Modelling of energy-driven switch for glucagon and insulin secretion
Abstract
We present a mathematical model of the energy-driven metabolic switch for glucagon and insulin secretion from pancreatic alpha and beta cells, respectively. The energy status related to hormone secretion is studied for various glucose concentrations. Additionally, the physiological response is studied with regards to the presence of other metabolites, particularly the free-fatty acids. At low glucose, the ATP production in alpha cells is high due to free-fatty acids oxidation in mitochondria, which enables glucagon secretion. When the glucose concentration is elevated above the threshold value, the glucagon secretion is switched off due to the contribution of glycolytic ATP production, representing an "anaerobic switch". On the other hand, during hypoglycemia, the ATP production in beta cells is low, reflecting a "waiting state" for glucose as the main metabolite. When glucose is elevated above the threshold value, the oxidative fate of glucose in mitochondria is the main source of energy required for effective insulin secretion, i.e. the "aerobic switch". Our results show the importance of well-regulated and fine-tuned energetic processes in pancreatic alpha and beta cells required for efficient hormone secretion and hence effective blood glucose regulation. These energetic processes have to be appropriately switched on and off based on the sensing of different metabolites by alpha and beta cells. Our computational results indicate that disturbances in cell energetics (e.g. mitochondrial dysfunction), and dysfunctional metabolite sensing and distribution throughout the cell might be related to pathologies such as metabolic syndrome and diabetes.
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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 [13]
Cites
Weyer, C., Bogardus, C., Mott, D. M., & Pratley, R. E. (1999) · Journal of Clinical Investigation · doi:10.1172/jci7231 · Cited by 1,940 · see citing works
Free fatty acids regulate insulin secretion from pancreatic β cells through GPR40
Itoh, Y., Kawamata, Y., Harada, M., Kobayashi, M., Fujii, R., Fukusumi, S., Ogi, K., Hosoya, M., Tanaka, Y., Uejima, H., et al. (2003) · Nature · doi:10.1038/nature01478 · Cited by 1,538 · see citing works
Pancreatic β Cell Dedifferentiation as a Mechanism of Diabetic β Cell Failure
Talchai, C., Xuan, S., Lin, H. V., Sussel, L., & Accili, D. (2012) · Cell · doi:10.1016/j.cell.2012.07.029 · Cited by 1,415 · see citing works
Targeting mitochondria metabolism for cancer therapy
Weinberg, S. E., & Chandel, N. S. (2014) · Nature Chemical Biology · doi:10.1038/nchembio.1712 · Cited by 1,385 · see citing works
Triggering and amplifying pathways of regulation of insulin secretion by glucose.
Henquin, J. C. (2000) · Diabetes · doi:10.2337/diabetes.49.11.1751 · Cited by 1,201 · see citing works
A hierarchy of ATP-consuming processes in mammalian cells
Buttgereit, F., & Brand, M. D. (1995) · Biochemical Journal · doi:10.1042/bj3120163 · Cited by 929 · see citing works
Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men
Rorsman, P., & Ashcroft, F. M. (2018) · Physiological Reviews · doi:10.1152/physrev.00008.2017 · Cited by 793 · see citing works
Pancreatic β‐cell mass in European subjects with type 2 diabetes
Rahier, J., Guiot, Y., Goebbels, R. M., Sempoux, C., & Henquin, J. C. (2008) · Diabetes, Obesity and Metabolism · doi:10.1111/j.1463-1326.2008.00969.x · Cited by 756 · see citing works
The randle cycle revisited: a new head for an old hat.
