{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T16:00:34Z","timestamp":1779984034304,"version":"3.53.1"},"reference-count":76,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2024,10,17]],"date-time":"2024-10-17T00:00:00Z","timestamp":1729123200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Canadian Institutes of Health Research","award":["MOP-15263"],"award-info":[{"award-number":["MOP-15263"]}]},{"name":"Lawson Foundation","award":["MOP-15263"],"award-info":[{"award-number":["MOP-15263"]}]},{"name":"Lawson Health Research Institute","award":["MOP-15263"],"award-info":[{"award-number":["MOP-15263"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Following the near-total depletion of pancreatic beta-cells with streptozotocin (STZ), a partial recovery of beta-cell mass (BCM) can occur, in part due to the alpha- to beta-cell transdifferentiation with an intermediary insulin\/glucagon bi-hormonal cell phenotype. However, human type 2 diabetes typically involves only a partial reduction in BCM and it is not known if recovery after therapeutic intervention involves islet cell transdifferentiation, or how this varies with age. Here, we used transgenic mouse models to examine if islet cell transdifferentiation contributes to BCM recovery following only a partial depletion of BCM. Cell lineage tracing was employed using Glucagon-Cre\/yellow fluorescent protein (YFP) transgenic mice treated with STZ (25 mg\/kg\u2014neonates; 70 mg\/kg\u2014adults) or vehicle alone on 3 consecutive days. Mice were euthanized 2\u201330 days later with a prior glucose tolerance test on day 30, and immunofluorescence histology performed on the pancreata. Beta-cell abundance was reduced by 30\u201340% two days post STZ in both neonates and adults, and subsequently partially recovered in adult but not neonatal mice. Glucose tolerance recovered in adult females, but not in males or neonates. Bi-hormonal cell abundance increased 2\u20133-fold in STZ-treated mice vs. controls in both neonates and adults, as did transdifferentiated cells expressing insulin and the YFP lineage tag, but not glucagon. Transdifferentiated cell presence was an order of magnitude lower than that of bi-hormonal cells. We conclude that alpha- to beta-cell transdifferentiation occurs in mice following only a moderate depletion in BCM, and that this was accompanied by a partial recovery of BCM in adults.<\/jats:p>","DOI":"10.3390\/ijms252011152","type":"journal-article","created":{"date-parts":[[2024,10,17]],"date-time":"2024-10-17T08:56:32Z","timestamp":1729155392000},"page":"11152","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Alpha- to Beta-Cell Transdifferentiation in Neonatal Compared with Adult Mouse Pancreas in Response to a Modest Reduction in Beta-Cells Using Streptozotocin"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3698-1993","authenticated-orcid":false,"given":"Jiwon","family":"Hahm","sequence":"first","affiliation":[{"name":"Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 3K7, Canada"},{"name":"Lawson Health Research Institute, St. Joseph\u2019s Health Care, London, ON N6A 4V2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bavina","family":"Thirunavukarasu","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 3K7, Canada"},{"name":"Lawson Health Research Institute, St. Joseph\u2019s Health Care, London, ON N6A 4V2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reva","family":"Gadoo","sequence":"additional","affiliation":[{"name":"Lawson Health Research Institute, St. Joseph\u2019s Health Care, London, ON N6A 4V2, Canada"},{"name":"Faculty of Science, McMaster University, Hamilton, ON L8S 4L8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan Andres Fernandez","family":"Andrade","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 3K7, Canada"},{"name":"Lawson Health Research Institute, St. Joseph\u2019s Health Care, London, ON N6A 4V2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tyler","family":"Dalton","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 3K7, Canada"},{"name":"Lawson Health Research Institute, St. Joseph\u2019s Health Care, London, ON N6A 4V2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9994-8958","authenticated-orcid":false,"given":"Edith","family":"Arany","sequence":"additional","affiliation":[{"name":"Lawson Health Research Institute, St. Joseph\u2019s Health Care, London, ON N6A 4V2, Canada"},{"name":"Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 3K7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2490-5678","authenticated-orcid":false,"given":"David J.","family":"Hill","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 3K7, Canada"},{"name":"Lawson Health Research Institute, St. Joseph\u2019s Health Care, London, ON N6A 4V2, Canada"},{"name":"Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 3K7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Wang, Q., Huang, Y.X., Liu, L., Zhao, X.H., Sun, Y., Mao, X., and Li, S.W. (2024). Pancreatic islet transplantation: Current advances and challenges. