{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T06:19:01Z","timestamp":1772173141008,"version":"3.50.1"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1010555","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,10,27]],"date-time":"2022-10-27T00:00:00Z","timestamp":1666828800000}}],"reference-count":119,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2022,10,17]],"date-time":"2022-10-17T00:00:00Z","timestamp":1665964800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006034","name":"University of Southern California","doi-asserted-by":"publisher","award":["USC Pancreatic Beta Cell Consortium"],"award-info":[{"award-number":["USC Pancreatic Beta Cell Consortium"]}],"id":[{"id":"10.13039\/100006034","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["1U01CA232137"],"award-info":[{"award-number":["1U01CA232137"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>\n                    Pancreatic \u03b2-cells respond to increased extracellular glucose levels by initiating a metabolic shift. That change in metabolism is part of the process of glucose-stimulated insulin secretion and is of particular interest in the context of diabetes. However, we do not fully understand how the coordinated changes in metabolic pathways and metabolite products influence insulin secretion. In this work, we apply systems biology approaches to develop a detailed kinetic model of the intracellular central carbon metabolic pathways in pancreatic \u03b2-cells upon stimulation with high levels of glucose. The model is calibrated to published metabolomics datasets for the INS1 823\/13 cell line, accurately capturing the measured metabolite fold-changes. We first employed the calibrated mechanistic model to estimate the stimulated cell\u2019s fluxome. We then used the predicted network fluxes in a data-driven approach to build a partial least squares regression model. By developing the combined kinetic and data-driven modeling framework, we gain insights into the link between \u03b2-cell metabolism and glucose-stimulated insulin secretion. The combined modeling framework was used to predict the effects of common anti-diabetic pharmacological interventions on metabolite levels, flux through the metabolic network, and insulin secretion. Our simulations reveal targets that can be modulated to enhance insulin secretion. The model is a promising tool to contextualize and extend the usefulness of metabolomics data and to predict dynamics and metabolite levels that are difficult to measure\n                    <jats:italic>in vitro<\/jats:italic>\n                    . In addition, the modeling framework can be applied to identify, explain, and assess novel and clinically-relevant interventions that may be particularly valuable in diabetes treatment.\n                  <\/jats:p>","DOI":"10.1371\/journal.pcbi.1010555","type":"journal-article","created":{"date-parts":[[2022,10,17]],"date-time":"2022-10-17T13:38:01Z","timestamp":1666013881000},"page":"e1010555","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":12,"title":["Kinetic and data-driven modeling of pancreatic \u03b2-cell central carbon metabolism and insulin secretion"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9721-5224","authenticated-orcid":true,"given":"Patrick E.","family":"Gelbach","sequence":"first","affiliation":[]},{"given":"Dongqing","family":"Zheng","sequence":"additional","affiliation":[]},{"given":"Scott E.","family":"Fraser","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8894-9621","authenticated-orcid":true,"given":"Kate L.","family":"White","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6811-1941","authenticated-orcid":true,"given":"Nicholas A.","family":"Graham","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6901-3692","authenticated-orcid":true,"given":"Stacey D.","family":"Finley","sequence":"additional","affiliation":[]}],"member":"340","published-online":{"date-parts":[[2022,10,17]]},"reference":[{"issue":"1464","key":"pcbi.1010555.ref001","doi-asserted-by":"crossref","first-page":"2211","DOI":"10.1098\/rstb.2005.1762","article-title":"Glucose-sensing mechanisms in pancreatic \u03b2-cells","volume":"360","author":"PE MacDonald","year":"2005","journal-title":"Philos Trans R Soc B Biol Sci."