{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T23:46:04Z","timestamp":1791848764471,"version":"4.3.4"},"reference-count":95,"publisher":"American Diabetes Association","issue":"6","license":[{"start":{"date-parts":[[2019,5,20]],"date-time":"2019-05-20T00:00:00Z","timestamp":1558310400000},"content-version":"vor","delay-in-days":7,"URL":"http:\/\/www.diabetesjournals.org\/content\/license"}],"funder":[{"DOI":"10.13039\/501100001648","name":"European Foundation for the Study of Diabetes","doi-asserted-by":"publisher","award":["(EFSD)\/Novo Nordisk"],"award-info":[{"award-number":["(EFSD)\/Novo Nordisk"]}],"id":[{"id":"10.13039\/501100001648","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001648","name":"European Foundation for the Study of Diabetes","doi-asserted-by":"publisher","award":["EFSD\/Lilly"],"award-info":[{"award-number":["EFSD\/Lilly"]}],"id":[{"id":"10.13039\/501100001648","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001648","name":"European Foundation for the Study of Diabetes","doi-asserted-by":"publisher","award":["EFSD\/AstraZeneca"],"award-info":[{"award-number":["EFSD\/AstraZeneca"]}],"id":[{"id":"10.13039\/501100001648","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005743","name":"Universit\u00e0 Cattolica del Sacro Cuore","doi-asserted-by":"crossref","award":["Fondi Ateneo Linea D.3.2 Sindrome Metabolica"],"award-info":[{"award-number":["Fondi Ateneo Linea D.3.2 Sindrome Metabolica"]}],"id":[{"id":"10.13039\/501100005743","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Italian Ministry of Education, University and Research","award":["PRIN 2010JS3PMZ_011"],"award-info":[{"award-number":["PRIN 2010JS3PMZ_011"]}]}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2019,6,1]]},"abstract":"<jats:p>Although it is well established that type 2 diabetes (T2D) is generally due to the progressive loss of \u03b2-cell insulin secretion against a background of insulin resistance, the actual correlation of reduced \u03b2-cell mass to its defective function continues to be debated. There is evidence that a compensatory increase in \u03b2-cell mass, and the consequent insulin secretion, can effectively cope with states of insulin resistance, until hyperglycemia supervenes. Recent data strongly indicate that the mechanisms by which islets are able to compensate in response to insulin resistance in peripheral tissues is secondary to hyperplasia, as well as the activation of multiple cellular machineries with diverse functions. Importantly, islet cells exhibit plasticity in altering their endocrine commitment; for example, by switching from secretion of glucagon to secretion of insulin and back (transdifferentiation) or from an active secretory state to a nonsecretory quiescent state (dedifferentiation) and back. Lineage tracing (a method used to track each cell though its differentiation process) has demonstrated these potentials in murine models. A limitation to drawing conclusions from human islet research is that most studies are derived from human autopsy and\/or organ donor samples, which lack in vivo functional and metabolic profiling. In this review, we specifically focus on evidence of islet plasticity in humans\u2014from the normal state, progressing to insulin resistance to overt T2D\u2014to explain the seemingly contradictory results from different cross-sectional studies in the literature. We hope the discussion on this intriguing scenario will provide a forum for the scientific community to better understand the disease and in the long term pave the way for personalized therapies.<\/jats:p>","DOI":"10.2337\/db18-0856","type":"journal-article","created":{"date-parts":[[2019,5,20]],"date-time":"2019-05-20T20:34:16Z","timestamp":1558384456000},"page":"1121-1129","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":145,"title":["\u03b2-Cell Fate in Human Insulin Resistance and Type 2 Diabetes: A Perspective on Islet Plasticity"],"prefix":"10.2337","volume":"68","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5407-9576","authenticated-orcid":false,"given":"Teresa","family":"Mezza","sequence":"first","affiliation":[{"name":"U.O.C. Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italia"},{"name":"Istituto di Patologia Speciale Medica e Semeiotica Clinica, Universit\u00e0 Cattolica del Sacro Cuore, Roma, Italia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Cinti","sequence":"additional","affiliation":[{"name":"U.O.C. Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italia"},{"name":"Istituto di Patologia Speciale Medica e Semeiotica Clinica, Universit\u00e0 Cattolica del Sacro Cuore, Roma, Italia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara Maria Assunta","family":"Cefalo","sequence":"additional","affiliation":[{"name":"U.O.C. Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italia"},{"name":"Istituto di Patologia Speciale Medica e Semeiotica Clinica, Universit\u00e0 Cattolica del Sacro Cuore, Roma, Italia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alfredo","family":"Pontecorvi","sequence":"additional","affiliation":[{"name":"U.O.C. Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italia"},{"name":"Istituto di Patologia Speciale Medica e Semeiotica Clinica, Universit\u00e0 Cattolica del Sacro Cuore, Roma, Italia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5029-6119","authenticated-orcid":false,"given":"Rohit N.","family":"Kulkarni","sequence":"additional","affiliation":[{"name":"Islet Cell & Regenerative Biology, Joslin Diabetes Center and Department of Medicine, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7462-7792","authenticated-orcid":false,"given":"Andrea","family":"Giaccari","sequence":"additional","affiliation":[{"name":"U.O.C. Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italia"},{"name":"Istituto di Patologia Speciale Medica e Semeiotica Clinica, Universit\u00e0 Cattolica del Sacro Cuore, Roma, Italia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2019,5,13]]},"reference":[{"key":"2022031303355517900_B1","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1111\/j.1463-1326.2008.00969.x","article-title":"Pancreatic beta-cell mass in European subjects with type 2 diabetes","volume":"10","author":"Rahier","year":"2008","journal-title":"Diabetes Obes Metab"},{"key":"2022031303355517900_B2","doi-asserted-by":"crossref","first-page":"102","DOI":"10.2337\/diabetes.52.1.102","article-title":"\u03b2-Cell deficit and increased \u03b2-cell apoptosis in humans with type 2 diabetes","volume":"52","author":"Butler","year":"2003","journal-title":"Diabetes"},{"key":"2022031303355517900_B3","doi-asserted-by":"crossref","first-page":"1044","DOI":"10.1210\/jc.2015-2860","article-title":"Evidence of \u03b2-cell dedifferentiation in human type 2 diabetes","volume":"101","author":"Cinti","year":"2016","journal-title":"J Clin Endocrinol Metab"},{"key":"2022031303355517900_B4","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1007\/s00125-013-3098-3","article-title":"Are we overestimating the loss of beta cells in type 2 diabetes","volume":"57","author":"Marselli","year":"2014","journal-title":"Diabetologia"},{"key":"2022031303355517900_B5","doi-asserted-by":"crossref","first-page":"2300","DOI":"10.1210\/jc.2002-020735","article-title":"Selective beta-cell loss and alpha-cell expansion in patients with type 2 diabetes mellitus in Korea","volume":"88","author":"Yoon","year":"2003","journal-title":"J Clin Endocrinol Metab"},{"key":"2022031303355517900_B6","doi-asserted-by":"crossref","first-page":"1720","DOI":"10.1007\/s00125-011-2118-4","article-title":"Pancreatic alpha cell mass in European subjects with type 2 diabetes","volume":"54","author":"Henquin","year":"2011","journal-title":"Diabetologia"},{"key":"2022031303355517900_B7","doi-asserted-by":"crossref","first-page":"2874","DOI":"10.1210\/jc.2016-1374","article-title":"Effects of obesity and diabetes on \u03b1- and \u03b2-cell mass in surgically resected human pancreas","volume":"101","author":"Inaishi","year":"2016","journal-title":"J Clin Endocrinol Metab"},{"key":"2022031303355517900_B8","doi-asserted-by":"crossref","first-page":"537","DOI":"10.2337\/dbi17-0040","article-title":"New understanding of \u03b2-cell heterogeneity and in situ islet function","volume":"67","author":"Benninger","year":"2018","journal-title":"Diabetes"},{"key":"2022031303355517900_B9","doi-asserted-by":"crossref","first-page":"R43","DOI":"10.1530\/JME-18-0011","article-title":"The role of beta cell heterogeneity in islet function and insulin release","volume":"61","author":"Nasteska","year":"2018","journal-title":"J Mol Endocrinol"},{"key":"2022031303355517900_B10","doi-asserted-by":"crossref","first-page":"22","DOI":"10.3389\/fgene.2017.00022","article-title":"Heterogeneity of the pancreatic beta cell","volume":"8","author":"Gutierrez","year":"2017","journal-title":"Front