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1391504"},{"key":"ref_2","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":"ref_3","doi-asserted-by":"crossref","first-page":"1584","DOI":"10.2337\/db07-1369","article-title":"Beta-cell replication is the primary mechanism subserving the postnatal expansion of beta-cell mass in humans","volume":"57","author":"Meier","year":"2008","journal-title":"Diabetes"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1341","DOI":"10.2337\/diabetes.49.8.1341","article-title":"Linear correlation between beta-cell mass and body weight throughout the lifespan in Lewis rats: Role of beta-cell hyperplasia and hypertrophy","volume":"49","author":"Montanya","year":"2000","journal-title":"Diabetes"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.2337\/db08-1198","article-title":"Adaptive-cell proliferation is severely restricted with advanced age","volume":"58","author":"Rankin","year":"2009","journal-title":"Diabetes"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2205","DOI":"10.2337\/db12-0018","article-title":"Human \u03b2-cell proliferation and intracellular signaling driving in the dark without a road map","volume":"61","author":"Kulkarni","year":"2012","journal-title":"Diabetes"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Spears, E., Serafimidis, I., Powers, A.C., and Gavalas, A. (2021). Debates in pancreatic beta cell biology: Proliferation versus progenitor differentiation and transdifferentiation in restoring \u03b2 cell mass. Front. Endocrinol., 12.","DOI":"10.3389\/fendo.2021.722250"},{"key":"ref_8","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":"Toschi","year":"2004","journal-title":"Pediatr. Diabetes"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/j.stem.2011.01.015","article-title":"The adult mouse and human pancreas contain rare multipotent stem cells that express insulin","volume":"8","author":"Smukler","year":"2011","journal-title":"Cell Stem Cell"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1080\/19382014.2016.1162367","article-title":"Insulin-positive, Glut2-low cells present within mouse pancreas exhibit lineage plasticity and are enriched within extra-islet endocrine cell clusters","volume":"8","author":"Beamish","year":"2016","journal-title":"Islets"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1530\/JOE-16-0475","article-title":"Decrease in Ins+Glut2LO \u03b2-cells with advancing age in mouse and human pancreas","volume":"233","author":"Beamish","year":"2017","journal-title":"J. Endocrinol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1038\/nature07314","article-title":"In vivo reprogramming of adult pancreatic exocrine cells to beta-cells","volume":"455","author":"Zhou","year":"2008","journal-title":"Nature"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1275","DOI":"10.1172\/JCI66514","article-title":"Epigenomic plasticity enables human pancreatic \u03b1 to \u03b2 cell reprogramming","volume":"123","author":"Bramswig","year":"2013","journal-title":"J. Clin. Investig."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1038\/nature13633","article-title":"Diabetes recovery by age-dependent conversion of pancreatic \u03b4-cells into insulin producers","volume":"514","author":"Chera","year":"2014","journal-title":"Nature"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2304","DOI":"10.2337\/diabetes.52.9.2304","article-title":"Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes","volume":"52","author":"Butler","year":"2003","journal-title":"Diabetes"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"193","DOI":"10.3892\/mmr.2024.13317","article-title":"Pancreatic \u03b2-cell apoptosis in type 2 diabetes is related to post-translational modifications of p53 (Review)","volume":"30","year":"2024","journal-title":"Mol. Med. Rep."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e1024405","DOI":"10.1080\/19382014.2015.1024405","article-title":"Structural similarities and differences between the human and the mouse pancreas","volume":"7","author":"Rupnik","year":"2015","journal-title":"Islets"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"36","DOI":"10.4161\/org.1.2.1409","article-title":"Transdifferentiation, metaplasia and tissue regeneration","volume":"1","author":"Shen","year":"2004","journal-title":"Organogenesis"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Ilievski, V., Toth, P.T., Valyi-Nagy, K., Valyi-Nagy, T., Green, S.J., Marattil, R.S., Aljewari, H.W., Wicksteed, B., O\u2019Brien-Simpson, N.M., and Reynolds, E.C. (2020). Identification of a periodontal pathogen and bihormonal cells in pancreatic islets of humans and a mouse model of periodontitis. Sci. Rep., 10.","DOI":"10.1038\/s41598-020-65828-x"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1763","DOI":"10.1101\/gad.12.12.1763","article-title":"Beta-cell-specific inactivation of the mouse Ipf1\/Pdx1 gene results in loss of the beta-cell phenotype and maturity onset diabetes","volume":"12","author":"Ahlgren","year":"1998","journal-title":"Genes. Devel."