Paracrine regulation of glucagon secretion: the β/α/δ model
Open accessAbstract
The regulation of glucagon secretion in the pancreatic α-cell is not well understood. It has been proposed that glucose suppresses glucagon secretion either directly through an intrinsic mechanism within the α-cell or indirectly through an extrinsic mechanism. Previously, we described a mathematical model for isolated pancreatic α-cells and used it to investigate possible intrinsic mechanisms of regulating glucagon secretion. We demonstrated that glucose can suppress glucagon secretion through both ATP-dependent potassium channels (K ATP ) and a store-operated current (SOC). We have now developed an islet model that combines previously published mathematical models of α- and β-cells with a new model of δ-cells and use it to explore the effects of insulin and somatostatin on glucagon secretion. We show that the model can reproduce experimental observations that the inhibitory effect of glucose remains even when paracrine modulators are no longer acting on the α-cell. We demonstrate how paracrine interactions can either synchronize α- and δ-cells to produce pulsatile oscillations in glucagon and somatostatin secretion or fail to do so. The model can also account for the paradoxical observation that glucagon can be out of phase with insulin, whereas α-cell calcium is in phase with insulin. We conclude that both paracrine interactions and the α-cell's intrinsic mechanisms are needed to explain the response of glucagon secretion to glucose.
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A relatively large set of mathematical models were developed with focus on glucagon secretion at cellular level.
“A relatively large set of mathematical models were developed with focus on glucagon secretion at cellular level (12–21).”
From Mathematical Model of Glucagon Kinetics for the Assessment of Insulin-Mediated Glucagon Inhibition During an Oral Glucose Tolerance Test (2021) · cites this paper as [18]
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Simulating, Analyzing, and Animating Dynamical Systems
Ermentrout, B. (2002) · Society for Industrial and Applied Mathematics eBooks · doi:10.1137/1.9780898718195 · Cited by 1,271 · see citing works
Ermentrout, B. (1987) · Cited by 1,126 · see citing works
α-Cells of the Endocrine Pancreas: 35 Years of Research but the Enigma Remains
Gromada, J., Franklin, I., & Wollheim, C. B. (2007) · Endocrine Reviews · doi:10.1210/er.2006-0007 · Cited by 574 · see citing works
Promotion of Insulin Secretion by Glucagon
Samols, E., Marri, G., & Marks, V. (1965) · The Lancet · doi:10.1016/s0140-6736(65)90761-0 · Cited by 521 · see citing works
Glucose-inhibition of glucagon secretion involves activation of GABAA-receptor chloride channels
Rorsman, P., Berggren, P., Bokvist, K. B., Ericson, H., Möhler, H., Östenson, C., & Smith, P. A. (1989) · Nature · doi:10.1038/341233a0 · Cited by 460 · see citing works
Islet β-cell secretion determines glucagon release from neighbouring α-cells
Ishihara, H., Maechler, P., Gjinovci, A., Herrera, P. L., & Wollheim, C. B. (2003) · Nature Cell Biology · doi:10.1038/ncb951 · Cited by 380 · see citing works
Strowski, M. Z., Parmar, R. M., Blake, A. D., & Schaeffer, J. M. (2000) · Endocrinology · doi:10.1210/endo.141.1.7263 · Cited by 358 · see citing works
Hauge-Evans, A. C., King, A. J., Carmignac, D., Richardson, C. C., Robinson, I. C. A. F., Low, M. J., Christie, M. R., Persaud, S. J., & Jones, P. M. (2009) · Diabetes · doi:10.2337/db08-0792 · Cited by 335 · see citing works