},{"issue":"1","key":"pcbi.1010555.ref002","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2337\/diabetes.50.1.1","article-title":"Glucose Sensing in Pancreatic \u03b2-Cells: A Model for the Study of Other Glucose-Regulated Cells in Gut, Pancreas, and Hypothalamus","volume":"50","author":"FC Schuit","year":"2001","journal-title":"Diabetes"},{"issue":"34","key":"pcbi.1010555.ref003","doi-asserted-by":"crossref","first-page":"20559","DOI":"10.1074\/jbc.271.34.20559","article-title":"Concentration Dependence and Time Course of the Effects of Glucose on Adenine and Guanine Nucleotides in Mouse Pancreatic Islets","volume":"271","author":"P Detimary","year":"1996","journal-title":"J Biol Chem"},{"issue":"10","key":"pcbi.1010555.ref004","doi-asserted-by":"crossref","first-page":"1990","DOI":"10.1007\/s00125-020-05205-5","article-title":"Metabolic and functional specialisations of the pancreatic beta cell: gene disallowance, mitochondrial metabolism and intercellular connectivity","volume":"63","author":"GA Rutter","year":"2020","journal-title":"Diabetologia"},{"issue":"1","key":"pcbi.1010555.ref005","doi-asserted-by":"crossref","first-page":"E1","DOI":"10.1152\/ajpendo.1984.246.1.E1","article-title":"New perspectives on pancreatic islet glucokinase","volume":"246","author":"MD Meglasson","year":"1984","journal-title":"Am J Physiol-Endocrinol Metab."},{"issue":"5","key":"pcbi.1010555.ref006","doi-asserted-by":"crossref","first-page":"1429","DOI":"10.1016\/j.jmb.2019.07.020","article-title":"Metabolomics Analysis of Nutrient Metabolism in \u03b2-Cells","volume":"432","author":"P Sp\u00e9gel","year":"2020","journal-title":"J Mol Biol"},{"issue":"3","key":"pcbi.1010555.ref007","doi-asserted-by":"crossref","first-page":"183","DOI":"10.2337\/diaspect.17.3.183","article-title":"Glucose Metabolism and Regulation: Beyond Insulin and Glucagon","volume":"17","author":"SL Aronoff","year":"2004","journal-title":"Diabetes Spectr"},{"issue":"4","key":"pcbi.1010555.ref008","doi-asserted-by":"crossref","first-page":"1385","DOI":"10.1152\/physrev.00009.2016","article-title":"The Pancreatic \u03b2-Cell: A Bioenergetic Perspective","volume":"96","author":"DG Nicholls","year":"2016","journal-title":"Physiol Rev"},{"issue":"12","key":"pcbi.1010555.ref009","doi-asserted-by":"crossref","first-page":"2510","DOI":"10.1007\/s00125-016-4111-4","article-title":"Metabolic coupling in pancreatic beta cells: lipolysis revisited","volume":"59","author":"H. Mulder","year":"2016","journal-title":"Diabetologia"},{"issue":"Suppl 1","key":"pcbi.1010555.ref010","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1111\/dom.12729","article-title":"Mechanisms of \u03b2-cell functional adaptation to changes in workload","volume":"18","author":"M Wortham","year":"2016","journal-title":"Diabetes Obes Metab"},{"issue":"1","key":"pcbi.1010555.ref011","doi-asserted-by":"crossref","first-page":"2474","DOI":"10.1038\/s41467-019-10189-x","article-title":"Diabetes causes marked inhibition of mitochondrial metabolism in pancreatic \u03b2-cells","volume":"10","author":"E Haythorne","year":"2019","journal-title":"Nat Commun"},{"key":"pcbi.1010555.ref012","doi-asserted-by":"crossref","first-page":"S169","DOI":"10.2337\/diabetes.50.2007.S169","article-title":"Decreased insulin secretion in type 2 diabetes: a problem of cellular mass or function?","volume":"501","author":"A Clark","year":"2001","journal-title":"Diabetes"},{"issue":"5","key":"pcbi.1010555.ref013","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1016\/S2213-8587(20)30119-4","article-title":"\u03b2-cell secretory dysfunction: a key cause of type 2 diabetes","volume":"8","author":"RR Holman","year":"2020","journal-title":"Lancet Diabetes Endocrinol"},{"issue":"8","key":"pcbi.1010555.ref014","doi-asserted-by":"crossref","first-page":"E303","DOI":"10.3390\/metabo10080303","article-title":"Metabolic Modelling as a Framework for Metabolomics Data Integration and Analysis","volume":"10","author":"S Volkova","year":"2020","journal-title":"Metabolites."},{"issue":"4","key":"pcbi.1010555.ref015","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1006\/jtbi.2000.2150","article-title":"A Model of \u03b2 -Cell Mass, Insulin, and Glucose Kinetics: Pathways to Diabetes","volume":"206","author":"B Topp","year":"2000","journal-title":"J Theor Biol"},{"issue":"4","key":"pcbi.1010555.ref016","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1016\/j.jtbi.2006.07.019","article-title":"A simplified model for mitochondrial ATP production","volume":"243","author":"R Bertram","year":"2006","journal-title":"J Theor Biol"},{"issue":"2","key":"pcbi.1010555.ref017","doi-asserted-by":"crossref","first-page":"C717","DOI":"10.1152\/ajpcell.1997.273.2.C717","article-title":"Minimal model of beta-cell mitochondrial Ca2+ handling","volume":"273","author":"G Magnus","year":"1997","journal-title":"Am J Physiol"},{"issue":"4","key":"pcbi.1010555.ref018","doi-asserted-by":"crossref","first-page":"C1158","DOI":"10.1152\/ajpcell.1998.274.4.C1158","article-title":"Model of beta-cell mitochondrial calcium handling and electrical activity. I. Cytoplasmic variables","volume":"274","author":"G Magnus","year":"1998","journal-title":"Am J Physiol"},{"issue":"11","key":"pcbi.1010555.ref019","doi-asserted-by":"crossref","first-page":"1795","DOI":"10.1093\/bioinformatics\/bth125","article-title":"A general computational model of mitochondrial metabolism in a whole organelle scale","volume":"20","author":"K Yugi","year":"2004","journal-title":"Bioinforma Oxf