},{"key":"ref_21","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 \u03b1 and subsequently \u03b2 cells","volume":"138","author":"Collombat","year":"2009","journal-title":"Cell"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.cell.2016.11.002","article-title":"Long-term GABA administration induces alpha cell-mediated beta-like cell neogenesis","volume":"168","author":"Vieira","year":"2017","journal-title":"Cell"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.1038\/nature08894","article-title":"Conversion of adult pancreatic \u03b1-cells to \u03b2-cells after extreme \u03b2-cell loss","volume":"464","author":"Thorel","year":"2010","journal-title":"Nature"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1177\/1535370220972686","article-title":"Increased alpha and beta cell mass during mouse pregnancy is not dependent on transdifferentiation","volume":"246","author":"Szlapinski","year":"2021","journal-title":"Exp. Biol. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1677\/joe.0.1650093","article-title":"Islet loss and alpha cell expansion in type 1 diabetes induced by multiple low-dose streptozotocin administration in mice","volume":"165","author":"Li","year":"2000","journal-title":"J. Endocrinol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1002\/biof.1938","article-title":"Taurine rescues pancreatic beta-cell stress by stimulating alpha-cell transdifferentiation","volume":"49","author":"Sarnobat","year":"2023","journal-title":"Biofactors"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1159\/000179062","article-title":"Influence of age on the sensitivity of the rat to streptozotocin","volume":"11","author":"Masiello","year":"1979","journal-title":"Horm. Res."},{"key":"ref_28","first-page":"8054073","article-title":"Improving the reliability and utility of streptozotocin-induced rat diabetic model","volume":"2018","author":"Garyantes","year":"2018","journal-title":"J. Diab. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1055\/s-2007-984471","article-title":"Circadian and age-dependent expression patterns of GLUT2 and glucokinase in the pancreatic beta-cell of diabetic and nondiabetic rats","volume":"39","author":"Frese","year":"2007","journal-title":"Horm. Metab. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2994","DOI":"10.1210\/endo.139.6.6042","article-title":"Apoptosis in the pancreatic islet cells of the neonatal rat is associated with a reduced expression of insulin-like growth factor II that may act as a survival factor","volume":"139","author":"Petrik","year":"1998","journal-title":"Endocrinology"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2337\/diabetes.49.1.1","article-title":"Neonatal beta-cell apoptosis: A trigger for autoimmune diabetes?","volume":"49","author":"Trudeau","year":"2000","journal-title":"Diabetes"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"111719","DOI":"10.1016\/j.celrep.2022.111719","article-title":"Glycemic control releases regenerative potential of pancreatic beta cells blocked by severe hyperglycemia","volume":"41","author":"Hija","year":"2022","journal-title":"Cell Rep."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Dobson, J.R., and Jacobson, D.A. (2024). Disrupted endoplasmic reticulum Ca2+ handling: A har\u03b2inger of \u03b2-cell failure. Biology, 13.","DOI":"10.3390\/biology13060379"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"5685","DOI":"10.1074\/jbc.RA120.012721","article-title":"The endoplasmic reticulum and calcium homeostasis in pancreatic beta cells","volume":"295","author":"Zhang","year":"2020","journal-title":"J. Biol. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"4142","DOI":"10.1038\/s41467-022-31829-9","article-title":"ZnT8 loss-of-function accelerates functional maturation of hESC-derived beta cells and resists metabolic stress in diabetes","volume":"13","author":"Ma","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1518","DOI":"10.1210\/endo-103-4-1518","article-title":"Sex differences in the multiple-dose streptozotocin model of diabetes","volume":"103","author":"Rossini","year":"1978","journal-title":"Endocrinology"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Kim, B., Kim, Y.Y., Nguyen, P.T.T., Nam, H., and Suh, J.G. (2020). Sex differences in glucose metabolism of streptozotocin-induced diabetes inbred mice (C57BL\/6J). Appl. Biol. Chem., 63.","DOI":"10.1186\/s13765-020-00547-5"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e230174","DOI":"10.1530\/JOE-23-0174","article-title":"Sex-based impact of pancreatic islet stressors in GluCreERT2\/Rosa26-eYFP mice","volume":"259","author":"Tanday","year":"2023","journal-title":"J. Endocrinol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"4735","DOI":"10.1074\/jbc.M117.805069","article-title":"Estrogen receptor \u03b1 protects pancreatic \u03b2-cells from apoptosis by preserving mitochondrial function and suppressing endoplasmic reticulum stress","volume":"293","author":"Zhou","year":"2018","journal-title":"J. Biol. Chem."},{"key":"ref_40","first-page":"E254","article-title":"Investigating the protective effects of estrogen on \u03b2-cell health and the progression of hyperglycemia-induced atherosclerosis. American journal of physiology","volume":"323","author":"Wood","year":"2022","journal-title":"Endocrinol. Metab."