Glucose-stimulated insulin secretion in isolated pancreatic islets: Multiphysics FEM model calculations compared to results of perifusion experiments with human islets

Peter Buchwald, Sirlene R. Cechin

Diabetes Research Institute, University of Miami, Miller School of Medicine, Miami, USA.

DOI: 10.4236/jbise.2013.65A006                

Abstract

Because insulin released by the β-cells of pancreatic islets is the main regulator of glucose levels, the quantitative modeling of their glucose-stimulated insulin secretion is of obvious interest not only to improve our understanding of the processes involved, but also to allow better assessment of β -cell function in diabetic patients or islet transplant recipients as well as the development of improved artificial or bioartificial pancreas devices. We have recently developed a general, local concentrations-based multiphysics computational model of insulin secretion in avascular pancreatic islets that can be used to calculate insulin secretion for arbitrary geometries of cultured, perifused, transplanted, or encapsulated islets in response to various glucose profiles. Here, experimental results obtained from two different dynamic glucose-stimulated insulin release (GSIR) perifusion studies performed by us following standard procedures are compared to those calculated by the model. Such perifusion studies allow the quantitative assessment of insulin release kinetics under fully controllable experimental conditions of varying external concentrations of glucose, oxygen, or other compounds of interest, and can provide an informative assessment of islet quality and function. The time-profile of the insulin secretion calculated by the model was in good agree- ment with the experimental results obtained with isolated human islets. Detailed spatial distributions of glucose, oxygen, and insulin were calculated and are presented to provide a quantitative visualization of various important aspects of the insulin secretion dynamics in perifused islets.

Keywords

COMSOL Multiphysics; Diabetes Mellitus; FEM Model; Glucose-Insulin Dynamics; Hill Equation; Islet Perifusion; Islets of Langerhans

