Modeling a simplified regulatory system of blood glucose at molecular levels.

In this paper, we propose a new mathematical control system for a simplified regulatory system of blood glucose by taking into account the dynamics of glucose and glycogen in liver and the dynamics of insulin and glucagon receptors at the molecular level. Numerical simulations show that the proposed feedback control system agrees approximately with published experimental data. Sensitivity analysis predicts that feedback control gains of insulin receptors and glucagon receptors are robust. Using the model, we develop a new formula to compute the insulin sensitivity. The formula shows that the insulin sensitivity depends on various parameters that determine the insulin influence on insulin-dependent glucose utilization and reflect the efficiency of binding of insulin to its receptors. Using Lyapunov indirect method, we prove that the new control system is input-output stable. The stability result provides theoretical evidence for the phenomenon that the blood glucose fluctuates within a narrow range in response to the exogenous glucose input from food. We also show that the regulatory system is controllable and observable. These structural system properties could explain why the glucose level can be regulated.

[1]  R N Bergman,et al.  Assessment of insulin sensitivity in vivo. , 1985, Endocrine reviews.

[2]  R. Hovorka Continuous glucose monitoring and closed‐loop systems , 2006, Diabetic medicine : a journal of the British Diabetic Association.

[3]  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.

[4]  D. Marquardt An Algorithm for Least-Squares Estimation of Nonlinear Parameters , 1963 .

[5]  J. A. Thomas,et al.  Effects of magnesium on the kinetic properties of bovine heart glycogen synthase D. , 1975, The Journal of biological chemistry.

[6]  A H Clemens,et al.  The development of Biostator, a Glucose Controlled Insulin Infusion System (GCIIS). , 1977, Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme.

[7]  C. Kahn Membrane receptors for hormones and neurotransmitters , 1976, The Journal of cell biology.

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

[9]  W. Zingg,et al.  An Artificial Endocrine Pancreas , 1974, Diabetes.

[10]  J. Henquin Pathways in beta-cell stimulus-secretion coupling as targets for therapeutic insulin secretagogues. , 2004, Diabetes.

[11]  L. Mandarino,et al.  Dose-response characteristics for effects of insulin on production and utilization of glucose in man. , 1981, The American journal of physiology.

[12]  Claudio Cobelli,et al.  Two-hour seven-sample oral glucose tolerance test and meal protocol: minimal model assessment of beta-cell responsivity and insulin sensitivity in nondiabetic individuals. , 2005, Diabetes.

[13]  G. Winston,et al.  Effects of chronic ethanol ingestion on liver glycogen phosphorylase in male and female rats. , 1981, The American journal of clinical nutrition.

[14]  G. Steil,et al.  Evaluation of the Effect of Gain on the Meal Response of an Automated Closed-Loop Insulin Delivery System , 2006, Diabetes.

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

[16]  A. Katz,et al.  Glucagon metabolism in the rat. , 1978, The Journal of clinical investigation.

[17]  T D Hockaday,et al.  Insulin deficiency and insulin resistance interaction in diabetes: estimation of their relative contribution by feedback analysis from basal plasma insulin and glucose concentrations. , 1979, Metabolism: clinical and experimental.

[18]  R. Bergman Toward Physiological Understanding of Glucose Tolerance: Minimal-Model Approach , 1989, Diabetes.

[19]  M. Lohse,et al.  Interplay of Ca2+ and cAMP signaling in the insulin-secreting MIN6 beta-cell line. , 2005, The Journal of biological chemistry.

[20]  Y. Kuang,et al.  Modeling the glucose-insulin regulatory system and ultradian insulin secretory oscillations with two explicit time delays. , 2006, Journal of theoretical biology.

[21]  Claudio Cobelli,et al.  Minimal model estimation of glucose absorption and insulin sensitivity from oral test: validation with a tracer method. , 2004, American journal of physiology. Endocrinology and metabolism.

[22]  O. McGuinness,et al.  Physiological consequences of phasic insulin release in the normal animal. , 2002, Diabetes.

[23]  Claudio Cobelli,et al.  The hot IVGTT two-compartment minimal model: an improved version. , 2003, American journal of physiology. Endocrinology and metabolism.

[24]  F. Schuit,et al.  Plasticity of the beta cell insulin secretory competence: preparing the pancreatic beta cell for the next meal. , 2004, The Journal of physiology.

[25]  G. Desir,et al.  Voltage-gated potassium channel Kv1.3 regulates GLUT4 trafficking to the plasma membrane via a Ca2+-dependent mechanism. , 2006, American journal of physiology. Cell physiology.

[26]  Claudio Cobelli,et al.  A minimal model of insulin secretion and kinetics to assess hepatic insulin extraction. , 2006, American journal of physiology. Endocrinology and metabolism.

[27]  E. Mosekilde,et al.  Modeling the insulin-glucose feedback system: the significance of pulsatile insulin secretion. , 2000, Journal of theoretical biology.

[28]  A. Tengholm,et al.  Glucose and Insulin Synergistically Activate Phosphatidylinositol 3-Kinase to Trigger Oscillations of Phosphatidylinositol 3,4,5-Trisphosphate in β-Cells* , 2006, Journal of Biological Chemistry.

[29]  E. Mosekilde,et al.  Computer model for mechanisms underlying ultradian oscillations of insulin and glucose. , 1991, The American journal of physiology.

[30]  O. McManus,et al.  Blockers of the delayed-rectifier potassium current in pancreatic beta-cells enhance glucose-dependent insulin secretion. , 2006, Diabetes.

[31]  R. Bergman,et al.  Insulin transport across capillaries is rate limiting for insulin action in dogs. , 1989, The Journal of clinical investigation.

[32]  G. Steil,et al.  Feasibility of Automating Insulin Delivery for the Treatment of Type 1 Diabetes , 2006, Diabetes.

[33]  J. Gromada,et al.  Removal of Ca2+ Channel β3 Subunit Enhances Ca2+ Oscillation Frequency and Insulin Exocytosis , 2004, Cell.

[34]  Hubert Roth,et al.  Glucose appearance in the peripheral circulation and liver glucose output in men after a large 13C starch meal. , 2004, The American journal of clinical nutrition.

[35]  A. Klip,et al.  Muscle, liver, and pancreas: Three Musketeers fighting to control glycemia. , 2006, American journal of physiology. Endocrinology and metabolism.

[36]  W Zingg,et al.  Clinical Control of Diabetes by the Artificial Pancreas , 1974, Diabetes.

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

[38]  M. Lohse,et al.  Interplay of Ca2+ and cAMP Signaling in the Insulin-secreting MIN6 β-Cell Line*[boxs] , 2005, Journal of Biological Chemistry.

[39]  Alessandra Bertoldo,et al.  Interactions Between Delivery, Transport, and Phosphorylation of Glucose in Governing Uptake Into Human Skeletal Muscle , 2006, Diabetes.

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

[41]  R. Sherwin,et al.  Renal extraction of glucagon in rats with normal and reduced renal function. , 1977, The American journal of physiology.

[42]  Kirsten Morris,et al.  Introduction to Feedback Control , 2001 .

[43]  P. Lefèbvre,et al.  Renal handling of endogenous glucagon in the dog: comparison with insulin. , 1974, Metabolism: clinical and experimental.

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

[45]  L. Philipson,et al.  Adenine nucleotide regulation in pancreatic beta-cells: modeling of ATP/ADP-Ca2+ interactions. , 2005, American journal of physiology. Endocrinology and metabolism.