Rodriguez‐Diaz, R., Dando, R., Jacques-Silva, M. C., Fachado, A., Molina, J., Abdulreda, M. H., Ricordi, C., Roper, S. D., Berggren, P., & Caicedo, A. (2011) · Nature Medicine · doi:10.1038/nm.2371 · Cited by 305 · see citing works
Insulin within islets is a physiologic glucagon release inhibitor
Maruyama, H., Hisatomi, A., Orci, L., Grodsky, G. M., & Unger, R. H. (1984) · Journal of Clinical Investigation · doi:10.1172/jci111658 · Cited by 303 · see citing works
Franklin, I., Gromada, J., Gjinovci, A., Theander, S., & Wollheim, C. (2005) · Diabetes · doi:10.2337/diabetes.54.6.1808 · Cited by 291 · see citing works
Insulin, Glucagon, and Glucose Exhibit Synchronous, Sustained Oscillations in Fasting Monkeys
Goodner, C. J., Walike, B. C., Koerker, D. J., Ensinck, J. W., Brown, A. C. L., Chideckel, E. W., Palmer, J. P., & Kalnasy, L. W. (1977) · Science · doi:10.1126/science.401543 · Cited by 281 · see citing works
Wendt, A., Birnir, B., Buschard, K., Gromada, J., Salehi, A. A., Sewing, S., Rorsman, P., & Braun, M. (2004) · Diabetes · doi:10.2337/diabetes.53.4.1038 · Cited by 257 · see citing works
Urocortin3 mediates somatostatin-dependent negative feedback control of insulin secretion
van der Meulen, T., Donaldson, C. J., Cáceres, E., Hunter, A. E., Cowing-Zitron, C., Pound, L. D., Adams, M. W., Zembrzycki, A., Grove, K. L., & Huising, M. O. (2015) · Nature Medicine · doi:10.1038/nm.3872 · Cited by 256 · see citing works
MacDonald, M. J., Fahien, L. A., Brown, L. J., Hasan, N. M., Buss, J. D., & Kendrick, M. A. (2004) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00218.2004 · Cited by 244 · see citing works
MacDonald, P. E., Marinis, Y. Z. D., Ramracheya, R. D., Salehi, A. A., Ma, X., Johnson, P., Cox, R., Eliasson, L., & Rorsman, P. (2007) · PLoS Biology · doi:10.1371/journal.pbio.0050143 · Cited by 243 · see citing works
Gap Junction Coupling and Calcium Waves in the Pancreatic Islet
Benninger, R. K. P., Zhang, M., Head, W. S., Satin, L. S., & Piston, D. W. (2008) · Biophysical Journal · doi:10.1529/biophysj.108.140863 · Cited by 240 · see citing works
γ-Aminobutyric Acid (GABA) Is an Autocrine Excitatory Transmitter in Human Pancreatic β-Cells
Braun, M., Ramracheya, R., Bengtsson, M., Clark, A., Walker, J. N., Johnson, P. R., & Rorsman, P. (2010) · Diabetes · doi:10.2337/db09-0797 · Cited by 239 · see citing works
Pulsatile insulin secretion, impaired glucose tolerance and type 2 diabetes
Satin, L. S., Butler, P. C., Ha, J., & Sherman, A. (2015) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2015.01.003 · Cited by 234 · see citing works
Zhang, Q., Ramracheya, R., Lahmann, C., Tarasov, A., Bengtsson, M., Braha, O., Braun, M., Brereton, M., Collins, S., Galvanovskis, J., et al. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.10.014 · Cited by 225 · see citing works
Glucose inhibits glucagon secretion by a direct effect on mouse pancreatic alpha cells
Vieira, E., Salehi, A., & Gylfe, E. (2007) · Diabetologia · doi:10.1007/s00125-006-0511-1 · Cited by 218 · see citing works
Are Metabolic Oscillations Responsible for Normal Oscillatory Insulin Secretion?
Tornheim, K. (1997) · Diabetes · doi:10.2337/diab.46.9.1375 · Cited by 211 · see citing works
Nadal, Á., Quesada, I., & Soria, B. (1999) · The Journal of Physiology · doi:10.1111/j.1469-7793.1999.0085z.x · Cited by 196 · see citing works
Metabolic and electrical oscillations: partners in controlling pulsatile insulin secretion
Bertram, R., Sherman, A., & Satin, L. S. (2007) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00359.2007 · Cited by 196 · see citing works
Regulation of glucagon secretion by glucose: paracrine, intrinsic or both?