Hue, L., & Taegtmeyer, H. (2009) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00093.2009 · Cited by 743 · see citing works
Glucagonocentric restructuring of diabetes: A pathophysiologic and therapeutic makeover
Unger, R. H., & Cherrington, A. D. (2012) · Journal of Clinical Investigation · doi:10.1172/jci60016 · Cited by 670 · 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
Evolution of Mitochondria as Signaling Organelles
Chandel, N. S. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.05.013 · Cited by 555 · see citing works
Mitochondrial function in normal and diabetic β-cells
Maechler, P., & Wollheim, C. B. (2001) · Nature · doi:10.1038/414807a · Cited by 519 · see citing works
Eto, K., Tsubamoto, Y., Terauchi, Y., 杉山, 拓., Kishimoto, T. E., Takahashi, N. K., Yamauchi, N., Kubota, N., Murayama, S., Aizawa, T., et al. (1999) · Science · doi:10.1126/science.283.5404.981 · Cited by 491 · see citing works
Sekine, N., Cirulli, V., Regazzi, R., Brown, L. J., Giné, E., Tamarit‐Rodriguez, J., Girotti, M., Marie, S., MacDonald, M. J., & Wollheim, C. B. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)37629-9 · Cited by 446 · see citing works
Metabolic Fate of Glucose in Purified Islet Cells
Schuit, F., De Vos, A., Farfari, S., Moens, K., Pipeleers, D., Brun, T., & Prentki, M. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.30.18572 · Cited by 421 · see citing works
Coenzyme Q10 Supplementation in Aging and Disease
Hernández‐Camacho, J. D., Bernier, M., López‐Lluch, G., & Navas, P. (2018) · Frontiers in Physiology · doi:10.3389/fphys.2018.00044 · Cited by 369 · see citing works
Increased uncoupling protein-2 and -3 mRNA expression during fasting in obese and lean humans.
Millet, L., Vidal, H., Andréelli, F., Larrouy, D., Riou, J. P., Ricquier, D., Laville, M., & Langin, D. (1997) · Journal of Clinical Investigation · doi:10.1172/jci119811 · Cited by 351 · see citing works
Diabetes causes marked inhibition of mitochondrial metabolism in pancreatic β-cells
Haythorne, E., Rohm, M., van de Bunt, M., Brereton, M. F., Tarasov, A. I., Blacker, T. S., Sachse, G., dos Santos, M. S., Terrón-Expósito, R., Davis, S. A., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-10189-x · Cited by 318 · see citing works
Islet β cell mass in diabetes and how it relates to function, birth, and death
Weir, G. C., & Bonner‐Weir, S. (2013) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.12031 · Cited by 296 · see citing works
Feasibility of a Mitochondrial Pyruvate Malate Shuttle in Pancreatic Islets
MacDonald, M. J. (1995) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)94588-6 · Cited by 274 · see citing works
Mitochondrial energy metabolism and ageing
Bratic, I., & Trifunović, A. (2010) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2010.01.004 · Cited by 268 · 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
Göpel, S. O., Kanno, T., Barg, S., Weng, X. ‐., Gromada, J., & Rorsman, P. (2000) · The Journal of Physiology · doi:10.1111/j.1469-7793.2000.00509.x · Cited by 229 · see citing works
Voltage‐gated and resting membrane currents recorded from B‐cells in intact mouse pancreatic islets
Göpel, S., Kanno, T., Barg, S., Galvanovskis, J., & Rorsman, P. (1999) · The Journal of Physiology · doi:10.1111/j.1469-7793.1999.00717.x · Cited by 226 · 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
Munger, B. L. (1958) · American Journal of Anatomy · doi:10.1002/aja.1001030207 · Cited by 222 · 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
Tight coupling between electrical activity and exocytosis in mouse glucagon-secreting alpha-cells.