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1172\/JCI119172","article-title":"Leptin accelerates the onset of puberty in normal female mice","volume":"99","author":"Ahima","year":"1997","journal-title":"J. Clin. Investig."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1210\/en.2015-1793","article-title":"Activin enhances alpha- to beta-cell transdifferentiation as a source for beta-cells in male FSTL3 knockout mice","volume":"157","author":"Brown","year":"2016","journal-title":"Endocrinology"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"van der Meulen, T., Xie, R., Kelly, O.G., Vale, W.W., Sander, M., and Huising, M.O. (2012). Urocortin 3 marks mature human primary and embryonic stem cell-derived pancreatic alpha and beta cells. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0052181"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1007\/s00125-011-2344-9","article-title":"Immunohistochemical characterisation of cells co-producing insulin and glucagon in the developing human pancreas","volume":"55","author":"Riedel","year":"2012","journal-title":"Diabetologia"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"e982949","DOI":"10.4161\/19382014.2014.982949","article-title":"Ultrastructural and immunohistochemical analysis of the 8-20 week human fetal pancreas","volume":"6","author":"Riopel","year":"2014","journal-title":"Islets"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.stem.2019.11.011","article-title":"Circadian entrainment triggers maturation of human in vitro islets","volume":"26","author":"Donaghey","year":"2020","journal-title":"Cell Stem Cell"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3628","DOI":"10.1210\/jc.2016-2496","article-title":"Increased frequency of hormone negative and polyhormonal endocrine cells in lean individuals with type 2 diabetes","volume":"101","author":"Dhawan","year":"2016","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1210\/jc.2015-2802","article-title":"Beta cell glucose sensitivity is linked to insulin\/glucagon bihormonal cells in nondiabetic humans","volume":"101","author":"Mezza","year":"2015","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"7621","DOI":"10.3390\/cimb46070453","article-title":"Targeting \u03b2-cell plasticity: A promising approach for diabetes treatment","volume":"46","author":"Gojani","year":"2024","journal-title":"Curr. Issues Mol. Biol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2137","DOI":"10.2337\/db07-1631","article-title":"PANIC-ATTAC: A mouse model for inducible and reversible beta-cell ablation","volume":"57","author":"Wang","year":"2008","journal-title":"Diabetes"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1016\/j.molmet.2016.05.001","article-title":"Autonomous interconversion between adult pancreatic \u03b1-cells and \u03b2-cells after differential metabolic challenges","volume":"5","author":"Ye","year":"2016","journal-title":"Mol. Metab."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.1007\/s00592-024-02295-0","article-title":"Extra-islet cells expressing insulin or glucagon in the pancreas of young organ donors","volume":"61","author":"Granlund","year":"2024","journal-title":"Acta Diabetol."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Mathisen, A.F., Larsen, U., Kavli, N., Unger, L., Daian, L.M., Vacaru, A.M., Vacaru, A.M., Herrera, P.L., Ghila, L., and Chera, S. (2024). Moderate beta-cell ablation triggers synergic compensatory mechanisms even in the absence of overt metabolic disruption. Commun. Biol., 7.","DOI":"10.1038\/s42003-024-06527-5"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1407","DOI":"10.1242\/dev.117911","article-title":"Glucagon is essential for alpha cell transdifferentiation and beta cell neogenesis","volume":"142","author":"Ye","year":"2015","journal-title":"Development"},{"key":"ref_55","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 \u03b2-cell regeneration","volume":"2","author":"Kilimnik","year":"2010","journal-title":"Islets"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"S73","DOI":"10.1016\/S1262-3636(08)73398-6","article-title":"GLP-1 receptor signaling: Effects on pancreatic beta-cell proliferation and survival","volume":"34","author":"Buteau","year":"2008","journal-title":"Diabetes Metab."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2583047","DOI":"10.1155\/2019\/2583047","article-title":"A new way for beta cell neogenesis: Transdifferentiation from alpha cells Induced by glucagon-like peptide 1","volume":"2019","author":"Zhang","year":"2019","journal-title":"J. Diabetes Res."