Cellular modeling: insight into oral minimal models of insulin secretion.

The oral glucose tolerance test and meal tolerance test are common clinical tests of the glucose-insulin system. Several mathematical models have been suggested as means to extract information about beta-cell function from data from oral tolerance tests. Any such model needs to be fairly simple but should at the same time be linked to the underlying biology of the insulin-secreting beta-cells. The scope of the present work is to present a way to make such a connection using a recent model describing intracellular mechanisms. We show how the three main components of oral minimal secretion models, derivative control, proportional control, and delay, are related to subcellular events, thus providing mechanistic underpinning of the assumptions of the minimal models.

[1]  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.

[2]  Claudio Cobelli,et al.  Pathogenesis of Pre-Diabetes , 2006, Diabetes.

[3]  F Tosi,et al.  Assessment of β‐cell function during the oral glucose tolerance test by a minimal model of insulin secretion , 2001, European journal of clinical investigation.

[4]  J. E. Manning Fox,et al.  Oscillatory membrane potential response to glucose in islet beta-cells: a comparison of islet-cell electrical activity in mouse and rat. , 2006, Endocrinology.

[5]  Andrea Mari,et al.  Meal and oral glucose tests for assessment of beta -cell function: modeling analysis in normal subjects. , 2002, American journal of physiology. Endocrinology and metabolism.

[6]  K. M. Erickson,et al.  Prehepatic insulin production in man: kinetic analysis using peripheral connecting peptide behavior. , 1980, The Journal of clinical endocrinology and metabolism.

[7]  Paolo Meda,et al.  Loss of connexin36 channels alters beta-cell coupling, islet synchronization of glucose-induced Ca2+ and insulin oscillations, and basal insulin release. , 2005, Diabetes.

[8]  Vojtech Ličko Threshold secretory mechanism: A model of derivative element in biological control , 1973 .

[9]  Paolo Meda,et al.  Cx36-Mediated Coupling Reduces β-Cell Heterogeneity, Confines the Stimulating Glucose Concentration Range, and Affects Insulin Release Kinetics , 2007, Diabetes.

[10]  Zhanxiang Wang,et al.  Glucose-stimulated Cdc42 Signaling Is Essential for the Second Phase of Insulin Secretion* , 2007, Journal of Biological Chemistry.

[11]  R. Hovorka,et al.  Pancreatic beta-cell responsiveness during meal tolerance test: model assessment in normal subjects and subjects with newly diagnosed noninsulin-dependent diabetes mellitus. , 1998, The Journal of clinical endocrinology and metabolism.

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

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

[14]  Piero Marchetti,et al.  Phasic insulin release and metabolic regulation in type 2 diabetes. , 2002, Diabetes.

[15]  M. Noda,et al.  Identification of the docked granule pool responsible for the first phase of glucose-stimulated insulin secretion. , 1999, Diabetes.

[16]  W. Zawalich,et al.  Effects of Glucose, Exogenous Insulin, and Carbachol on C-peptide and Insulin Secretion from Isolated Perifused Rat Islets* , 2002, The Journal of Biological Chemistry.

[17]  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.

[18]  P. Rorsman,et al.  Insulin granule dynamics in pancreatic beta cells , 2003, Diabetologia.

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

[20]  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.

[21]  C Cobelli,et al.  Quantitative indexes of beta-cell function during graded up&down glucose infusion from C-peptide minimal models. , 2001, American journal of physiology. Endocrinology and metabolism.

[22]  David W Piston,et al.  Microfluidic glucose stimulation reveals limited coordination of intracellular Ca2+ activity oscillations in pancreatic islets. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[23]  Zhanxiang Wang,et al.  Mechanisms of biphasic insulin-granule exocytosis – roles of the cytoskeleton, small GTPases and SNARE proteins , 2009, Journal of Cell Science.

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

[25]  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.

[26]  Camillo Ricordi,et al.  The unique cytoarchitecture of human pancreatic islets has implications for islet cell function , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[27]  Roman Hovorka,et al.  Pancreatic β-Cell Responsiveness during Meal Tolerance Test: Model Assessment in Normal Subjects and Subjects with Newly Diagnosed Noninsulin-Dependent Diabetes Mellitus1 , 1998 .

[28]  E. Ferrannini,et al.  Effect of acute hyperglycemia on insulin secretion in humans. , 2002, Diabetes.

[29]  Lena Eliasson,et al.  Fast insulin secretion reflects exocytosis of docked granules in mouse pancreatic B-cells , 2002, Pflügers Archiv.

[30]  J. Gerich,et al.  Is reduced first-phase insulin release the earliest detectable abnormality in individuals destined to develop type 2 diabetes? , 2002, Diabetes.

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

[32]  L. Eliasson,et al.  Impaired insulin exocytosis in neural cell adhesion molecule-/- mice due to defective reorganization of the submembrane F-actin network. , 2009, Endocrinology.

[33]  Myriam Nenquin,et al.  Nutrient Control of Insulin Secretion in Isolated Normal Human Islets , 2006, Diabetes.

[34]  Bard Ermentrout,et al.  Simulating, analyzing, and animating dynamical systems - a guide to XPPAUT for researchers and students , 2002, Software, environments, tools.

[35]  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.

[36]  C Cobelli,et al.  Beta-cell function during insulin-modified intravenous glucose tolerance test successfully assessed by the C-peptide minimal model. , 1999, Metabolism: clinical and experimental.

[37]  A. Kowluru,et al.  Novel regulation by Rac1 of glucose- and forskolin-induced insulin secretion in INS-1 beta-cells. , 2004, American journal of physiology. Endocrinology and metabolism.

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