Walker, J. N., Ramracheya, R. D., Zhang, Q., Johnson, P., Braun, M., & Rorsman, P. (2011) · Diabetes Obesity and Metabolism · doi:10.1111/j.1463-1326.2011.01450.x · Cited by 174 · see citing works
Head, W. S., Orseth, M. L., Nunemaker, C. S., Satin, L. S., Piston, D. W., & Benninger, R. K. P. (2012) · Diabetes · doi:10.2337/db11-1312 · Cited by 171 · see citing works
Benninger, R. K. P., Head, W. S., Zhang, M., Satin, L. S., & Piston, D. W. (2011) · The Journal of Physiology · doi:10.1113/jphysiol.2011.218909 · Cited by 165 · see citing works
Gerich, J. E., Lovinger, R. D., & Grodsky, G. M. (1975) · Endocrinology · doi:10.1210/endo-96-3-749 · Cited by 165 · see citing works
Gromada, J., Ma, X., Høy, M., Bokvist, K., Salehi, A., Berggren, P.-O., & Rorsman, P. (2004) · Diabetes · doi:10.2337/diabetes.53.suppl_3.s181 · Cited by 164 · see citing works
SSTR2 is the functionally dominant somatostatin receptor in human pancreatic β- and α-cells
Kailey, B., van de Bunt, M., Cheley, S., Johnson, P. R., MacDonald, P. E., Gloyn, A. L., Rorsman, P., & Braun, M. (2012) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00207.2012 · Cited by 164 · see citing works
Paradoxical Stimulation of Glucagon Secretion by High Glucose Concentrations
Salehi, A., Vieira, E., & Gylfe, E. (2006) · Diabetes · doi:10.2337/db06-0080 · Cited by 159 · see citing works
The impact of mathematical modeling on the understanding of diabetes and related complications
Ajmera, I., Swat, M., Laibe, C., Le Novère, N., & Chelliah, V (2013) · CPT: Pharmacometrics & Systems Pharmacology · doi:10.1038/psp.2013.30 · Cited by 153 · see citing works
Regulation of Adenosine 3′,5′-Monophosphate Levels in the Pancreatic B Cell*
Schuit, F. C., & PIPELEERS, D. G. (1985) · Endocrinology · doi:10.1210/endo-117-3-834 · Cited by 152 · see citing works
Calcium and Glycolysis Mediate Multiple Bursting Modes in Pancreatic Islets
Bertram, R., Satin, L. S., Zhang, M., Smolen, P. D., & Sherman, A. (2004) · Biophysical Journal · doi:10.1529/biophysj.104.049262 · Cited by 149 · see citing works
Control of Insulin Secretion by Cholinergic Signaling in the Human Pancreatic Islet
Molina, J., Rodriguez-Diaz, R., Fachado, A., Jacques-Silva, M. C., Berggren, P.-O., & Caicedo, A. (2014) · Diabetes · doi:10.2337/db13-1371 · Cited by 149 · see citing works
Patch‐clamp characterisation of somatostatin‐secreting δ‐cells in intact mouse pancreatic islets
Göpel, S., Kanno, T., Barg, S., & Rorsman, P. (2000) · The Journal of Physiology · doi:10.1111/j.1469-7793.2000.00497.x · Cited by 143 · see citing works
Menge, B. A., Grüber, L., Jørgensen, S. M., Deacon, C. F., Schmidt, W. E., Veldhuis, J. D., Holst, J. J., & Meier, J. J. (2011) · Diabetes · doi:10.2337/db11-0251 · Cited by 137 · see citing works
Pulsatile, Synchronous Basal Insulin and Glucagon Secretion in Man
Lang, D. A., Matthews, D. R., Burnett, M. A., Ward, G. M., & Turner, R. C. (1982) · Diabetes · doi:10.2337/diab.31.1.22 · Cited by 124 · see citing works
Gromada, J., Høy, M., Buschard, K., Salehi, A., & Rorsman, P. (2001) · The Journal of Physiology · doi:10.1111/j.1469-7793.2001.00519.x · Cited by 120 · see citing works
Glucose Suppression of Glucagon Secretion
Marchand, S. L., & Piston, D. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.069195 · Cited by 119 · see citing works
Elliott, A. D., Ustione, A., & Piston, D. W. (2014) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00344.2014 · Cited by 118 · see citing works
Liu, Y.-J., Vieira, E., & Gylfe, E. (2004) · Cell Calcium · doi:10.1016/j.ceca.2003.10.002 · Cited by 118 · see citing works
Hellman, B., Salehi, A. A., Gylfe, E., Dansk, H., & Grapengiesser, E. (2009) · Endocrinology · doi:10.1210/en.2009-0600 · Cited by 115 · see citing works
R-type Ca2+-channel-evoked CICR regulates glucose-induced somatostatin secretion