Barg, S., Galvanovskis, J., Göpel, S. O., Rorsman, P., & Eliasson, L. (2000) · Diabetes · doi:10.2337/diabetes.49.9.1500 · Cited by 209 · see citing works
German, M. S. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.5.1781 · Cited by 208 · 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
Pancreatic alpha cell mass in European subjects with type 2 diabetes
Henquin, J., & Rahier, J. (2011) · Diabetologia · doi:10.1007/s00125-011-2118-4 · Cited by 195 · see citing works
Minimal model of beta-cell mitochondrial Ca2+ handling
Magnus, G., & Keizer, J. (1997) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.1997.273.2.c717 · Cited by 194 · see citing works
Heimberg, H., De Vos, A., Pipeleers, D., Thorens, B., & Schuit, F. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.15.8971 · Cited by 188 · see citing works
Tissue-specific disallowance of housekeeping genes: The other face of cell differentiationPreprint
Thorrez, L., Laudadio, I., Deun, K. V., Quintens, R., Hendrickx, N., Granvik, M., Lemaire, K., Schraenen, A., Lommel, L. V., Lehnert, S., et al. (2010) · Genome Research · doi:10.1101/gr.109173.110 · Cited by 182 · 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
A simplified model for mitochondrial ATP production
Bertram, R., Pedersen, M. G., Luciani, D. S., & Sherman, A. (2006) · Journal of Theoretical Biology · doi:10.1016/j.jtbi.2006.07.019 · Cited by 168 · see citing works
Model of β-cell mitochondrial calcium handling and electrical activity. II. Mitochondrial variables
Magnus, G., & Keizer, J. (1998) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.1998.274.4.c1174 · Cited by 167 · 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
Detimary, P., Dejonghe, S., Ling, Z., Pipeleers, D., Schuit, F., & Henquin, J.-C. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.51.33905 · Cited by 159 · see citing works
Plasticity and Dedifferentiation within the Pancreas: Development, Homeostasis, and Disease
Puri, S., Folias, A. E., & Hebrok, M. (2014) · Cell Stem Cell · doi:10.1016/j.stem.2014.11.001 · Cited by 158 · see citing works
Olsen, H. L., Theander, S., Bokvist, K., Buschard, K., Wollheim, C. B., & Gromada, J. (2005) · Endocrinology · doi:10.1210/en.2005-0800 · Cited by 156 · see citing works
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
Elusive Proximal Signals of β-Cells for Insulin Secretion
MacDonald, M. J. (1990) · Diabetes · doi:10.2337/diab.39.12.1461 · Cited by 152 · see citing works
Effects of depletion of mitochondrial DNA in metabolism secretion coupling in INS-1 cells.
Kennedy, E. D., Maechler, P., & Wollheim, C. B. (1998) · Diabetes · doi:10.2337/diabetes.47.3.374 · Cited by 151 · see citing works
Q&A: insulin secretion and type 2 diabetes: why do β-cells fail?
Cantley, J., & Ashcroft, F. M. (2015) · BMC Biology · doi:10.1186/s12915-015-0140-6 · Cited by 150 · see citing works
Bouillaud, F. (2009) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2009.01.003 · Cited by 146 · see citing works
Model of β-cell mitochondrial calcium handling and electrical activity. I. Cytoplasmic variables
Magnus, G., & Keizer, J. (1998) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.1998.274.4.c1158 · Cited by 143 · see citing works
The glucose sensor protein glucokinase is expressed in glucagon-producing alpha-cells.
Heimberg, H., De Vos, A., Moens, K., Quartier, E., Bouwens, L., Pipeleers, D., Van Schaftingen, E., Madsen, O., & Schuit, F. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.14.7036 · Cited by 142 · see citing works
Intra- and inter-islet synchronization of metabolically driven insulin secretion.