Engl"},{"key":"pcbi.1010555.ref020","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/1742-4682-7-15","article-title":"Glucose sensing in the pancreatic beta cell: a computational systems analysis","volume":"7","author":"LE Fridlyand","year":"2010","journal-title":"Theor Biol Med Model"},{"issue":"6","key":"pcbi.1010555.ref021","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1007\/s00335-007-9011-y","article-title":"A kinetic core model of the glucose-stimulated insulin secretion network of pancreatic \u03b2 cells","volume":"18","author":"N Jiang","year":"2007","journal-title":"Mamm Genome"},{"key":"pcbi.1010555.ref022","article-title":"Computational Model Predicts the Effects of Targeting Cellular Metabolism in Pancreatic Cancer","author":"M Roy","year":"2017","journal-title":"Front Physiol [Internet]."},{"issue":"1","key":"pcbi.1010555.ref023","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.bpj.2014.11.1857","article-title":"From Metabolomics to Fluxomics: A Computational Procedure to Translate Metabolite Profiles into Metabolic Fluxes","volume":"108","author":"S Cortassa","year":"2015","journal-title":"Biophys J"},{"key":"pcbi.1010555.ref024","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.pisc.2014.12.002","article-title":"One hundred years of Michaelis\u2013Menten kinetics","volume":"4","author":"A. 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Efrat","year":"1994","journal-title":"Trends Biochem Sci"},{"key":"pcbi.1010555.ref029","article-title":"The Central Role of Glucokinase in Glucose Homeostasis: A Perspective 50 Years After Demonstrating the Presence of the Enzyme in Islets of Langerhans","author":"FM Matschinsky","year":"2019","journal-title":"Front Physiol [Internet]"},{"issue":"10","key":"pcbi.1010555.ref030","doi-asserted-by":"crossref","first-page":"2540","DOI":"10.1016\/j.bbamcr.2016.03.012","article-title":"Beta-cell mitochondrial carriers and the diabetogenic stress response","volume":"1863","author":"T Brun","year":"2016","journal-title":"Biochim Biophys Acta BBA\u2014Mol Cell Res"},{"key":"pcbi.1010555.ref031","doi-asserted-by":"crossref","first-page":"365","DOI":"10.3389\/fendo.2020.00365","article-title":"The Role of the Pentose Phosphate Pathway in Diabetes and Cancer","volume":"11","author":"T Ge","year":"2020","journal-title":"Front Endocrinol"},{"key":"pcbi.1010555.ref032","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.pharmthera.2017.05.003","article-title":"Mechanisms of the Amplifying Pathway of Insulin Secretion in the \u03b2 Cell","volume":"179","author":"MA Kalwat","year":"2017","journal-title":"Pharmacol Ther"},{"issue":"3","key":"pcbi.1010555.ref033","doi-asserted-by":"crossref","first-page":"210","DOI":"10.4161\/isl.20141","article-title":"Metabolomic analysis of pancreatic \u03b2-cell insulin release in response to glucose","volume":"4","author":"M Huang","year":"2012","journal-title":"Islets."},{"issue":"15","key":"pcbi.1010555.ref034","doi-asserted-by":"crossref","first-page":"10923","DOI":"10.1074\/jbc.M112.414961","article-title":"Metabolome response to glucose in the \u03b2-cell line INS-1 832\/13","volume":"288","author":"MA Lorenz","year":"2013","journal-title":"J Biol Chem"},{"issue":"10","key":"pcbi.1010555.ref035","doi-asserted-by":"crossref","first-page":"2584","DOI":"10.1007\/s00125-011-2249-7","article-title":"Identification of an intracellular metabolic signature impairing beta cell function in the rat beta cell line INS-1E and human islets","volume":"54","author":"I Goehring","year":"2011","journal-title":"Diabetologia"},{"issue":"6","key":"pcbi.1010555.ref036","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1007\/s00125-010-1685-0","article-title":"Regulation of insulin secretion: role of mitochondrial signalling","volume":"53","author":"S Jitrapakdee","year":"2010","journal-title":"Diabetologia"},{"key":"pcbi.1010555.ref037","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1146\/annurev.bi.64.070195.003353","article-title":"Metabolic coupling factors in pancreatic beta-cell signal transduction","volume":"64","author":"CB Newgard","year":"1995","journal-title":"Annu Rev Biochem"},{"issue":"suppl 3","key":"pcbi.1010555.ref038","doi-asserted-by":"crossref","first-page":"S389","DOI":"10.2337\/diabetes.51.2007.S389","article-title":"Stimulus\/Secretion Coupling Factors in Glucose-Stimulated Insulin Secretion: Insights Gained From a Multidisciplinary Approach","volume":"51","author":"CB Newgard","year":"2002","journal-title":"Diabetes"},{"issue":"2","key":"pcbi.1010555.ref039","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/j.cmet.2013.05.018","article-title":"Metabolic Signaling in Fuel-Induced Insulin Secretion","volume":"18","author":"M Prentki","year":"2013","journal-title":"Cell Metab"},{"issue":"2","key":"pcbi.1010555.ref040","doi-asserted-by":"crossref","first-page":"E191","DOI":"10.1152\/ajpendo.00465.2011","article-title":"NAD kinase regulates the size of the NADPH pool and insulin secretion in pancreatic \u03b2-cells","volume":"303","author":"JP Gray","year":"2012","journal-title":"Am J Physiol-Endocrinol Metab."