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	Hallgreen, C.E., Korsgaard, T.V., Hansen, R.N., and Colding-Jørgensen, M. (2008) The glucose-insulin control system. In: Bertau, M., Mosekilde, E. and Westerhoff, H.V., Eds., Biosimulation in Drug Development, WileyVCH, Weinheim, 141-196.
[2]	van Belle, T.L., Coppieters, K.T. and von Herrath, M.G. (2011) Type 1 diabetes: Etiology, immunology, and therapeutic strategies. Physiological Reviews, 91, 79-118. doi:10.1152/physrev.00003.2010
[3]	Galletti, P.M., Colton, C.K., Jaffrin, M. and Reach, G. (2006) Artificial pancreas. In: Bronzino, J.D., Ed., The Biomedical Engineering Handbook. Tissue Engineering and Artificial Organs, 3rd Edition, CRC Press, Boca Raton, 71.71-71.18.
[4]	Steil, G.M., Panteleon, A.E. and Rebrin, K. (2004) Closed-loop insulin delivery-the path to physiological glucose control. Advanced Drug Delivery Reviews, 56, 125-144. doi:10.1016/j.addr.2003.08.011
[5]	Hovorka, R. (2006) Continuous glucose monitoring and closed-loop systems. Diabetic Medicine, 23, 1-12. doi:10.1111/j.1464-5491.2005.01672.x
[6]	Fort, A., Fort, N., Ricordi, C. and Stabler, C.L. (2008) Biohybrid devices and encapsulation technologies for engineering a bioartificial pancreas. Cell Transplantation, 17, 997-1003. doi:10.3727/096368908786991498
[7]	Silva, A.I., de Matos, A.N., Brons, I.G. and Mateus, M. (2006) An overview on the development of a bio-artificial pancreas as a treatment of insulin-dependent diabetes mellitus. Medicinal Research Reviews, 26, 181-222. doi:10.1002/med.20047
[8]	Teramura, Y. and Iwata, H. (2010) Bioartificial pancreas microencapsulation and conformal coating of islet of Langerhans. Advanced Drug Delivery Reviews, 62, 827840. doi:10.1016/j.addr.2010.01.005
[9]	O'Sullivan, E.S., Vegas, A., Anderson, D.G. and Weir, G.C. (2011) Islets transplanted in immunoisolation devices: A review of the progress and the challenges that remain. Endocrine Reviews, 32, 827-844. doi:10.1210/er.2010-0026
[10]	Bergman, R.N., Ider, Y.Z., Bowden, C.R. and Cobelli, C. (1979) Quantitative estimation of insulin sensitivity. American Journal of Physiology—Endocrinology and Metabolism, 236, E667-E677.
[11]	Toffolo, G.M. and Cobelli, C. (2001) Insulin modeling. In: Carson, E. and Cobelli, C., Eds., Modeling Methodology for Physiology and Medicine, Academic Press, San Diego, 305-335. doi:10.1016/B978-012160245-1/50012-X
[12]	Makroglou, A., Li, J. and Kuang, Y. (2006) Mathematical models and software tools for the glucose-insulin regulatory system and diabetes: An overview. Applied Numerical Mathematics, 56, 559-573. doi:10.1016/j.apnum.2005.04.023
[13]	Boutayeb, A. and Chetouani, A. (2006) A critical review of mathematical models and data used in diabetology. BioMedical Engineering OnLine, 5, 43. doi:10.1186/1475-925X-5-43
[14]	Matthews, D.R., Hosker, J.P., Rudenski, A.S., Naylor, B.A., Treacher, D.F. and Turner, R.C. (1985) Homeostasis model assessment: Insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia, 28, 412-419. doi:10.1007/BF00280883
[15]	Wallace, T.M., Levy, J.C. and Matthews, D.R. (2004) Use and abuse of HOMA modeling. Diabetes Care, 27, 1487-1495. doi:10.2337/diacare.27.6.1487
[16]	Caumo, A., Maffi, P., Nano, R., Luzi, L., Hilbrands, R., Gillard, P., Jacobs-Tulleneers-Thevissen, D., Secchi, A., Keymeulen, B., Pipeleers, D. and Piemonti, L. (2011) Comparative evaluation of simple indices of graft function after islet transplantation. Transplantation, 92, 815821. doi:10.1097/TP.0b013e31822ca79b
[17]	Buchwald, P. (2011) A local glucose-and oxygen concentration-based insulin secretion model for pancreatic islets. Theoretical Biology and Medical Modelling, 8, 20. doi:10.1186/1742-4682-8-20
[18]	Buchwald, P. (2009) FEM-based oxygen consumption and cell viability models for avascular pancreatic islets. Theoretical Biology and Medical Modelling, 6, 5. doi:10.1186/1742-4682-6-5
[19]	Reach, G. and Jaffrin, M.Y. (1990) Kinetic modelling as a tool for the design of a vascular bioartificial pancreas: Feedback between modelling and experimental validation. Comput. Computer Methods and Programs in Biomedicine, 32, 277-285. doi:10.1016/0169-2607(90)90110-U