Pedersen, M. G., Bertram, R., & Sherman, A. (2005) · Biophysical Journal · doi:10.1529/biophysj.104.055681 · Cited by 140 · see citing works
Dependence on NADH produced during glycolysis for beta-cell glucose signaling
Dukes, I. D., McIntyre, M. S., Mertz, R. J., Philipson, L. H., Roe, M. W., Spencer, B., & Worley, J. F. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)78078-8 · Cited by 137 · see citing works
Ramracheya, R., Ward, C., Shigeto, M., Walker, J. N., Amisten, S., Zhang, Q., Johnson, P. R., Rorsman, P., & Braun, M. (2010) · Diabetes · doi:10.2337/db09-1505 · Cited by 136 · 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
Uncoupling protein 3 content is decreased in skeletal muscle of patients with type 2 diabetes
Schrauwen, P., Hesselink, M. K. C., Blaak, E. E., Borghouts, L. B., Schaart, G., Saris, W. H. M., & Keizer, H. A. (2001) · Diabetes · doi:10.2337/diabetes.50.12.2870 · Cited by 112 · see citing works
Glucagon secretion from pancreatic α-cells
Briant, L., Salehi, A., Vergari, E., Zhang, Q., & Rorsman, P. (2016) · Upsala Journal of Medical Sciences · doi:10.3109/03009734.2016.1156789 · Cited by 109 · see citing works
A calcium-based phantom bursting model for pancreatic islets
Bertram, R. (2004) · Bulletin of Mathematical Biology · doi:10.1016/j.bulm.2003.12.005 · Cited by 108 · see citing works
Gloyn, A. L., Odili, S., Zelent, D., Buettger, C., Castleden, H. A. J., Steele, A. M., Stride, A., Shiota, C., Magnuson, M. A., Lorini, R., et al. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m413146200 · Cited by 108 · see citing works
KATP-channels and glucose-regulated glucagon secretion
Rorsman, P., Salehi, A. A., Abdulkader, F., Braun, M., & MacDonald, P. E. (2008) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2008.07.003 · Cited by 101 · see citing works
Metabolic Oscillations in β-Cells
Kennedy, R., Kauri, L., Dahlgren, G. M., & Jung, S.-K. (2002) · Diabetes · doi:10.2337/diabetes.51.2007.s152 · Cited by 100 · see citing works
Glucose regulation of glucagon secretion
Gylfe, E., & Gilon, P. (2013) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2013.11.019 · Cited by 98 · see citing works
Briant, L. J. B., Dodd, M. S., Chibalina, M. V., Rorsman, N. J. G., Johnson, P., Carmeliet, P., Rorsman, P., & Knudsen, J. G. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.05.035 · Cited by 97 · see citing works
Doliba, N. M., Qin, W., Najafi, H., Liu, C., Buettger, C. W., Sotiris, J., Collins, H. W., Li, C., Stanley, C. A., Wilson, D. F., et al. (2012) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00218.2011 · Cited by 96 · see citing works
Differences in glucose handling by pancreatic A- and B-cells.
Gorus, F., Malaisse, W. J., & PIPELEERS, D. G. (1984) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)43587-3 · Cited by 95 · see citing works
Olofsson, C., Salehi, A., Göpel, S., Holm, C., & Rorsman, P. (2004) · Diabetes · doi:10.2337/diabetes.53.11.2836 · Cited by 95 · see citing works
The Pancreatic β-Cell: A Bioenergetic Perspective
Nicholls, D. G. (2016) · Physiological Reviews · doi:10.1152/physrev.00009.2016 · Cited by 95 · see citing works
Rorsman, P., Ramracheya, R. D., Rorsman, N. J. G., & Zhang, Q. (2014) · Diabetologia · doi:10.1007/s00125-014-3279-8 · Cited by 89 · 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
Glucose controls glucagon secretion by directly modulating cAMP in alpha cells
Yu, Q., Shuai, H., Ahooghalandari, P., Gylfe, E., & Tengholm, A. (2019) · Diabetologia · doi:10.1007/s00125-019-4857-6 · Cited by 84 · see citing works
Edwards, J. C., & Taylor, K. W. (1970) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/0304-4165(70)90029-2 · Cited by 80 · see citing works
Cell coupling in mouse pancreatic β-cells measured in intact islets of Langerhans
Zhang, Q., Galvanovskis, J., Abdulkader, F., Partridge, C. J., Göpel, S. O., Eliasson, L., & Rorsman, P. (2008) · Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences · doi:10.1098/rsta.2008.0110 · Cited by 80 · see citing works
Knudsen, J. G., Hamilton, A., Ramracheya, R. D., Tarasov, A. I., Brereton, M. F., Haythorne, E., Chibalina, M. V., Spégel, P., Mulder, H., Zhang, Q., et al. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.10.003 · Cited by 74 · see citing works
MacDonald, M. J., & Marshall, L. K. (2000) · Archives of Biochemistry and Biophysics · doi:10.1006/abbi.2000.2107 · Cited by 73 · see citing works
UCP2 is highly expressed in pancreatic α-cells and influences secretion and survival
Diao, J., Allister, E. M., Koshkin, V., Lee, S. C., Bhattacharjee, A., Tang, C., Giacca, A., Chan, C. B., & Wheeler, M. B. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0710434105 · Cited by 72 · see citing works
Glucose control of glucagon secretion—‘There’s a brand-new gimmick every year’
Gylfe, E. (2016) · Upsala Journal of Medical Sciences · doi:10.3109/03009734.2016.1154905 · Cited by 71 · see citing works
Mathematical modeling of the glucose-insulin system: a review.