Zhang, Q., Bengtsson, M., Partridge, C., Salehi, A., Braun, M., Cox, R., Eliasson, L., Johnson, P. R., Renström, E., Schneider, T., et al. (2007) · Nature Cell Biology · doi:10.1038/ncb1563 · Cited by 110 · see citing works
Newcomer insulin secretory granules as a highly calcium-sensitive pool
Pedersen, M. G., & Sherman, A. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0901202106 · Cited by 107 · see citing works
GABA in the Endocrine Pancreas
Franklin, I., & Wollheim, C. B. (2004) · The Journal of General Physiology · doi:10.1085/jgp.200409016 · Cited by 105 · see citing works
Bertram, R., Satin, L. S., Pedersen, M. G., Luciani, D. S., & Sherman, A. (2007) · Biophysical Journal · doi:10.1529/biophysj.106.097154 · Cited by 105 · see citing works
Braun, M., Ramracheya, R., Amisten, S., Bengtsson, M., Moritoh, Y., Zhang, Q., Johnson, P. R. V., & Rorsman, P. (2009) · Diabetologia · doi:10.1007/s00125-009-1382-z · Cited by 104 · see citing works
Too Much Glucagon, Too Little Insulin
Brown, R. J., Sinaii, N., & Rother, K. I. (2008) · Diabetes Care · doi:10.2337/dc08-0575 · Cited by 104 · see citing works
Quesada, I., Todorova, M. G., Alonso-Magdalena, P., Beltrá, M., Carneiro, E. M., Martin, F., Nadal, A., & Soria, B. (2006) · Diabetes · doi:10.2337/db06-0272 · Cited by 104 · see citing works
Function and expression of somatostatin receptors of the endocrine pancreas
Strowski, M. Z., & Blake, A. D. (2008) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2008.02.007 · Cited by 101 · see citing works
Braun, M., Wendt, A., Karanauskaite, J., Galvanovskis, J., Clark, A., MacDonald, P. E., & Rorsman, P. (2007) · The Journal of General Physiology · doi:10.1085/jgp.200609658 · Cited by 100 · see citing works
Tolbutamide Controls Glucagon Release From Mouse Islets Differently Than Glucose
Cheng, R., Gómez-Ruiz, A., Antoine, N., Noël, L. A., Chae, H., Ravier, M. A., Chimienti, F., Schuit, F. C., & Gilon, P. (2013) · Diabetes · doi:10.2337/db12-0347 · Cited by 88 · see citing works
Samols, E., & Stagner, J. (1988) · American Journal of Medicine · doi:10.1016/0002-9343(88)90395-6 · Cited by 84 · see citing works
Leung, Y., Ahmed, I., Sheu, L., Gao, X., Hara, M., Tsushima, R. G., Diamant, N. E., & Gaisano, H. Y. (2006) · Endocrinology · doi:10.1210/en.2005-1249 · Cited by 83 · see citing works
Yoshimoto, Y., Fukuyama, Y., Horio, Y., Inanobe, A., Gotoh, M., & Kurachi, Y. (1999) · FEBS Letters · doi:10.1016/s0014-5793(99)00076-9 · Cited by 80 · see citing works
Quoix, N., Cheng, R., Mattart, L., Zeinoun, Z., Guiot, Y., Beauvois, M. C., Henquin, J., & Gilon, P. (2008) · Diabetes · doi:10.2337/db07-1298 · Cited by 78 · see citing works
Ca2+ Oscillations in Pancreatic Islet Cells Secreting Glucagon and Somatostatin
Berts, A., Gylfe, E., & Hellman, B. (1995) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1995.1387 · Cited by 72 · see citing works
Unperturbed islet α‐cell function examined in mouse pancreas tissue slices
Huang, Y., Rupnik, M. S., & Gaisano, H. Y. (2010) · The Journal of Physiology · doi:10.1113/jphysiol.2010.200345 · Cited by 71 · see citing works
Submembrane ATP and Ca2+kinetics in α-cells: unexpected signaling for glucagon secretion
Li, J., Yu, Q., Ahooghalandari, P., Gribble, F. M., Reimann, F. M., Tengholm, A., & Gylfe, E. (2015) · The FASEB Journal · doi:10.1096/fj.14-265918 · Cited by 67 · see citing works
Karimian, N., Qin, T., Liang, T., Osundiji, M., Huang, Y., Teich, T., Riddell, M. C., Cattral, M. S., Coy, D. H., Vranic, M., et al. (2013) · Diabetes · doi:10.2337/db13-0164 · Cited by 66 · see citing works
Neurotransmitter control of islet hormone pulsatility
Gylfe, E., & Tengholm, A. (2014) · Diabetes Obesity and Metabolism · doi:10.1111/dom.12345 · Cited by 65 · see citing works
Brunicardi, F. C., Kleinman, R. M., Moldovan, S., Nguyen, T.-H. L., Watt, P. C., Walsh, J. H., & Gingerich, R. L. (2001) · Pancreas · doi:10.1097/00006676-200110000-00012 · Cited by 64 · see citing works
