Multiscale Modeling of Insulin Secretion

Insulin secretion from pancreatic beta cells is a fundamental physiological process, and its impairment plays a pivotal role in the development of diabetes. Mathematical modeling of insulin secretion has a long history, both on the level of the entire body and on the cellular and subcellular scale. However, little direct communication between these disparate scales has been included in mathematical models so far. Recently, we have proposed a minimal model for the incretin effect by which the gut hormone glucagon-like peptide 1 (GLP-1) enhances insulin secretion. To understand how this model couples to cellular events, we use a previously published mechanistic model of insulin secretion, and show mathematically that induction of glucose competence in beta cells by GLP-1 can underlie derivative control by GLP-1.

[1]  Claudio Cobelli,et al.  Assessment of beta-cell function in humans, simultaneously with insulin sensitivity and hepatic extraction, from intravenous and oral glucose tests. , 2007, American journal of physiology. Endocrinology and metabolism.

[2]  Claudio Cobelli,et al.  Oral Glucose Tolerance Test Minimal Model Indexes of β-Cell Function and Insulin Sensitivity , 2001 .

[3]  J. Keizer,et al.  Minimal model for membrane oscillations in the pancreatic beta-cell. , 1983, Biophysical journal.

[4]  J. Habener,et al.  Pancreatic beta-cells are rendered glucose-competent by the insulinotropic hormone glucagon-like peptide-1(7-37) , 1993, Nature.

[5]  Arthur Sherman,et al.  Newcomer insulin secretory granules as a highly calcium-sensitive pool , 2009, Proceedings of the National Academy of Sciences.

[6]  W. Marsden.  I and J , 2012 .

[7]  Arthur Sherman,et al.  Identifying the targets of the amplifying pathway for insulin secretion in pancreatic beta-cells by kinetic modeling of granule exocytosis. , 2008, Biophysical journal.

[8]  M. G. Pedersen,et al.  Insulin Secretory Granules Enter a Highly Calcium‐Sensitive State following Palmitate‐Induced Dissociation from Calcium Channels: A Theoretical Study , 2010, Journal of neuroendocrinology.

[9]  Claudio Cobelli,et al.  A subcellular model of glucose-stimulated pancreatic insulin secretion , 2008, Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences.

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

[11]  C Cobelli,et al.  Estimation of β-Cell Sensitivity From Intravenous Glucose Tolerance Test C-Peptide Data: Knowledge of the Kinetics Avoids Errors in Modeling the Secretion , 1995, Diabetes.

[12]  Lena Eliasson,et al.  Novel aspects of the molecular mechanisms controlling insulin secretion , 2008, The Journal of physiology.

[13]  J. Habener,et al.  A role for Ca2+-sensitive nonselective cation channels in regulating the membrane potential of pancreatic beta-cells. , 1998, Diabetes.

[14]  Claudio Cobelli,et al.  Incretin effect potentiates beta-cell responsivity to glucose as well as to its rate of change: OGTT and matched intravenous study. , 2007, American journal of physiology. Endocrinology and metabolism.

[15]  S. Kahn,et al.  The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of Type 2 diabetes , 2003, Diabetologia.

[16]  Claudio Cobelli,et al.  A model of GLP-1 action on insulin secretion in nondiabetic subjects. , 2010, American journal of physiology. Endocrinology and metabolism.

[17]  Morten Gram Pedersen,et al.  A biophysical model of electrical activity in human β-cells. , 2010, Biophysical journal.

[18]  Claudio Cobelli,et al.  Cellular modeling: insight into oral minimal models of insulin secretion. , 2010, American journal of physiology. Endocrinology and metabolism.

[19]  Alessandro Bertuzzi,et al.  Insulin granule trafficking in beta-cells: mathematical model of glucose-induced insulin secretion. , 2007, American journal of physiology. Endocrinology and metabolism.

[20]  Michael B Wheeler,et al.  The multiple actions of GLP-1 on the process of glucose-stimulated insulin secretion. , 2002, Diabetes.

[21]  J. Henquin,et al.  Measurements of cytoplasmic Ca2+ in islet cell clusters show that glucose rapidly recruits beta-cells and gradually increases the individual cell response. , 2001, Diabetes.

[22]  J. Holst,et al.  Glucagon-Like Peptide 1(7-36) Amide Stimulates Exocytosis in Human Pancreatic β-Cells by Both Proximal and Distal Regulatory Steps in Stimulus-Secretion Coupling , 1998, Diabetes.

[23]  Mark I McCarthy,et al.  Type 2 diabetes: new genes, new understanding. , 2008, Trends in genetics : TIG.

[24]  J. Holst.  The physiology of glucagon-like peptide 1. , 2007, Physiological reviews.

[25]  Claudio Cobelli,et al.  Insulin release in impaired glucose tolerance: oral minimal model predicts normal sensitivity to glucose but defective response times. , 2002, Diabetes.

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

[27]  R. Bertram,et al.  Metabolic and electrical oscillations: partners in controlling pulsatile insulin secretion. , 2007, American journal of physiology. Endocrinology and metabolism.

[28]  C Cobelli,et al.  Oral glucose tolerance test minimal model indexes of beta-cell function and insulin sensitivity. , 2001, Diabetes.