Genet"},{"key":"2022031303355517900_B11","doi-asserted-by":"crossref","first-page":"994","DOI":"10.2337\/db13-1013","article-title":"Insulin resistance alters islet morphology in nondiabetic humans","volume":"63","author":"Mezza","year":"2014","journal-title":"Diabetes"},{"key":"2022031303355517900_B12","doi-asserted-by":"crossref","first-page":"2053","DOI":"10.1210\/jc.2012-3832","article-title":"Predominance of \u03b2-cell neogenesis rather than replication in humans with an impaired glucose tolerance and newly diagnosed diabetes","volume":"98","author":"Yoneda","year":"2013","journal-title":"J Clin Endocrinol Metab"},{"key":"2022031303355517900_B13","doi-asserted-by":"crossref","first-page":"S10","DOI":"10.1016\/j.amjmed.2013.06.009","article-title":"Options for combination therapy in type 2 diabetes: comparison of the ADA\/EASD position statement and AACE\/ACE algorithm","volume":"126","author":"Bailey","year":"2013","journal-title":"Am J Med"},{"key":"2022031303355517900_B14","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1016\/S0095-4543(05)70130-5","article-title":"The natural history of type 2 diabetes. Implications for clinical practice","volume":"26","author":"Ramlo-Halsted","year":"1999","journal-title":"Prim Care"},{"key":"2022031303355517900_B15","doi-asserted-by":"crossref","first-page":"1342","DOI":"10.1056\/NEJMcp021106","article-title":"Clinical practice. Initial management of glycemia in type 2 diabetes mellitus","volume":"347","author":"Nathan","year":"2002","journal-title":"N Engl J Med"},{"key":"2022031303355517900_B16","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/S0092-8674(00)80546-2","article-title":"Tissue-specific knockout of the insulin receptor in pancreatic beta cells creates an insulin secretory defect similar to that in type 2 diabetes","volume":"96","author":"Kulkarni","year":"1999","journal-title":"Cell"},{"key":"2022031303355517900_B17","doi-asserted-by":"crossref","first-page":"1701","DOI":"10.2337\/dbi18-0025","article-title":"Insulin action research and the future of diabetes treatment: the 2017 Banting Medal for Scientific Achievement Lecture","volume":"67","author":"Accili","year":"2018","journal-title":"Diabetes"},{"key":"2022031303355517900_B18","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1016\/j.cmet.2009.02.007","article-title":"Insulin signaling in alpha cells modulates glucagon secretion in vivo","volume":"9","author":"Kawamori","year":"2009","journal-title":"Cell Metab"},{"key":"2022031303355517900_B19","doi-asserted-by":"crossref","first-page":"301","DOI":"10.2337\/db11-1067","article-title":"Insulin augmentation of glucose-stimulated insulin secretion is impaired in insulin-resistant humans","volume":"61","author":"Halperin","year":"2012","journal-title":"Diabetes"},{"key":"2022031303355517900_B20","doi-asserted-by":"crossref","first-page":"8977","DOI":"10.1073\/pnas.0608703104","article-title":"Insulin receptors in beta-cells are critical for islet compensatory growth response to insulin resistance","volume":"104","author":"Okada","year":"2007","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2022031303355517900_B21","doi-asserted-by":"crossref","first-page":"1549","DOI":"10.1172\/JCI105646","article-title":"The significance of basal insulin levels in the evaluation of the insulin response to glucose in diabetic and nondiabetic subjects","volume":"46","author":"Bagdade","year":"1967","journal-title":"J Clin Invest"},{"key":"2022031303355517900_B22","doi-asserted-by":"crossref","first-page":"667","DOI":"10.2337\/diab.37.6.667","article-title":"Lilly lecture 1987. The triumvirate: \u03b2-Cell, muscle, liver. A collusion responsible for NIDDM","volume":"37","author":"DeFronzo","year":"1988","journal-title":"Diabetes"},{"key":"2022031303355517900_B23","doi-asserted-by":"crossref","first-page":"18","DOI":"10.2337\/diab.40.2.S18","article-title":"Insulin secretion and insulin resistance in pregnancy and GDM. Implications for diagnosis and management","volume":"40","author":"K\u00fchl","year":"1991","journal-title":"Diabetes"},{"key":"2022031303355517900_B24","doi-asserted-by":"crossref","first-page":"1717","DOI":"10.2337\/diacare.20.11.1717","article-title":"Pronounced insulin resistance and inadequate \u03b2-cell secretion characterize lean gestational diabetes during and after pregnancy","volume":"20","author":"Kautzky-Willer","year":"1997","journal-title":"Diabetes