Chen, Y.-D., Wang, S., & Sherman, A. (2008) · Biophysical Journal · doi:10.1529/biophysj.107.124990 · Cited by 63 · see citing works
Hellman, B., Salehi, A., Grapengiesser, E., & Gylfe, E. (2012) · Biochemical and Biophysical Research Communications - BBRC · doi:10.1016/j.bbrc.2011.12.113 · Cited by 60 · see citing works
Marchand, S. J. L., & Piston, D. W. (2012) · PLoS ONE · doi:10.1371/journal.pone.0047084 · Cited by 56 · see citing works
Salehi, A. A., Qader, S. S., Grapengiesser, E., & Hellman, B. (2007) · Regulatory Peptides · doi:10.1016/j.regpep.2007.06.003 · Cited by 51 · see citing works
STUDIES ON THE MECHANISM OF SOMATOSTATIN ACTION ON INSULIN RELEASE IN MAN
Efendić, S., & Luft, R. (1975) · European Journal of Endocrinology · doi:10.1530/acta.0.0780516 · Cited by 51 · see citing works
Suppression of Ca2+ oscillations in glucagon-producing α2-cells by insulin/glucose and amino acids
Berts, A., Ball, A., Gylfe, E., & Hellman, B. (1996) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/0167-4889(95)00173-5 · Cited by 50 · see citing works
Pörksen, S., Nielsen, L. B., Kaas, A., Kočova, M., Chiarelli, F., Ørskov, C., Holst, J. J., Ploug, K. B., Hougaard, P., Hansen, L., et al. (2007) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2007-0244 · Cited by 48 · see citing works
The Role of Glucagon in the Endogenous Hyperglycemia of Diabetes Mellitus
Unger, R. H. (1977) · Annual Review of Medicine · doi:10.1146/annurev.me.28.020177.001003 · Cited by 46 · see citing works
Modeling the pancreatic α-cell: dual mechanisms of glucose suppression of glucagon secretion
Watts, M., & Sherman, A. (2014) · Biophysical Journal · doi:10.1016/j.bpj.2013.11.4504 · Cited by 45 · see citing works
Guardado Mendoza, R., Perego, C., Finzi, G., La Rosa, S., Capella, C., Jimenez-Ceja, L. M., Velloso, L. A., Saad, M. J. A., Sessa, F., Bertuzzi, F., et al. (2015) · Diabetologia · doi:10.1007/s00125-015-3625-5 · Cited by 41 · see citing works
TASK-1 Potassium Channels Limit Pancreatic α-Cell Calcium Influx and Glucagon Secretion
Dadi, P. K., Luo, B., Vierra, N. C., & Jacobson, D. A. (2015) · Molecular Endocrinology · doi:10.1210/me.2014-1321 · Cited by 40 · see citing works
Grapengiesser, E., Salehi, A. A., Qader, S. S., & Hellman, B. (2006) · Endocrinology · doi:10.1210/en.2005-1431 · Cited by 39 · see citing works
Gi2 proteins couple somatostatin receptors to low-conductance K+ channels in rat pancreatic α-cells
Gromada, J., Høy, M., Olsen, H. L., Gotfredsen, C. F., Buschard, K., Rorsman, P., & Bokvist, K. B. (2001) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s004240000474 · Cited by 35 · see citing works
Montefusco, F., & Pedersen, M. G. (2015) · The Journal of Physiology · doi:10.1113/jp270777 · Cited by 35 · see citing works
Glucagon and forskolin have dual effects upon islet cell electrical activity
Ikeuchi, M., & Cook, D. L. (1984) · Life Sciences · doi:10.1016/0024-3205(84)90264-9 · Cited by 32 · see citing works
STUDIES ON THE MECHANISMS OF SOMATOSTATIN ACTION ON INSULIN RELEASE
CLARO, A., Grill, V. E., Efendić, S., & Luft, R. (1977) · European Journal of Endocrinology · doi:10.1530/acta.0.0850379 · Cited by 26 · see citing works
Claro, A., Grill, V., Efendić, S., & Luft, R. (1977) · PubMed · Cited by 25 · see citing works
Farhy, L. S., Du, Z., Zeng, Q., Veldhuis, P. P., Johnson, M. L., Brayman, K. L., & McCall, A. L. (2008) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.90372.2008 · Cited by 19 · see citing works
Stable and flexible system for glucose homeostasis
Hong, H., Jo, J., & Sang-jin Sin, A. (2013) · Physical Review E · doi:10.1103/physreve.88.032711 · Cited by 16 · see citing works
Chapter 21 Pancreatic Network Control of Glucagon Secretion and Counterregulation