[20]	Pillarella, M.R. and Zydney, A.L. (1990) Theoretical analysis of the effect of convective flow on solute transport and insulin release in a hollow fiber bioartificial pancreas. Journal of Biomechanical Engineering, 112, 220-228. doi:10.1115/1.2891175
[21]	Tziampazis, E. and Sambanis, A. (1995) Tissue engineering of a bioartificial pancreas: Modeling the cell environment and device function. Biotechnology Progress, 11, 115-126. doi:10.1021/bp00032a001
[22]	Buladi, B.M., Chang, C.C., Belovich, J.M. and Gatica, J.E. (1996) Transport phenomena and kinetics in an extravascular bioartificial pancreas. AIChE Journal, 42, 2668-2682. doi:10.1002/aic.690420928
[23]	Dulong, J.L., and Legallais, C. (2005) What are the relevant parameters for the geometrical optimization of an implantable bioartificial pancreas? Journal of Biomechanical Engineering, 127, 1054-1061. doi:10.1115/1.2073407
[24]	Henquin, J.C., Dufrane, D. and Nenquin, M. (2006) Nutrient control of insulin secretion in isolated normal human islets. Diabetes, 55, 3470-3477. doi:10.2337/db06-0868
[25]	Grodsky, G.M. (1972) A threshold distribution hypothesis for packet storage of insulin and its mathematical modeling. Journal of Clinical Investigation, 51, 20472059. doi:10.1172/JCI107011
[26]	Bocca, N., Pileggi, A., Molano, R.D., Marzorati, S., Wu, W., Bodor, N., Ricordi, C. and Buchwald, P. (2008) Soft corticosteroids for local immunosuppression: Exploring the possibility for the use of loteprednol etabonate in islet transplantation. Pharmazie, 63, 226-232.
[27]	Cechin, S.R., Perez-Alvarez, I., Fenjves, E., Molano, R.D., Pileggi, A., Berggren, P.O., Ricordi, C. and Pastori, R.L. (2012) Anti-inflammatory properties of exenatide in human pancreatic islets. Cell Transplantation, 21, 633648. doi:10.3727/096368911X576027
[28]	Dionne, K.E., Colton, C.K. and Yarmush, M.L. (1993) Effect of hypoxia on insulin secretion by isolated rat and canine islets of Langerhans. Diabetes, 42, 12-21. doi:10.2337/diabetes.42.1.12
[29]	Sweet, I.R., Khalil, G., Wallen, A.R., Steedman, M., Schenkman, K.A., Reems, J.A., Kahn, S.E. and Callis, J.B. (2002) Continuous measurement of oxygen consumption by pancreatic islets. Diabetes Technology & Therapeutics, 4, 661-672. doi:10.1089/152091502320798303
[30]	Cabrera, O., Jacques-Silva, M.C., Berman, D.M., Fachado, A., Echeverri, F., Poo, R.E., Khan, A., Kenyon, N.S., Ricordi, C., Berggren, P.-O. and Caicedo, A. (2008) Automated, high-throughput assays for evaluation of human pancreatic islet function. Cell Transplantation, 16, 10391048. doi:10.3727/000000007783472408
[31]	Pileggi, A., Ricordi, C., Kenyon, N.S., Froud, T., Baidal, D.A., Kahn, A., Selvaggi, G. and Alejandro, R. (2004) Twenty years of clinical islet transplantation at the Diabetes Research Institute—University of Miami. Clinical Transplantation, 2004, 177-204.
[32]	Ichii, H., Pileggi, A., Molano, R.D., Baidal, D.A., Khan, A., Kuroda, Y., Inverardi, L., Goss, J.A., Alejandro, R. and Ricordi, C. (2005) Rescue purification maximizes the use of human islet preparations for transplantation. American Journal of Transplantation, 5, 21-30. doi:10.1111/j.1600-6143.2005.00698.x
[33]	Ricordi, C., Lacy, P.E., Finke, E.H., Olack, B.J. and Scharp, D.W. (1988) Automated method for isolation of human pancreatic islets. Diabetes, 37, 413-420. doi:10.2337/diabetes.37.4.413
[34]	Ichii, H., Sakuma, Y., Pileggi, A., Fraker, C., Alvarez, A., Montelongo, J., Szust, J., Khan, A., Inverardi, L., Naziruddin, B., Levy, M.F., Klintmalm, G.B., Goss, J.A., Alejandro, R. and Ricordi, C. (2007) Shipment of human islets for transplantation. American Journal of Transplantation, 7, 1010-1020. doi:10.1111/j.1600-6143.2006.01687.x
[35]	Comsol, AB (2007) COMSOL multiphysics modeling guide, version 3.4. COMSOL AB.
[36]	Buchwald, P., Wang, X., Khan, A., Bernal, A., Fraker, C., Inverardi, L. and Ricordi, C. (2009) Quantitative assessment of islet cell products: Estimating the accuracy of the existing protocol and accounting for islet size distribution. Cell Transplantation, 18, 1223-1235. doi:10.3727/096368909X476968.