Palumbo, P., Ditlevsen, S., Bertuzzi, A., & Gaetano, A. D. (2013) · Mathematical Biosciences · doi:10.1016/j.mbs.2013.05.006 · Cited by 70 · 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
MacDonald, M. J., Tang, J., & Polonsky, K. S. (1996) · Diabetes · doi:10.2337/diab.45.11.1626 · Cited by 63 · see citing works
Quesada, I., Todorova, M. G., & Soria, B. (2006) · Biophysical Journal · doi:10.1529/biophysj.105.069906 · Cited by 63 · see citing works
Liang, Y. T., Bai, G., Doliba, N. M., Buettger, C. W., Wang, L., Berner, D. K., & Matschinsky, F. M. (1996) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1996.270.5.e846 · Cited by 61 · 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
Göke, B. (2008) · International Journal of Clinical Practice · doi:10.1111/j.1742-1241.2007.01686.x · Cited by 58 · see citing works
Kristinsson, H., Sargsyan, E., Manell, H., Smith, D. M., Göpel, S., & Bergsten, P. (2017) · Scientific Reports · doi:10.1038/s41598-017-04730-5 · Cited by 56 · see citing works
Paracrine regulation of glucagon secretion: the β/α/δ model
Watts, M., Ha, J., Kimchi, O., & Sherman, A. (2016) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00415.2015 · Cited by 53 · see citing works
Insulin granule trafficking in β-cells: mathematical model of glucose-induced insulin secretion
BERTUZZI, A., Salinari, S., & Mingrone, G. (2007) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00647.2006 · Cited by 50 · see citing works
(Re)generating Human Beta Cells: Status, Pitfalls, and Perspectives
Baeyens, L., Lemper, M., Staels, W., Groef, S. D., Leu, N. D., Heremans, Y., German, M. S., & Heimberg, H. (2018) · Physiological Reviews · doi:10.1152/physrev.00034.2016 · Cited by 50 · see citing works
Viollet, B., & Foretz, M. (2016) · Proceedings of the Fourth International Symposium on Polarization Phenomena in Nuclear Reactions · doi:10.1007/978-3-319-43589-3 · Cited by 47 · see citing works
Pedersen, M. G. (2009) · Journal of Diabetes Science and Technology · doi:10.1177/193229680900300103 · 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
Mikami, S., & Mutoh, K. (1971) · Cell and Tissue Research · doi:10.1007/bf00331262 · Cited by 43 · see citing works
Lai, B. K., Chae, H., Gómez-Ruiz, A., Cheng, P., Gallo, P., Antoine, N., Beauloye, C., Jonas, J., Seghers, V. J., Seino, S., et al. (2018) · Diabetes · doi:10.2337/db17-0880 · Cited by 40 · see citing works
Fatty acid‐induced effect on glucagon secretion is mediated via fatty acid oxidation
Hong, J., Jeppesen, P. B., Nordentoft, I., & Hermansen, K. (2006) · Diabetes/Metabolism Research and Reviews · doi:10.1002/dmrr.663 · 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
Pedersen, M. G., Cortese, G., & Eliasson, L. (2011) · Progress in Biophysics and Molecular Biology · doi:10.1016/j.pbiomolbio.2011.07.012 · Cited by 31 · see citing works
Diderichsen, P. M., & Göpel, S. (2006) · Journal of Biological Physics · doi:10.1007/s10867-006-9013-0 · Cited by 30 · see citing works
Myocardial fatty acid utilization as a determinant of cardiac efficiency and function
Jaswal, J. S., & Ussher, J. R. (2009) · Clinical Lipidology · doi:10.2217/clp.09.18 · Cited by 29 · see citing works