Farhy, L. S., & McCall, A. L. (2009) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(09)67021-x · Cited by 12 · see citing works
Flagged first, then by citations
1 of the 84 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
δ‐cells and β‐cells are electrically coupled and regulate α‐cell activity via somatostatin
Briant, L. J. B., Reinbothe, T. M., Spiliotis, I., Miranda, C., Rodriguez, B., & Rorsman, P. (2018) · The Journal of Physiology · doi:10.1113/jp274581 · Cited by 155 · see citing works
Integrating the inputs that shape pancreatic islet hormone release
Noguchi, G. M., & Huising, M. O. (2019) · Nature Metabolism · doi:10.1038/s42255-019-0148-2 · Cited by 130 · see citing works
The Human Islet: Mini-Organ With Mega-Impact
Walker, J. T., Saunders, D. C., Briššová, M., & Powers, A. C. (2021) · Endocrine Reviews · doi:10.1210/endrev/bnab010 · Cited by 80 · see citing works
Functional identification of islet cell types by electrophysiological fingerprinting
Briant, L. J. B., Zhang, Q., Vergari, E., Kellard, J. A., Rodriguez, B., Ashcroft, F. M., & Rorsman, P. (2017) · Journal of The Royal Society Interface · doi:10.1098/rsif.2016.0999 · Cited by 59 · see citing works
A pathway model of glucose-stimulated insulin secretion in the pancreatic β-cell
Maheshvare, M. D., Raha, S., König, M., & Pal, D. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1185656 · Cited by 43 · see citing works
Pancreatic Islet Blood Flow Dynamics in Primates
Diez, J. A., Drigo, R., Zheng, X.-F., Stelmashenko, O., Chua, M., Rodriguez-Diaz, R., Fukuda, M., Köhler, M., Leibiger, I., Tun, S. B. B., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.07.039 · Cited by 39 · see citing works
The Role of the α Cell in the Pathogenesis of Diabetes: A World beyond the Mirror
Martínez, M. S., Manzano, A., Olivar, L. C., Nava, M., Salazar, J. J., D’Marco, L., Ortíz, R., Chacín, M., Guerrero‐Wyss, M., de Bravo, M. C., et al. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22179504 · Cited by 37 · see citing works
Pancreatic α and β cells are globally phase-locked
Ren, H., Li, Y., Han, C., Yu, Y., Shi, B., Peng, X., Zhang, T., Wu, S., Yang, X., Sneppen, K., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-31373-6 · Cited by 32 · see citing works
Repositioning the Alpha Cell in Postprandial Metabolism
EL, K. M., Capozzi, M. E., & Campbell, J. E. (2020) · Endocrinology · doi:10.1210/endocr/bqaa169 · Cited by 31 · see citing works
Morettini, M., Burattini, L., Göbl, C., Pacini, G., Ahrén, B., & Tura, A. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.611147 · Cited by 27 · see citing works
Exploring pancreatic beta-cell subgroups and their connectivity
Rutter, G. A., Gresch, A., Delgadillo-Silva, L. F., & Benninger, R. K. P. (2024) · Nature Metabolism · doi:10.1038/s42255-024-01097-6 · Cited by 24 · see citing works
Design principles of the paradoxical feedback between pancreatic alpha and beta cells
Garzilli, I., & Itzkovitz, S. (2018) · Scientific Reports · doi:10.1038/s41598-018-29084-4 · Cited by 21 · see citing works
Targeting the Pancreatic α-Cell to Prevent Hypoglycemia in Type 1 Diabetes
Panzer, J. K., & Caicedo, A. (2021) · Diabetes · doi:10.2337/dbi20-0048 · Cited by 20 · see citing works
The Glucagon-Like Adipokinetic Hormone in Drosophila melanogaster – Biosynthesis and Secretion
Hughson, B. N. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.710652 · Cited by 21 · see citing works
Mathematical modelling of glucose dynamics
Huard, B., & Kirkham, G. (2022) · Current Opinion in Endocrine and Metabolic Research · doi:10.1016/j.coemr.2022.100379 · Cited by 20 · see citing works
Postprandial Suppression of Glucagon Secretion: A Puzzlement
Geary, N. (2017) · Diabetes · doi:10.2337/dbi16-0075 · Cited by 19 · see citing works
Gap junction coupling and islet delta-cell function in health and disease.
