , 2002, American journal of physiology. Endocrinology and metabolism.

[59]  J. Treadway,et al.  Differential regulation of glucose transporter activity and expression in red and white skeletal muscle. , 1991, The Journal of biological chemistry.

[60]  Claudio Cobelli,et al.  Carbohydrate metabolism: Quantitative physiology and mathematical modelling , 1981 .

[61]  G. Grodsky,et al.  A threshold distribution hypothesis for packet storage of insulin and its mathematical modeling. , 1972, The Journal of clinical investigation.

[62]  Richard Bertram,et al.  Intra- and inter-islet synchronization of metabolically driven insulin secretion. , 2005, Biophysical journal.

[63]  S. Wanant,et al.  Insulin receptor binding kinetics: modeling and simulation studies. , 2000, Journal of theoretical biology.

[64]  R. Farese,et al.  Protein Kinase C-ζ as a Downstream Effector of Phosphatidylinositol 3-Kinase during Insulin Stimulation in Rat Adipocytes , 1997, The Journal of Biological Chemistry.