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"e141851","DOI":"10.1172\/jci.insight.141851","article-title":"GLP-1 receptor signaling increases PCSK1 and \u03b2 cell features in human \u03b1 cells","volume":"6","author":"Saikia","year":"2021","journal-title":"JCI Insight"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2601","DOI":"10.2337\/db18-0155","article-title":"Glucagon-like peptide 1 increases \u03b2-cell regeneration by promoting \u03b1- to \u03b2-cell transdifferentiation","volume":"67","author":"Lee","year":"2018","journal-title":"Diabetes"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"170349","DOI":"10.1016\/j.peptides.2020.170349","article-title":"Glucagon receptor antagonism promotes the production of gut proglucagon-derived peptides in diabetic mice","volume":"131","author":"Lang","year":"2020","journal-title":"Peptides"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1111\/dom.12721","article-title":"\u03b2-Cell replacement as a treatment for type 1 diabetes: An overview of possible cell sources and current axes of research","volume":"18","author":"Vieira","year":"2016","journal-title":"Diabetes Obes. Metab."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.cell.2016.11.010","article-title":"Artemisinins target GABA(A) receptor signaling and impair alpha cell identity","volume":"168","author":"Li","year":"2017","journal-title":"Cell"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Szlapinski, S., Strutt, B., Deane, M., Arany, E., Bennett, J., and Hill, D.J. (2021). Acetone ingestion mimics a fasting state to improve glucose tolerance in a mouse model of gestational hyperglycemia. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222312914"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"100982","DOI":"10.1016\/j.molmet.2020.100982","article-title":"Characterizing pancreatic \u03b2-cell heterogeneity in the streptozotocin model by single-cell transcriptomic analysis","volume":"37","author":"Feng","year":"2020","journal-title":"Mol. Metab."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1203\/PDR.0b013e3181e17c90","article-title":"The effects of low protein during gestation on mouse pancreatic development and beta cell regeneration","volume":"68","author":"Cox","year":"2010","journal-title":"Pediatr. Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1080\/19382014.2021.1987827","article-title":"Comparative analysis of reconstructed architectures from mice and human islets","volume":"14","year":"2022","journal-title":"Islets"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1202","DOI":"10.2337\/db09-1177","article-title":"Unique arrangement of alpha- and beta-cells in human islets of Langerhans","volume":"59","author":"Bosco","year":"2010","journal-title":"Diabetes"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"2399","DOI":"10.1007\/s00125-017-4425-x","article-title":"Gcg CreERT2 knockin mice as a tool for genetic manipulation in pancreatic alpha cells","volume":"60","author":"Shiota","year":"2017","journal-title":"Diabetologia"},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Srinivas, S., Watanabe, T., Lin, C.S., William, C.M., Tanabe, Y., Jessell, T.M., and Costantini, F. (2001). Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus. BMC Dev. Biol., 1.","DOI":"10.1186\/1471-213X-1-4"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"pdb-rot077966","DOI":"10.1101\/pdb.prot077966","article-title":"Tamoxifen administration to mice","volume":"2015","author":"Whitfield","year":"2015","journal-title":"Cold Spring Harbor Prot."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1016\/j.molmet.2017.01.003","article-title":"High-fidelity glucagon-CreER mouse line generated by CRISPR-Cas9 assisted gene targeting","volume":"6","author":"Ackermann","year":"2017","journal-title":"Mol. Metab."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1007\/s13340-015-0212-4","article-title":"Glucose area under the curve during oral glucose tolerance test as an index of glucose intolerance","volume":"7","author":"Sakaguchi","year":"2015","journal-title":"Diabetol. Int."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"2655","DOI":"10.1529\/biophysj.107.104125","article-title":"Size distribution of mouse Langerhans islets","volume":"93","author":"Jo","year":"2007","journal-title":"Biophys. J."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1152\/physrev.00008.2017","article-title":"Pancreatic \u03b2-cell electrical activity and insulin secretion: Of mice and men","volume":"98","author":"Rorsman","year":"2018","journal-title":"Physiol. Rev."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1038\/nmeth.2089","article-title":"NIH Image to ImageJ: 25 years of image analysis","volume":"9","author":"Schneider","year":"2012","journal-title":"Nat. Methods"},{"key":"ref_76","unstructured":"Phansalkar, N., More, S., Sabale, A., and Joshi, M. (2011, January 10\u201312). Adaptive local thresholding for detection of nuclei in diversity stained cytology images. Proceedings of the International Conference on Communications and Signal Processing, Kerala, India."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/20\/11152\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:15:04Z","timestamp":1760112904000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/20\/11152"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,17]]},"references-count":76,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2024,10]]}},"alternative-id":["ijms252011152"],"URL":"https:\/\/doi.org\/10.3390\/ijms252011152","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,10,17]]}}}