Care"},{"key":"2022031303355517900_B25","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1210\/jcem-65-3-499","article-title":"Characterization of groups of hyperandrogenic women with acanthosis nigricans, impaired glucose tolerance, and\/or hyperinsulinemia","volume":"65","author":"Dunaif","year":"1987","journal-title":"J Clin Endocrinol Metab"},{"key":"2022031303355517900_B26","doi-asserted-by":"crossref","first-page":"111","DOI":"10.2337\/dc12-0421","article-title":"\u03b2-Cell mass and turnover in humans: effects of obesity and aging","volume":"36","author":"Saisho","year":"2013","journal-title":"Diabetes Care"},{"key":"2022031303355517900_B27","doi-asserted-by":"crossref","first-page":"2167","DOI":"10.1007\/s00125-010-1809-6","article-title":"Adaptive changes in pancreatic beta cell fractional area and beta cell turnover in human pregnancy","volume":"53","author":"Butler","year":"2010","journal-title":"Diabetologia"},{"key":"2022031303355517900_B28","doi-asserted-by":"crossref","first-page":"2236","DOI":"10.1007\/s00125-005-1933-x","article-title":"Severe hypoglycaemia post-gastric bypass requiring partial pancreatectomy: evidence for inappropriate insulin secretion and pancreatic islet hyperplasia","volume":"48","author":"Patti","year":"2005","journal-title":"Diabetologia"},{"key":"2022031303355517900_B29","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1016\/S0092-8674(00)81896-6","article-title":"Development of a novel polygenic model of NIDDM in mice heterozygous for IR and IRS-1 null alleles","volume":"88","author":"Br\u00fcning","year":"1997","journal-title":"Cell"},{"key":"2022031303355517900_B30","first-page":"110","article-title":"Islet pathology and the pathogenesis of type 1 and type 2 diabetes mellitus revisited","volume":"4","author":"Kl\u00f6ppel","year":"1985","journal-title":"Surv Synth Pathol Res"},{"key":"2022031303355517900_B31","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1210\/jc.2015-2802","article-title":"\u03b2-Cell glucose sensitivity is linked to insulin\/glucagon bihormonal cells in nondiabetic humans","volume":"101","author":"Mezza","year":"2016","journal-title":"J Clin Endocrinol Metab"},{"key":"2022031303355517900_B32","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1016\/j.molmet.2014.01.010","article-title":"Islet cell plasticity and regeneration","volume":"3","author":"Migliorini","year":"2014","journal-title":"Mol Metab"},{"key":"2022031303355517900_B33","doi-asserted-by":"crossref","first-page":"1291","DOI":"10.1007\/s00125-014-3251-7","article-title":"The regulation of pre- and post-maturational plasticity of mammalian islet cell mass","volume":"57","author":"Mezza","year":"2014","journal-title":"Diabetologia"},{"key":"2022031303355517900_B34","doi-asserted-by":"crossref","first-page":"1660","DOI":"10.2337\/db15-1127","article-title":"Inhibition of DYRK1A stimulates human \u03b2-cell proliferation","volume":"65","author":"Dirice","year":"2016","journal-title":"Diabetes"},{"key":"2022031303355517900_B35","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.cmet.2015.05.021","article-title":"Osteoprotegerin and denosumab stimulate human beta cell proliferation through inhibition of the receptor activator of NF-\u03baB ligand pathway","volume":"22","author":"Kondegowda","year":"2015","journal-title":"Cell Metab"},{"key":"2022031303355517900_B36","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/nature02520","article-title":"Adult pancreatic beta-cells are formed by self-duplication rather than stem-cell differentiation","volume":"429","author":"Dor","year":"2004","journal-title":"Nature"},{"key":"2022031303355517900_B37","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1016\/j.devcel.2007.04.011","article-title":"Growth and regeneration of adult beta cells does not involve specialized progenitors","volume":"12","author":"Teta","year":"2007","journal-title":"Dev Cell"},{"key":"2022031303355517900_B38","first-page":"868","article-title":"Insulin signaling regulates the FoxM1\/PLK1\/CENP-a pathway to promote adaptive pancreatic \u03b2 cell proliferation","volume-title":"Cell Metab","author":"Shirakawa","year":"2017"},{"key":"2022031303355517900_B39","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.2337\/db15-1331","article-title":"Inhibition of TGF-\u03b2 signaling promotes human pancreatic \u03b2-cell replication","volume":"65","author":"Dhawan","year":"2016","journal-title":"Diabetes"},{"key":"2022031303355517900_B40","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1038\/nm.3820","article-title":"A