},{"key":"pcbi.1010555.ref041","first-page":"e512618","article-title":"Roles of Pyruvate, NADH, and Mitochondrial Complex I in Redox Balance and Imbalance in \u03b2 Cell Function and Dysfunction","volume":"2015","author":"X Luo","year":"2015","journal-title":"J Diabetes Res"},{"issue":"3","key":"pcbi.1010555.ref042","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1089\/ars.2017.7216","article-title":"NAD(H) and NADP(H) Redox Couples and Cellular Energy Metabolism","volume":"28","author":"W Xiao","year":"2018","journal-title":"Antioxid Redox Signal"},{"issue":"3","key":"pcbi.1010555.ref043","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1254\/fpj.111.137","article-title":"[Aldose reductase in the polyol pathway: a potential target for the therapeutic intervention of diabetic complications]","volume":"111","author":"C. Nishimura-Yabe","year":"1998","journal-title":"Nihon Yakurigaku Zasshi Folia Pharmacol Jpn."},{"issue":"6","key":"pcbi.1010555.ref044","doi-asserted-by":"crossref","first-page":"1435","DOI":"10.1073\/pnas.69.6.1435","article-title":"Inhibition of Glucose-Induced Release of Insulin by Aldose Reductase Inhibitors","volume":"69","author":"KH Gabbay","year":"1972","journal-title":"Proc Natl Acad Sci"},{"issue":"41","key":"pcbi.1010555.ref045","doi-asserted-by":"crossref","first-page":"42351","DOI":"10.1074\/jbc.R400019200","article-title":"Chronic Oxidative Stress as a Central Mechanism for Glucose Toxicity in Pancreatic Islet Beta Cells in Diabetes *","volume":"279","author":"RP Robertson","year":"2004","journal-title":"J Biol Chem"},{"key":"pcbi.1010555.ref046","article-title":"Aldose Reductase, Oxidative Stress, and Diabetic Mellitus.","author":"W Tang","year":"2012","journal-title":"Front Pharmacol [Internet]"},{"issue":"2","key":"pcbi.1010555.ref047","first-page":"239","article-title":"A Comparison of Three Methods for Selecting Values of Input Variables in the Analysis of Output from a Computer Code.","volume":"21","author":"MD McKay","year":"1979","journal-title":"Technometrics"},{"issue":"3","key":"pcbi.1010555.ref048","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1016\/j.jtbi.2008.09.037","article-title":"Mitochondrial energetic metabolism: A simplified model of TCA cycle with ATP production","volume":"258","author":"C Nazaret","year":"2009","journal-title":"J Theor Biol"},{"issue":"1","key":"pcbi.1010555.ref049","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/S0301-4622(98)00122-7","article-title":"Sustained oscillations in glycolysis: an experimental and theoretical study of chaotic and complex periodic behavior and of quenching of simple oscillations","volume":"72","author":"K Nielsen","year":"1998","journal-title":"Biophys Chem"},{"issue":"3","key":"pcbi.1010555.ref050","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1042\/BJ20121349","article-title":"Time-resolved metabolomics analysis of \u03b2-cells implicates the pentose phosphate pathway in the control of insulin release","volume":"450","author":"P Sp\u00e9gel","year":"2013","journal-title":"Biochem J"},{"issue":"17","key":"pcbi.1010555.ref051","doi-asserted-by":"crossref","first-page":"11973","DOI":"10.1074\/jbc.M112.422527","article-title":"Coordinate Changes in Histone Modifications, mRNA Levels, and Metabolite Profiles in Clonal INS-1 832\/13 \u03b2-Cells Accompany Functional Adaptations to Lipotoxicity *","volume":"288","author":"S Malmgren","year":"2013","journal-title":"J Biol Chem"},{"issue":"6","key":"pcbi.1010555.ref052","doi-asserted-by":"crossref","first-page":"1995","DOI":"10.1210\/en.2014-1391","article-title":"Unique and Shared Metabolic Regulation in Clonal \u03b2-Cells and Primary Islets Derived From Rat Revealed by Metabolomics Analysis","volume":"156","author":"P Sp\u00e9gel","year":"2015","journal-title":"Endocrinology"},{"issue":"1","key":"pcbi.1010555.ref053","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1042\/BJ20100655","article-title":"Metabolomic analyses reveal profound differences in glycolytic and tricarboxylic acid cycle metabolism in glucose-responsive and -unresponsive clonal \u03b2-cell lines","volume":"435","author":"P Sp\u00e9gel","year":"2011","journal-title":"Biochem J"},{"issue":"5","key":"pcbi.1010555.ref054","doi-asserted-by":"crossref","first-page":"1653","DOI":"10.1210\/en.2013-1805","article-title":"Assessment of the Metabolic Pathways Associated With Glucose-Stimulated Biphasic Insulin Secretion","volume":"155","author":"M Huang","year":"2014","journal-title":"Endocrinology"},{"issue":"19","key":"pcbi.1010555.ref055","doi-asserted-by":"crossref","first-page":"13575","DOI":"10.1074\/jbc.M113.531970","article-title":"Increased glucose metabolism and glycerolipid formation by fatty acids and GPR40 receptor signaling underlies the fatty acid potentiation of insulin secretion","volume":"289","author":"M El-Azzouny","year":"2014","journal-title":"J Biol Chem"},{"issue":"10","key":"pcbi.1010555.ref056","doi-asserted-by":"crossref","first-page":"e77097","DOI":"10.1371\/journal.pone.0077097","article-title":"A role for cytosolic isocitrate dehydrogenase as a negative regulator of glucose signaling for insulin secretion in pancreatic \u00df-cells","volume":"8","author":"C Guay","year":"2013","journal-title":"PloS One."