Control of pancreatic β-cell bioenergetics
Affourtit, C., Alberts, B. M., Barlow, J. P., Carré, J. E., & Wynne, A. G. (2018) · Biochemical Society Transactions · doi:10.1042/bst20170505 · Cited by 27 · see citing works
Glucose Control of Glucagon Secretion: There Is More to It Than KATP Channels
Gylfe, E. (2013) · Diabetes · doi:10.2337/db13-0193 · Cited by 23 · see citing works
The thermodynamic basis of glucose-stimulated insulin release: a model of the core mechanism
Wilson, D. F., Cember, A., & Matschinsky, F. M. (2017) · Physiological Reports · doi:10.14814/phy2.13327 · Cited by 20 · see citing works
Endocytosis of KATP Channels Drives Glucose-Stimulated Excitation of Pancreatic β Cells.
Han, Y.-E., Chun, J., Kwon, M., Ji, Y.-S., Jeong, M., Kim, H.-H., Park, S.-H., Rah, J., Kang, J.-S., Lee, S.-H., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2017.12.049 · Cited by 20 · see citing works
Electron Microscopic Observations on the Islet Alpha Cells of the Domestic Fowl Pancreas
MACHINO, M., Tohru, O. N. O. E., & SAKUMA, H. (1966) · Journal of Electron Microscopy · doi:10.1093/oxfordjournals.jmicro.a049531 · Cited by 16 · see citing works
Recent advances in mathematical modeling and statistical analysis of exocytosis in endocrine cells
Pedersen, M. G., Tagliavini, A., Cortese, G., Riz, M., & Montefusco, F. (2016) · Mathematical Biosciences · doi:10.1016/j.mbs.2016.11.010 · Cited by 13 · see citing works
Pyruvate dehydrogenase, Randle cycle, and skeletal muscle insulin resistance
Guo, Z. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1505398112 · Cited by 10 · see citing works
Buchwald, P., & Cechin, S. R. (2013) · Journal of Biomedical Science and Engineering · doi:10.4236/jbise.2013.65a006 · Cited by 10 · see citing works
Effects of metabolic inhibitors on the regulation of pancreatic glucagon release
Östenson, C., Ågren, A., & Andersson, A. (1980) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/0304-4165(80)90362-1 · Cited by 9 · see citing works
Luchini, L., Wicki, G., & Romano, L. A. (2015) · Journal of Histology · doi:10.1155/2015/686571 · Cited by 8 · see citing works
PROBE: patient and physician behaviour and education in prostate disease
Hindley, R. G. (2007) · International Journal of Clinical Practice · doi:10.1111/j.1742-1241.2007.01648.x · Cited by 2 · see citing works
Flagged first, then by citations
2 of the 110 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Lipotoxic Impairment of Mitochondrial Function in β-Cells: A Review
Römer, A., Linn, T., & Petry, S. F. (2021) · Antioxidants · doi:10.3390/antiox10020293 · Cited by 48 · 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
Grubelnik, V., Zmazek, J., Markovič, R., Gosak, M., & Marhl, M. (2020) · Life · doi:10.3390/life10120348 · Cited by 28 · see citing works
Mechanisms of the Regulation and Dysregulation of Glucagon Secretion
Onyango, A. N. (2020) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2020/3089139 · Cited by 23 · see citing works
El‐Shafai, N. M., Ramadan, M. S., & El‐Mehasseb, I. M. (2022) · International Journal of Energy Research · doi:10.1002/er.8107 · Cited by 20 · see citing works