high-throughput chemical screen reveals that harmine-mediated inhibition of DYRK1A increases human pancreatic beta cell replication","volume":"21","author":"Wang","year":"2015","journal-title":"Nat Med"},{"key":"2022031303355517900_B41","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.1074\/jbc.RA118.006031","article-title":"Forkhead box protein O1 (FoxO1) regulates hepatic serine protease inhibitor B1 (serpinB1) expression in a non-cell-autonomous fashion","volume":"294","author":"El Ouaamari","year":"2019","journal-title":"J Biol Chem"},{"key":"2022031303355517900_B42","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1038\/s41467-017-00992-9","article-title":"Insights into beta cell regeneration for diabetes via integration of molecular landscapes in human insulinomas","volume":"8","author":"Wang","year":"2017","journal-title":"Nat Commun"},{"key":"2022031303355517900_B43","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.cmet.2017.08.007","article-title":"Pancreatic \u03b2 cell regeneration as a possible therapy for diabetes","volume":"27","author":"Aguayo-Mazzucato","year":"2018","journal-title":"Cell Metab"},{"key":"2022031303355517900_B44","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1111\/j.1399-543X.2004.00075.x","article-title":"The pancreatic ductal epithelium serves as a potential pool of progenitor cells","volume":"5","author":"Bonner-Weir","year":"2004","journal-title":"Pediatr Diabetes"},{"key":"2022031303355517900_B45","doi-asserted-by":"crossref","first-page":"155","DOI":"10.3109\/03009734.2016.1154906","article-title":"Dynamic development of the pancreas from birth to adulthood","volume":"121","author":"Bonner-Weir","year":"2016","journal-title":"Ups J Med Sci"},{"key":"2022031303355517900_B46","doi-asserted-by":"crossref","first-page":"19915","DOI":"10.1073\/pnas.0805803105","article-title":"Carbonic anhydrase II-positive pancreatic cells are progenitors for both endocrine and exocrine pancreas after birth","volume":"105","author":"Inada","year":"2008","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2022031303355517900_B47","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.1038\/nature08894","article-title":"Conversion of adult pancreatic alpha-cells to beta-cells after extreme beta-cell loss","volume":"464","author":"Thorel","year":"2010","journal-title":"Nature"},{"key":"2022031303355517900_B48","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1016\/j.cell.2009.05.035","article-title":"The ectopic expression of Pax4 in the mouse pancreas converts progenitor cells into alpha and subsequently beta cells","volume":"138","author":"Collombat","year":"2009","journal-title":"Cell"},{"key":"2022031303355517900_B49","doi-asserted-by":"crossref","first-page":"e1003934","DOI":"10.1371\/journal.pgen.1003934","article-title":"The inactivation of Arx in pancreatic \u03b1-cells triggers their neogenesis and conversion into functional \u03b2-like cells","volume":"9","author":"Courtney","year":"2013","journal-title":"PLoS Genet"},{"key":"2022031303355517900_B50","doi-asserted-by":"crossref","first-page":"410","DOI":"10.2337\/diabetes.53.2.410","article-title":"Reduction in glucagon receptor expression by an antisense oligonucleotide ameliorates diabetic syndrome in db\/db mice","volume":"53","author":"Liang","year":"2004","journal-title":"Diabetes"},{"key":"2022031303355517900_B51","doi-asserted-by":"crossref","first-page":"3217","DOI":"10.1172\/JCI24196","article-title":"Increased glucose tolerance and reduced adiposity in the absence of fasting hypoglycemia in mice with liver-specific Gs alpha deficiency","volume":"115","author":"Chen","year":"2005","journal-title":"J Clin Invest"},{"key":"2022031303355517900_B52","doi-asserted-by":"crossref","first-page":"1438","DOI":"10.1073\/pnas.0237106100","article-title":"Lower blood glucose, hyperglucagonemia, and pancreatic alpha cell hyperplasia in glucagon receptor knockout mice","volume":"100","author":"Gelling","year":"2003","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2022031303355517900_B53","first-page":"1348","article-title":"Amino acid transporter Slc38a5 controls glucagon receptor inhibition-induced pancreatic alpha cell hyperplasia in mice","volume-title":"Cell Metab","author":"Kim","year":"2017"},{"key":"2022031303355517900_B54","first-page":"1362","article-title":"Interrupted glucagon signaling reveals