},{"issue":"18","key":"pcbi.1010555.ref057","doi-asserted-by":"crossref","first-page":"7407","DOI":"10.1074\/jbc.M116.763060","article-title":"Metabolic fate of glucose and candidate signaling and excess-fuel detoxification pathways in pancreatic \u03b2-cells","volume":"292","author":"Y Mugabo","year":"2017","journal-title":"J Biol Chem"},{"issue":"3","key":"pcbi.1010555.ref058","doi-asserted-by":"crossref","first-page":"372","DOI":"10.2337\/db16-1441","article-title":"Glutamine-Elicited Secretion of Glucagon-Like Peptide 1 Is Governed by an Activated Glutamate Dehydrogenase","volume":"67","author":"LE Andersson","year":"2018","journal-title":"Diabetes"},{"issue":"1","key":"pcbi.1010555.ref059","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1042\/BJ20140697","article-title":"Inhibition of the malate-aspartate shuttle in mouse pancreatic islets abolishes glucagon secretion without affecting insulin secretion","volume":"468","author":"JA Stamenkovic","year":"2015","journal-title":"Biochem J"},{"issue":"1","key":"pcbi.1010555.ref060","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1186\/1752-0509-7-91","article-title":"Identification of parameter correlations for parameter estimation in dynamic biological models","volume":"7","author":"P Li","year":"2013","journal-title":"BMC Syst Biol"},{"issue":"6","key":"pcbi.1010555.ref061","doi-asserted-by":"crossref","first-page":"1795","DOI":"10.1007\/s00285-012-0614-x","article-title":"On the identifiability of metabolic network models","volume":"67","author":"S Berthoumieux","year":"2013","journal-title":"J Math Biol"},{"issue":"1","key":"pcbi.1010555.ref062","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1080\/00401706.1999.10485594","article-title":"A Quantitative Model-Independent Method for Global Sensitivity Analysis of Model Output.","volume":"41","author":"A Saltelli","year":"1999","journal-title":"Technometrics."},{"key":"pcbi.1010555.ref063","doi-asserted-by":"crossref","first-page":"1942","DOI":"10.1109\/ICNN.1995.488968","volume-title":".Proceedings of ICNN\u201995\u2014International Conference on Neural Networks","author":"J Kennedy","year":"1995"},{"issue":"4","key":"pcbi.1010555.ref064","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1093\/bioinformatics\/btx676","article-title":"PESTO: Parameter EStimation TOolbox","volume":"34","author":"P Stapor","year":"2018","journal-title":"Bioinformatics"},{"issue":"2","key":"pcbi.1010555.ref065","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/S0169-7439(01)00154-X","article-title":"Some theoretical aspects of partial least squares regression","volume":"58","author":"IS Helland","year":"2001","journal-title":"Chemom Intell Lab Syst"},{"issue":"3","key":"pcbi.1010555.ref066","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/0169-7439(93)85002-X","article-title":"SIMPLS: An alternative approach to partial least squares regression","volume":"18","author":"S. de Jong","year":"1993","journal-title":"Chemom Intell Lab Syst"},{"key":"pcbi.1010555.ref067","first-page":"9","author":"S Akter","year":"2011","journal-title":"An evaluation of PLS based complex models: the roles of power analysis, predictive relevance and GoF index"},{"key":"pcbi.1010555.ref068","article-title":"CUTOFF THRESHOLD OF VARIABLE IMPORTANCE IN PROJECTION FOR VARIABLE SELECTION.","author":"N Akarachantachote","year":"2014","journal-title":"Int J Pure Apllied Math [Internet]"},{"issue":"9","key":"pcbi.1010555.ref069","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1007\/s00125-017-4342-z","article-title":"The mechanisms of action of metformin","volume":"60","author":"G Rena","year":"2017","journal-title":"Diabetologia"},{"issue":"47","key":"pcbi.1010555.ref070","doi-asserted-by":"crossref","first-page":"19458","DOI":"10.1074\/jbc.M117.808105","article-title":"Identification of the signals for glucose-induced insulin secretion in INS1 (832\/13) \u03b2-cells using metformin-induced metabolic deceleration as a model","volume":"292","author":"J Lamontagne","year":"2017","journal-title":"J Biol Chem"},{"issue":"3","key":"pcbi.1010555.ref071","doi-asserted-by":"crossref","first-page":"E367","DOI":"10.1152\/ajpendo.00447.2016","article-title":"Effects of metformin on compensatory pancreatic \u03b2-cell hyperplasia in mice fed a high-fat diet","volume":"313","author":"K Tajima","year":"2017","journal-title":"Am J Physiol-Endocrinol Metab."