Corduas, F., Mancuso, E., & Lamprou, D. A. (2020) · Journal of Drug Delivery Science and Technology · doi:10.1016/j.jddst.2020.101952 · Cited by 15 · see citing works
Chaowei, Z. H. O. U., Zhou, Y., Xu, L., Fei, L. I. U., Luo, L., He, G. A. O., Li, J., Fu, S., Duan, Y., Yougang, T. A. N., et al. (2024) · Integrative Zoology · doi:10.1111/1749-4877.12910 · Cited by 13 · see citing works
The role of anaplerotic metabolism of glucose and glutamine in insulin secretion: A model approach
Grubelnik, V., Zmazek, J., Gosak, M., & Marhl, M. (2024) · Biophysical Chemistry · doi:10.1016/j.bpc.2024.107270 · Cited by 10 · see citing works
Adaptive controller based an extended model of glucose-insulin-glucagon system for type 1 diabetes
Saoussane, M., Mohammed, T., & Mesaoud, C. (2022) · International Journal of Modelling and Simulation · doi:10.1080/02286203.2022.2068214 · Cited by 10 · see citing works
Lipotoxicity in a Vicious Cycle of Pancreatic Beta Cell Exhaustion
Grubelnik, V., Zmazek, J., Završnik, M., & Marhl, M. (2022) · Biomedicines · doi:10.3390/biomedicines10071627 · Cited by 10 · see citing works
Role of cAMP in Double Switch of Glucagon Secretion
Zmazek, J., Grubelnik, V., Markovič, R., & Marhl, M. (2021) · Cells · doi:10.3390/cells10040896 · Cited by 5 · see citing works
What do stimulated beta cells have in common with cancer cells?
Marhl, M. (2024) · Biosystems · doi:10.1016/j.biosystems.2024.105257 · Cited by 4 · see citing works
Modeling the Amino Acid Effect on Glucagon Secretion from Pancreatic Alpha Cells
Zmazek, J., Grubelnik, V., Markovič, R., & Marhl, M. (2022) · Metabolites · doi:10.3390/metabo12040348 · Cited by 4 · see citing works
An integrated glucose-insulin simulation model for normal meal interaction in Type 2 diabetes
Ezzat, K. A., & Mahdy, L. N. (2025) · Soft Computing · doi:10.1007/s00500-025-10927-y
Effect of Ketogenic Diet (after Modification) on the Health of Patients with DMT2 in Mosul City
Daood, I. I., Bakr, O. Z., & Ahmad, H. M. (2026) · Medical Journal of Babylon · doi:10.4103/mjbl.mjbl_1008_23
- Authors
- Grubelnik, V., Zmazek, J., Markovič, R., Gosak, M., & Marhl, M.
- Affiliations
- University of Maribor (SI)
- Corresponding author
- Marhl, Marko
- Venue
- Journal of Theoretical Biology
- Publisher
- Elsevier BV
- Published
- 2020-05
- Volume
- 493
- Pages
- 110213
- ISSN
- 0022-5193 (ISSN-L)
- OpenAlex
- W3007379472
- Cited by
- 15
- References
- 110
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 3 · 2022: 4 · 2021: 3 · 2020: 3
- FWCI
- 2.28
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Theoretical Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Javna Agencija za Raziskovalno Dejavnost RS (P1-0055, P3-0396)
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- glucagon secretion, insulin secretion, alpha cells, pancreatic beta cells, ATP production, free fatty acid oxidation, glycolysis, glucose threshold, hypoglycemia, mitochondrial dysfunction, blood glucose regulation, metabolic syndrome, diabetes mellitus
- MeSH terms
- Insulin Secretion, Glucagon, Glucose, Humans, Hypoglycemia, Insulin
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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