Miranda, C., Begum, M., Vergari, E., & Briant, L. (2021) · Peptides · doi:10.1016/j.peptides.2021.170704 · Cited by 18 · see citing works
Modelling of energy-driven switch for glucagon and insulin secretion
Grubelnik, V., Zmazek, J., Markovič, R., Gosak, M., & Marhl, M. (2020) · Journal of Theoretical Biology · doi:10.1016/j.jtbi.2020.110213 · Cited by 15 · see citing works
The Role of GJD2 (Cx36) in Refractive Error Development
van der Sande, E., Haarman, A. E. G., Quint, W. H., Tadema, K. C. D., Meester‐Smoor, M. A., Kamermans, M., Zeeuw, C. I. D., Klaver, C. C. W., Winkelman, B. H. J., & Iglesias, A. I. (2022) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.63.3.5 · Cited by 15 · see citing works
Santos-Silva, J. C., da Silva, P. M. R., de Souza, D. N., Teixeira, C. J., Bordin, S. A., & Anhê, G. F. (2020) · Life Sciences · doi:10.1016/j.lfs.2020.117810 · Cited by 14 · see citing works
Jara, C., Oyarzun-Ampuero, F. A., Carrión, F., González-Echeverría, E., Cappelli, C., & Caviedes, P. A. (2020) · Diabetology & Metabolic Syndrome · doi:10.1186/s13098-020-00573-9 · Cited by 13 · see citing works
Asadi, F., & Dhanvantari, S. (2021) · Islets · doi:10.1080/19382014.2021.2011550 · Cited by 13 · see citing works
Xu, S.-Y., Ke-Li, Zhang, Z., Liu, C., Guo, Q., Lu, B., Gu, P., & Shao, J. (2021) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2021.108684 · Cited by 11 · see citing works
Félix‐Martínez, G. J., & Godínez-Fernández, J. R. (2023) · Islets · doi:10.1080/19382014.2023.2231609 · Cited by 9 · see citing works
González‐Vélez, V., Piron, A., & Dupont, G. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.602844 · Cited by 10 · see citing works
Brüning, D., Morsi, M., Früh, E., Scherneck, S., & Rustenbeck, I. (2022) · Endocrinology · doi:10.1210/endocr/bqac125 · Cited by 8 · see citing works
Loosening the shackles of scientific disciplines with network science
Gosak, M., Markovič, R., Dolenšek, J., Rupnik, M. S., Marhl, M., Stožer, A., & Perc, M. (2018) · Physics of Life Reviews · doi:10.1016/j.plrev.2018.01.008 · Cited by 8 · see citing works
A glucose-insulin-glucagon coupled model of the isoglycemic intravenous glucose infusion experiment
Subramanian, V., Bagger, J. I., Holst, J. J., Knop, F. K., & Vilsbøll, T. (2022) · Frontiers in Physiology · doi:10.3389/fphys.2022.911616 · Cited by 9 · see citing works
Brown, A., & Tzanakakis, E. S. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1212749 · Cited by 8 · see citing works
Chen, X., Merovci, A., DeFronzo, R. A., & Tripathy, D. (2023) · Metabolism · doi:10.1016/j.metabol.2023.155512 · Cited by 7 · see citing works
Pacini, G., Åhrén, B., Göbl, C. S., & Tura, A. (2022) · Biomedicines · doi:10.3390/biomedicines10051060 · Cited by 6 · see citing works
Félix-Martínez, G. J., González-Vélez, V., Godínez-Fernández, J. R., & Gil, A. (2019) · International Journal for Numerical Methods in Biomedical Engineering · doi:10.1002/cnm.3296 · Cited by 5 · see citing works
Hossain, M. K., & Kim, H.-R. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27031280 · Cited by 5 · see citing works
Computational Reconstruction of Pancreatic Islets as a Tool for Structural and Functional Analysis
Félix‐Martínez, G. J., Mata, A. N., & Godínez-Fernández, J. R. (2022) · Journal of Visualized Experiments · doi:10.3791/63351 · Cited by 5 · see citing works
A Graph-Based Framework for Multiscale Modeling of Physiological Transport
Maheshvare, M. D., Raha, S., & Pal, D. (2022) · Frontiers in Network Physiology · doi:10.3389/fnetp.2021.802881 · Cited by 5 · see citing works
Tripartite cell networks for glucose homeostasis
Song, T., & Jo, J. (2019) · Physical Biology · doi:10.1088/1478-3975/ab2a9d · Cited by 5 · see citing works
Fogagnolo, C., Ortiz, G. U., Travieso, S. G., Venturini, A. C. R., Abud, G. F., Silva, B. M., da Silva, A. S. R., & de Freitas, E. C. (2025) · Current Nutrition Reports · doi:10.1007/s13668-025-00711-7 · Cited by 4 · see citing works