hepatic \u03b1 cell axis and role for L-glutamine in \u03b1 cell proliferation","volume-title":"Cell Metab","author":"Dean","year":"2017"},{"key":"2022031303355517900_B55","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1007\/s00125-007-0637-9","article-title":"Pancreatic deletion of insulin receptor substrate 2 reduces beta and alpha cell mass and impairs glucose homeostasis in mice","volume":"50","author":"Cantley","year":"2007","journal-title":"Diabetologia"},{"key":"2022031303355517900_B56","doi-asserted-by":"crossref","first-page":"e16096","DOI":"10.1371\/journal.pone.0016096","article-title":"Insulin and glucagon regulate pancreatic \u03b1-cell proliferation","volume":"6","author":"Liu","year":"2011","journal-title":"PLoS One"},{"key":"2022031303355517900_B57","first-page":"911","article-title":"Virgin beta cells persist throughout life at a neogenic niche within pancreatic islets","volume-title":"Cell Metab","author":"van der Meulen","year":"2017"},{"key":"2022031303355517900_B58","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1016\/j.cmet.2016.08.020","article-title":"Single-cell transcriptome profiling of human pancreatic islets in health and type 2 diabetes","volume":"24","author":"Segerstolpe","year":"2016","journal-title":"Cell Metab"},{"key":"2022031303355517900_B59","doi-asserted-by":"crossref","first-page":"3028","DOI":"10.2337\/db16-0405","article-title":"Single-cell transcriptomics of the human endocrine pancreas","volume":"65","author":"Wang","year":"2016","journal-title":"Diabetes"},{"key":"2022031303355517900_B60","first-page":"787","article-title":"GABA and artesunate do not induce pancreatic \u03b1-to-\u03b2 cell transdifferentiation in vivo","volume-title":"Cell Metab","author":"Ackermann","year":"2018"},{"key":"2022031303355517900_B61","first-page":"218","article-title":"Artemether does not turn \u03b1 cells into \u03b2 cells","volume-title":"Cell Metab","author":"van der Meulen","year":"2018"},{"key":"2022031303355517900_B62","doi-asserted-by":"crossref","first-page":"3262","DOI":"10.1007\/s00125-012-2716-9","article-title":"A local glucagon-like peptide 1 (GLP-1) system in human pancreatic islets","volume":"55","author":"Marchetti","year":"2012","journal-title":"Diabetologia"},{"key":"2022031303355517900_B63","doi-asserted-by":"crossref","first-page":"2131","DOI":"10.1053\/j.gastro.2007.03.054","article-title":"Biology of incretins: GLP-1 and GIP","volume":"132","author":"Baggio","year":"2007","journal-title":"Gastroenterology"},{"key":"2022031303355517900_B64","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1111\/jdi.12065","article-title":"Glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1: incretin actions beyond the pancreas","volume":"4","author":"Seino","year":"2013","journal-title":"J Diabetes Investig"},{"key":"2022031303355517900_B65","doi-asserted-by":"crossref","first-page":"482","DOI":"10.2337\/diabetes.54.2.482","article-title":"\u03b2-Cell Pdx1 expression is essential for the glucoregulatory, proliferative, and cytoprotective actions of glucagon-like peptide-1","volume":"54","author":"Li","year":"2005","journal-title":"Diabetes"},{"key":"2022031303355517900_B66","doi-asserted-by":"crossref","first-page":"10293","DOI":"10.1073\/pnas.162352599","article-title":"Disruption of PC1\/3 expression in mice causes dwarfism and multiple neuroendocrine peptide processing defects","volume":"99","author":"Zhu","year":"2002","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2022031303355517900_B67","doi-asserted-by":"crossref","first-page":"5149","DOI":"10.1210\/en.2003-0323","article-title":"Glucagon-like peptide 1 inhibits cell apoptosis and improves glucose responsiveness of freshly isolated human islets","volume":"144","author":"Farilla","year":"2003","journal-title":"Endocrinology"},{"key":"2022031303355517900_B68","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1074\/jbc.M209423200","article-title":"Glucagon-like peptide-1 receptor signaling modulates beta cell apoptosis","volume":"278","author":"Li","year":"2003","journal-title":"J Biol Chem"},{"key":"2022031303355517900_B69","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1007\/s00125-004-1379-6","article-title":"Glucagon-like peptide-1 prevents beta cell glucolipotoxicity","volume":"47","author":"Buteau","year":"2004","journal-title":"Diabetologia"},{"key":"2022031303355517900_B70","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1111\/jdi.12465","article-title":"Glucagon-like