},{"key":"pcbi.1010555.ref072","doi-asserted-by":"crossref","first-page":"e9163052","DOI":"10.1155\/2018\/9163052","article-title":"Metformin Inhibits Mouse Islet Insulin Secretion and Alters Intracellular Calcium in a Concentration-Dependent and Duration-Dependent Manner near the Circulating Range","volume":"2018","author":"L Gelin","year":"2018","journal-title":"J Diabetes Res"},{"issue":"1","key":"pcbi.1010555.ref073","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jep.2003.12.031","article-title":"Natural medicines used in the traditional Chinese medical system for therapy of diabetes mellitus","volume":"92","author":"WL Li","year":"2004","journal-title":"J Ethnopharmacol"},{"issue":"1","key":"pcbi.1010555.ref074","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1017\/S0007114598001834","article-title":"Actions of the traditional anti-diabetic plant, Agrimony eupatoria (agrimony): effects on hyperglycaemia, cellular glucose metabolism and insulin secretion","volume":"80","author":"AM Gray","year":"1998","journal-title":"Br J Nutr"},{"key":"pcbi.1010555.ref075","doi-asserted-by":"crossref","first-page":"8309894","DOI":"10.1155\/2017\/8309894","article-title":"Antioxidant, Anti-Inflammatory, and Analgesic Activities of Agrimonia eupatoria L. 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Tiganis","year":"2011","journal-title":"Trends Pharmacol Sci"},{"issue":"1","key":"pcbi.1010555.ref078","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1172\/JCI119126","article-title":"Glycation-dependent, reactive oxygen species-mediated suppression of the insulin gene promoter activity in HIT cells","volume":"99","author":"T Matsuoka","year":"1997","journal-title":"J Clin Invest"},{"issue":"3","key":"pcbi.1010555.ref079","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1016\/j.mehy.2008.09.062","article-title":"NADPH oxidase mediates glucolipotoxicity-induced beta cell dysfunction\u2014clinical implications","volume":"74","author":"MF McCarty","year":"2010","journal-title":"Med Hypotheses"},{"issue":"3","key":"pcbi.1010555.ref080","doi-asserted-by":"crossref","first-page":"C420","DOI":"10.1152\/ajpcell.00141.2019","article-title":"Oxidative stress pathways in pancreatic \u03b2-cells and insulin-sensitive cells and tissues: importance to cell metabolism, function, and dysfunction","volume":"317","author":"P Newsholme","year":"2019","journal-title":"Am J Physiol-Cell Physiol."},{"issue":"4","key":"pcbi.1010555.ref081","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1016\/j.gendis.2017.09.001","article-title":"6 phosphatase dehydrogenase (G6PD) and neurodegenerative disorders: Mapping diagnostic and therapeutic opportunities","volume":"4","author":"Tiwari M. Glucose","year":"2017","journal-title":"Genes Dis."},{"issue":"3","key":"pcbi.1010555.ref082","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/j.bj.2020.08.001","article-title":"G6PD: A hub for metabolic reprogramming and redox signaling in cancer","volume":"44","author":"HC Yang","year":"2021","journal-title":"Biomed J"},{"issue":"4","key":"pcbi.1010555.ref083","doi-asserted-by":"crossref","first-page":"526","DOI":"10.3390\/antiox10040526","article-title":"Redox Homeostasis in Pancreatic \u03b2-Cells: From Development to Failure","volume":"10","author":"\u0160 Ben\u00e1kov\u00e1","year":"2021","journal-title":"Antioxidants"},{"key":"pcbi.1010555.ref084","doi-asserted-by":"crossref","first-page":"932838","DOI":"10.1155\/2012\/932838","article-title":"Redox Homeostasis in Pancreatic \u03b2 Cells","volume":"2012","author":"P Je\u017eek","year":"2012","journal-title":"Oxid Med Cell Longev"},{"issue":"5","key":"pcbi.1010555.ref085","doi-asserted-by":"crossref","first-page":"1461","DOI":"10.1016\/j.jmb.2019.10.012","article-title":"Nutrient Metabolism, Subcellular Redox State, and Oxidative Stress in Pancreatic Islets and \u03b2-Cells","volume":"432","author":"LP Roma","year":"2020","journal-title":"J Mol Biol"},{"issue":"13","key":"pcbi.1010555.ref086","doi-asserted-by":"crossref","first-page":"4543","DOI":"10.1021\/bi9726133","article-title":"Fundamental Metabolic Differences between Hepatocytes and Islet \u03b2-cells Revealed by Glucokinase Overexpression","volume":"37","author":"HK Berman","year":"1998","journal-title":"Biochemistry"},{"issue":"2","key":"pcbi.1010555.ref087","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.ab.2010.12.019","article-title":"Oscillatory glucose flux in INS 1 pancreatic \u03b2 cells: A self-referencing microbiosensor study","volume":"411","author":"J Shi","year":"2011","journal-title":"Anal Biochem"},{"issue":"43","key":"pcbi.1010555.ref088","doi-asserted-by":"crossref","first-page":"44370","DOI":"10.1074\/jbc.M311842200","article-title":"13C NMR Isotopomer Analysis of Anaplerotic Pathways in INS-1 Cells *","volume":"279","author":"GW Cline","year":"2004","journal-title":"J Biol Chem"},{"issue":"9","key":"pcbi.1010555.ref089","doi-asserted-by":"crossref","first-page":"1566","DOI":"10.1007\/s00125-017-4318-z","article-title":"Metformin: historical overview","volume":"60","author":"CJ Bailey","year":"2017","journal-title":"Diabetologia"},{"issue":"2","key":"pcbi.1010555.ref090","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1007\/s00125-014-3451-1","article-title":"GLUT2, glucose sensing and glucose homeostasis","volume":"58","author":"B. Thorens","year":"2015","journal-title":"Diabetologia"},{"issue":"5","key":"pcbi.1010555.ref091","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.1172\/JCI25102","article-title":"Inflammation, stress, and diabetes","volume":"115","author":"KE Wellen","year":"2005","journal-title":"J Clin Invest"},{"issue":"1","key":"pcbi.1010555.ref092","doi-asserted-by":"crossref","first-page":"50","DOI":"10.15420\/ecr.2018.33.1","article-title":"The Role of Inflammation in Diabetes: Current Concepts and Future Perspectives","volume":"14","author":"S Tsalamandris","year":"2019","journal-title":"Eur Cardiol Rev"},{"issue":"Suppl 2","key":"pcbi.1010555.ref093","doi-asserted-by":"crossref","first-page":"S267","DOI":"10.4103\/2230-8210.104057","article-title":"Antioxidants and diabetes","volume":"16","author":"S Bajaj","year":"2012","journal-title":"Indian J Endocrinol Metab"},{"issue":"12","key":"pcbi.1010555.ref094","doi-asserted-by":"crossref","first-page":"2398","DOI":"10.2337\/diabetes.48.12.2398","article-title":"Beneficial effects of antioxidants in diabetes: possible protection of pancreatic beta-cells against glucose toxicity","volume":"48","author":"H Kaneto","year":"1999","journal-title":"Diabetes"},{"issue":"2","key":"pcbi.1010555.ref095","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.mce.2012.06.020","article-title":"Role of AMPK in pancreatic beta cell function","volume":"366","author":"A Fu","year":"2013","journal-title":"Mol Cell Endocrinol"},{"issue":"1","key":"pcbi.1010555.ref096","doi-asserted-by":"crossref","first-page":"25","DOI":"10.2174\/157339913804143225","article-title":"Regulation of Insulin Synthesis and Secretion and Pancreatic Beta-Cell Dysfunction in Diabetes","volume":"9","author":"Z Fu","year":"2013","journal-title":"Curr Diabetes Rev"},{"issue":"47","key":"pcbi.1010555.ref097","doi-asserted-by":"crossref","first-page":"35624","DOI":"10.1074\/jbc.M602606200","article-title":"The mitochondrial citrate\/isocitrate carrier plays a regulatory role in glucose-stimulated insulin secretion","volume":"281","author":"JW Joseph","year":"2006","journal-title":"J Biol Chem"},{"issue":"28","key":"pcbi.1010555.ref098","doi-asserted-by":"crossref","first-page":"16544","DOI":"10.1074\/jbc.271.28.16544","article-title":"Suppression of Adenylate Kinase Catalyzed Phosphotransfer Precedes and Is Associated with Glucose-induced Insulin Secretion in Intact HIT-T15 Cells*","volume":"271","author":"LK Olson","year":"1996","journal-title":"J Biol Chem"},{"issue":"10","key":"pcbi.1010555.ref099","doi-asserted-by":"crossref","first-page":"2126","DOI":"10.1007\/s00125-007-0742-9","article-title":"An adenylate kinase is involved in KATP channel regulation of mouse pancreatic beta cells","volume":"50","author":"DU Schulze","year":"2007","journal-title":"Diabetologia"},{"issue":"3","key":"pcbi.1010555.ref100","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1016\/j.bbrc.2008.01.109","article-title":"Cytosolic adenylate kinases regulate K-ATP channel activity in human \u03b2-cells","volume":"368","author":"V Stanojevic","year":"2008","journal-title":"Biochem Biophys Res Commun"},{"issue":"3","key":"pcbi.1010555.ref101","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1007\/s00125-010-2036-x","article-title":"Rat neonatal beta cells lack the specialised metabolic phenotype of mature beta cells","volume":"54","author":"A Jermendy","year":"2011","journal-title":"Diabetologia"},{"issue":"06","key":"pcbi.1010555.ref102","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1055\/s-0028-1093914","article-title":"Effects of Glucose on Insulin Biosynthesis in Foetal and Newborn Rats","volume":"5","author":"K. Asplund","year":"1973","journal-title":"Horm Metab Res"},{"issue":"13","key":"pcbi.1010555.ref103","doi-asserted-by":"crossref","first-page":"3135","DOI":"10.1016\/j.celrep.2017.08.093","article-title":"Fumarate Hydratase Deletion in Pancreatic \u03b2 Cells Leads to Progressive Diabetes","volume":"20","author":"J Adam","year":"2017","journal-title":"Cell Rep"},{"key":"pcbi.1010555.ref104","first-page":"16","journal-title":"The harmony of the spheres: inducible nitric oxide synthase and related genes in pancreatic beta cells."},{"issue":"6","key":"pcbi.1010555.ref105","doi-asserted-by":"crossref","first-page":"E910","DOI":"10.1152\/ajpendo.00339.2010","article-title":"\u03b2-Cell-specific pyruvate dehydrogenase deficiency impairs glucose-stimulated insulin secretion","volume":"299","author":"M Srinivasan","year":"2010","journal-title":"Am J Physiol\u2014Endocrinol Metab."