Yang, Z., Zhao, J., Liu, J., Liu, B., & Xie, M. (2019) · Journal of Traditional Chinese Medical Sciences · doi:10.1016/j.jtcms.2019.01.004 · Cited by 2 · see citing works
Ofuji, H., Wasa, Y., Hirata, K., Kimura, H., & Uchida, K. (2023) · IFAC-PapersOnLine · doi:10.1016/j.ifacol.2023.10.1525 · Cited by 2 · see citing works
The effect of HNF4α knockout in beta cells is age and sex dependent
Villaca, C. B. P., Oliveira, V. R., dos Santos, G. J., & Ortis, F. (2025) · Islets · doi:10.1080/19382014.2025.2552549 · Cited by 2 · see citing works
Abitbol, A., Riddell, M. C., Peers, S. H., Simonson, E., Evans, M. L., Knop, F. K., & Liggins, R. (2026) · Diabetologia · doi:10.1007/s00125-026-06748-9 · Cited by 2 · see citing works
Piro, S., Urbano, F., Folli, F., Finzi, G., Marselli, L., & Marchetti, P. (2016) · Endocrinology · doi:10.1007/978-3-319-27318-1_31-1
Analysis of Non-Human Primate Pancreatic Islet Oxygen Consumption
Elsakr, J. M., Deeter, C., RICCIARDI, V. F., & GANNON, M. A. (2019) · Journal of Visualized Experiments · doi:10.3791/60696 · Cited by 1 · see citing works
Piro, S., Urbano, F., Folli, F. B., Finzi, G., Marselli, L., & Marchetti, P. (2018) · Endocrinology · doi:10.1007/978-3-319-44675-2_31 · Cited by 1 · see citing works
Pancreatic α and β cells are globally phase-lockedPreprint
Ren, H., Li, Y., Han, C., Yu, Y., Shi, B., Peng, X., Wu, S., Yang, X., Sneppen, K., Chen, L., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.08.16.252304 · Cited by 1 · see citing works
Bayesian Metamodeling of pancreatic islet architecture and functional dynamicsPreprint
Lieberman, R., Mintz, R., & Raveh, B. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.11.07.467656 · Cited by 1 · see citing works
The effect of HNF4α knockout in beta cells is age and gender dependentPreprint
Villaca, C. B. P., Oliveira, V. R., dos Santos, G. J., & Ortis, F. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.12.16.628662
Sun, Y., Zhang, F., & Chen, X. (2025) · International Congress on Image and Signal Processing (CISP) · doi:10.1109/cisp-bmei68103.2025.11259381
Jara, C., Oyarzun-Ampuero, F., Carrión, F., González-Echeverría, E., Cappelli, C., & Caviedes, P. (2020) · Figshare · doi:10.6084/m9.figshare.12768649
Chang, N., Ugulini, S., & Dhanvantari, S. (2026) · The Journal of Physiology · doi:10.1113/jp291537 · Cited by 1 · see citing works
Dalton, M., Asante-Asamani, E. O., & Greene, J. M. (2026) · Mathematical Biosciences & Engineering · doi:10.3934/mbe.2026060
Computational modeling of the pancreas and pancreatic function
Félix‐Martínez, G. J. (2026) · Elsevier eBooks · doi:10.1016/b978-0-443-30263-3.00018-x
- Authors
- Watts, M., Ha, J., Kimchi, O., & Sherman, A.
- Affiliations
- National Institutes of Health (US)
- Princeton University (US)
- Corresponding author
- Sherman, Arthur
- Venue
- American Journal of Physiology-Endocrinology and Metabolism
- Publisher
- American Physiological Society
- Published
- 2016-04-15
- Volume
- 310
- Issue
- 8
- Pages
- E597-E611
- ISSN
- 0193-1849 (ISSN-L)
- 1522-1555
- PMC
- PMC4835945
- OpenAlex
- W2300512885
- Cited by
- 53
- References
- 84
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 2 · 2023: 5 · 2022: 9 · 2021: 9 · 2020: 7 · 2019: 5 · 2018: 3 · 2017: 4 · 2016: 1
- FWCI
- 4.80
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- American Journal of Physiology-Endocrinology and Metabolism (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Keywords
- glucagon secretion, alpha cells, paracrine regulation, delta cells, pancreatic beta cells, ATP-sensitive potassium channels, insulin, somatostatin, pulsatile secretion, mathematical model
- MeSH terms
- Calcium, Glucagon, Glucose, Humans, Insulin, Models, Theoretical, Somatostatin, Somatostatin-Secreting Cells, Paracrine Communication, Glucagon-Secreting Cells, Insulin-Secreting Cells
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