peptide-1 and cholecystokinin production and signaling in the pancreatic islet as an adaptive response to obesity","volume":"7","author":"Linnemann","year":"2016","journal-title":"J Diabetes Investig"},{"key":"2022031303355517900_B71","doi-asserted-by":"crossref","first-page":"1272","DOI":"10.2337\/db16-1009","article-title":"Glucagon-like peptide 1 protects pancreatic \u03b2-cells from death by increasing autophagic flux and restoring lysosomal function","volume":"66","author":"Zummo","year":"2017","journal-title":"Diabetes"},{"key":"2022031303355517900_B72","doi-asserted-by":"crossref","first-page":"149","DOI":"10.4161\/isl.2.3.11396","article-title":"Intraislet production of GLP-1 by activation of prohormone convertase 1\/3 in pancreatic \u03b1-cells in mouse models of \u00df-cell regeneration","volume":"2","author":"Kilimnik","year":"2010","journal-title":"Islets"},{"key":"2022031303355517900_B73","doi-asserted-by":"crossref","first-page":"978","DOI":"10.1210\/me.2015-1030","article-title":"Glucagon-like peptide-1 regulates cholecystokinin production in \u03b2-cells to protect from apoptosis","volume":"29","author":"Linnemann","year":"2015","journal-title":"Mol Endocrinol"},{"key":"2022031303355517900_B74","first-page":"73","article-title":"Long-term GABA administration induces alpha cell-mediated beta-like cell neogenesis","volume-title":"Cell","author":"Ben-Othman","year":"2017"},{"key":"2022031303355517900_B75","first-page":"86","article-title":"Artemisinins target GABAA receptor signaling and impair \u03b1 cell identity","volume-title":"Cell","author":"Li","year":"2017"},{"key":"2022031303355517900_B76","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1016\/S0140-6736(98)07019-6","article-title":"Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33)","volume":"352","author":"UK Prospective Diabetes Study (UKPDS) Group","year":"1998","journal-title":"Lancet"},{"key":"2022031303355517900_B77","doi-asserted-by":"crossref","first-page":"1299","DOI":"10.2337\/db06-1654","article-title":"Lineage tracing evidence for in vitro dedifferentiation but rare proliferation of mouse pancreatic \u03b2-cells","volume":"56","author":"Weinberg","year":"2007","journal-title":"Diabetes"},{"key":"2022031303355517900_B78","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1016\/j.bbrc.2004.12.043","article-title":"Redifferentiation of insulin-secreting cells after in vitro expansion of adult human pancreatic islet tissue","volume":"327","author":"Lechner","year":"2005","journal-title":"Biochem Biophys Res Commun"},{"key":"2022031303355517900_B79","doi-asserted-by":"crossref","first-page":"1223","DOI":"10.1016\/j.cell.2012.07.029","article-title":"Pancreatic \u03b2 cell dedifferentiation as a mechanism of diabetic \u03b2 cell failure","volume":"150","author":"Talchai","year":"2012","journal-title":"Cell"},{"key":"2022031303355517900_B80","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1210\/jc.2018-00968","article-title":"\u03b2 cell dedifferentiation in patients with T2D with adequate glucose control and nondiabetic chronic pancreatitis","volume":"104","author":"Sun","year":"2019","journal-title":"J Clin Endocrinol Metab"},{"key":"2022031303355517900_B81","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1210\/jc.2015-3566","article-title":"\u03b2-Cell deficit in obese type 2 diabetes, a minor role of \u03b2-cell dedifferentiation and degranulation","volume":"101","author":"Butler","year":"2016","journal-title":"J Clin Endocrinol Metab"},{"key":"2022031303355517900_B82","doi-asserted-by":"crossref","first-page":"2092","DOI":"10.2337\/db16-1213","article-title":"Pair feeding, but not insulin, phloridzin, or rosiglitazone treatment, curtails markers of \u03b2-cell dedifferentiation in db\/db mice","volume":"66","author":"Ishida","year":"2017","journal-title":"Diabetes"},{"key":"2022031303355517900_B83","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1016\/j.cmet.2014.03.010","article-title":"Pancreatic \u03b2 cell dedifferentiation in diabetes and redifferentiation following insulin therapy","volume":"19","author":"Wang","year":"2014","journal-title":"Cell Metab"},{"key":"2022031303355517900_B84","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1111\/dom.12723","article-title":"When \u03b2-cells fail: lessons from dedifferentiation","volume":"18","author":"Accili","year":"2016","journal-title":"Diabetes Obes