},{"issue":"12","key":"pcbi.1010555.ref106","doi-asserted-by":"crossref","first-page":"2729","DOI":"10.2337\/diabetes.50.12.2729","article-title":"Selective Modification of Pyruvate Dehydrogenase Kinase Isoform Expression in Rat Pancreatic Islets Elicited by Starvation and Activation of Peroxisome Proliferator\u2013Activated Receptor-\u03b1: Implications for Glucose-Stimulated Insulin Secretion","volume":"50","author":"MC Sugden","year":"2001","journal-title":"Diabetes"},{"key":"pcbi.1010555.ref107","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1111\/j.1749-6632.2010.05838.x","article-title":"The genetics of type 2 diabetes: what have we learned from GWAS?","volume":"1212","author":"LK Billings","year":"2010","journal-title":"Ann N Y Acad Sci"},{"issue":"7","key":"pcbi.1010555.ref108","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1038\/s41574-020-0355-7","article-title":"Pancreatic \u03b2-cells in type 1 and type 2 diabetes mellitus: different pathways to failure","volume":"16","author":"DL Eizirik","year":"2020","journal-title":"Nat Rev Endocrinol"},{"issue":"42","key":"pcbi.1010555.ref109","doi-asserted-by":"crossref","first-page":"28048","DOI":"10.1074\/jbc.M804170200","article-title":"Impaired Anaplerosis and Insulin Secretion in Insulinoma Cells Caused by Small Interfering RNA-mediated Suppression of Pyruvate Carboxylase *","volume":"283","author":"NM Hasan","year":"2008","journal-title":"J Biol Chem"},{"issue":"49","key":"pcbi.1010555.ref110","doi-asserted-by":"crossref","first-page":"35657","DOI":"10.1074\/jbc.M707294200","article-title":"A Role for ATP-Citrate Lyase, Malic Enzyme, and Pyruvate\/Citrate Cycling in Glucose-induced Insulin Secretion*","volume":"282","author":"C Guay","year":"2007","journal-title":"J Biol Chem"},{"issue":"11","key":"pcbi.1010555.ref111","doi-asserted-by":"crossref","first-page":"5104","DOI":"10.1016\/j.bbagen.2013.07.013","article-title":"Knockdown of both mitochondrial isocitrate dehydrogenase enzymes in pancreatic beta cells inhibits insulin secretion","volume":"1830","author":"MJ MacDonald","year":"2013","journal-title":"Biochim Biophys Acta"},{"issue":"4","key":"pcbi.1010555.ref112","doi-asserted-by":"crossref","first-page":"1509","DOI":"10.3390\/ijms22041509","article-title":"The Role of Oxidative Stress in Pancreatic \u03b2 Cell Dysfunction in Diabetes","volume":"22","author":"N Eguchi","year":"2021","journal-title":"Int J Mol Sci"},{"issue":"19","key":"pcbi.1010555.ref113","doi-asserted-by":"crossref","first-page":"3743","DOI":"10.1016\/j.febslet.2007.03.087","article-title":"Pancreatic islet \u03b2-cell and oxidative stress: The importance of glutathione peroxidase","volume":"581","author":"RP Robertson","year":"2007","journal-title":"FEBS Lett"},{"issue":"4","key":"pcbi.1010555.ref114","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41419-019-1552-y","article-title":"Glutathione prevents chronic oscillating glucose intake-induced \u03b2-cell dedifferentiation and failure","volume":"10","author":"J Zhang","year":"2019","journal-title":"Cell Death Dis"},{"issue":"8","key":"pcbi.1010555.ref115","doi-asserted-by":"crossref","first-page":"e6500","DOI":"10.1371\/journal.pone.0006500","article-title":"Diabetic \u03b2-Cells Can Achieve Self-Protection against Oxidative Stress through an Adaptive Up-Regulation of Their Antioxidant Defenses","volume":"4","author":"G Lacraz","year":"2009","journal-title":"PLOS ONE."},{"issue":"5","key":"pcbi.1010555.ref116","doi-asserted-by":"crossref","first-page":"1497","DOI":"10.1096\/fj.09-136572","article-title":"High glucose inhibits glucose-6-phosphate dehydrogenase, leading to increased oxidative stress and \u03b2-cell apoptosis","volume":"24","author":"Z Zhang","year":"2010","journal-title":"FASEB J"},{"issue":"5","key":"pcbi.1010555.ref117","doi-asserted-by":"crossref","first-page":"2750","DOI":"10.1074\/jbc.274.5.2750","article-title":"Enhanced glutathione levels and oxidoresistance mediated by increased glucose-6-phosphate dehydrogenase expression","volume":"274","author":"F Salvemini","year":"1999","journal-title":"J Biol Chem"},{"issue":"21","key":"pcbi.1010555.ref118","doi-asserted-by":"crossref","first-page":"5209","DOI":"10.1002\/j.1460-2075.1995.tb00205.x","article-title":"Targeted disruption of the housekeeping gene encoding glucose 6-phosphate dehydrogenase (G6PD): G6PD is dispensable for pentose synthesis but essential for defense against oxidative stress","volume":"14","author":"PP Pandolfi","year":"1995","journal-title":"EMBO J"},{"key":"pcbi.1010555.ref119","volume-title":"Innovative Medicine: Basic Research and Development [Internet]","author":"E Mullarky","year":"2015"}],"updated-by":[{"DOI":"10.1371\/journal.pcbi.1010555","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,10,27]],"date-time":"2022-10-27T00:00:00Z","timestamp":1666828800000}}],"container-title":["PLOS Computational 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