Metab"},{"key":"2022031303355517900_B85","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1084\/jem.5.5.527","article-title":"The relation of diabetes mellitus to lesions of the pancreas. Hyaline degeneration of the islands of Langerhans","volume":"5","author":"Opie","year":"1901","journal-title":"J Exp Med"},{"key":"2022031303355517900_B86","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1007\/s12022-014-9297-8","article-title":"Pancreatic pathology in type 1 diabetes mellitus","volume":"25","author":"Richardson","year":"2014","journal-title":"Endocr Pathol"},{"key":"2022031303355517900_B87","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1111\/pedi.12286","article-title":"Organ donor specimens: what can they tell us about type 1 diabetes","volume":"16","author":"Campbell-Thompson","year":"2015","journal-title":"Pediatr Diabetes"},{"key":"2022031303355517900_B88","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1007\/s00125-018-4546-x","article-title":"Organ donor pancreases for the study of human islet cell histology and pathophysiology: a precious and valuable resource","volume":"61","author":"Marchetti","year":"2018","journal-title":"Diabetologia"},{"key":"2022031303355517900_B89","doi-asserted-by":"crossref","first-page":"1698","DOI":"10.2337\/db14-1675","article-title":"Reduced Ki67 staining in the postmortem state calls into question past conclusions about the lack of turnover of adult human \u03b2-cells","volume":"64","author":"Sullivan","year":"2015","journal-title":"Diabetes"},{"key":"2022031303355517900_B90","doi-asserted-by":"crossref","first-page":"954","DOI":"10.1007\/s00125-017-4494-x","article-title":"Hospital time prior to death and pancreas histopathology: implications for future studies","volume":"61","author":"Kusmartseva","year":"2018","journal-title":"Diabetologia"},{"key":"2022031303355517900_B91","doi-asserted-by":"crossref","first-page":"e67454","DOI":"10.1371\/journal.pone.0067454","article-title":"Regional differences in islet distribution in the human pancreas--preferential beta-cell loss in the head region in patients with type 2 diabetes","volume":"8","author":"Wang","year":"2013","journal-title":"PLoS One"},{"key":"2022031303355517900_B92","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1097\/00075197-200209000-00007","article-title":"Mathematical modeling in glucose metabolism and insulin secretion","volume":"5","author":"Mari","year":"2002","journal-title":"Curr Opin Clin Nutr Metab Care"},{"key":"2022031303355517900_B93","first-page":"E214","article-title":"Glucose clamp technique: a method for quantifying insulin secretion and resistance","volume":"237","author":"DeFronzo","year":"1979","journal-title":"Am J Physiol"},{"key":"2022031303355517900_B94","doi-asserted-by":"crossref","first-page":"798","DOI":"10.1007\/s00125-003-1103-y","article-title":"Gastric inhibitory polypeptide (GIP) dose-dependently stimulates glucagon secretion in healthy human subjects at euglycaemia","volume":"46","author":"Meier","year":"2003","journal-title":"Diabetologia"},{"key":"2022031303355517900_B95","first-page":"3575","article-title":"Degradation of endogenous and exogenous gastric inhibitory polypeptide in healthy and in type 2 diabetic subjects as revealed using a new assay for the intact peptide","volume":"85","author":"Deacon","year":"2000","journal-title":"J Clin Endocrinol Metab"}],"container-title":["Diabetes"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/diabetes.diabetesjournals.org\/syndication\/doi\/10.2337\/db18-0856","content-type":"unspecified","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/journals.org\/diabetes\/diabetes\/article-pdf\/68\/6\/1121\/553816\/db180856.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article-pdf\/68\/6\/1121\/553816\/db180856.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,2]],"date-time":"2022-11-02T12:37:52Z","timestamp":1667392672000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article\/68\/6\/1121\/39708\/Cell-Fate-in-Human-Insulin-Resistance-and-Type-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,5,13]]},"references-count":95,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2019,5,13]]},"published-print":{"date-parts":[[2019,6,1]]}},"URL":"https:\/\/doi.org\/10.2337\/db18-0856","relation":{},"ISSN":["0012-1797","1939-327X"],"issn-type":[{"value":"0012-1797","type":"print"},{"value":"1939-327X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,5,13]]}}}