{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,19]],"date-time":"2026-01-19T00:14:01Z","timestamp":1768781641690,"version":"3.49.0"},"posted":{"date-parts":[[2023,6,14]]},"group-title":"Physiology","reference-count":53,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,6,26]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Reduced glutathione (GSH) is an abundant antioxidant that regulates intracellular redox homeostasis by scavenging reactive oxygen species (ROS). Glutamate-cysteine ligase catalytic (GCLC) subunit is the rate-limiting step in GSH biosynthesis. Using the\n                  <jats:italic>Pax6-Cre<\/jats:italic>\n                  driver mouse line, we deleted expression of the\n                  <jats:italic>Gclc<\/jats:italic>\n                  gene in all pancreatic endocrine progenitor cells. Intriguingly,\n                  <jats:italic>Gclc<\/jats:italic>\n                  knockout (KO) mice, following weaning, exhibited an age-related, progressive diabetes phenotype, manifested as strikingly increased blood glucose and decreased plasma insulin levels. This severe diabetes trait is preceded by pathologic changes in islet of weanling mice.\n                  <jats:italic>Gclc<\/jats:italic>\n                  KO weanlings showed progressive abnormalities in pancreatic morphology including: islet-specific cellular vacuolization, decreased islet-cell mass, and alterations in islet hormone expression. Islets from newly-weaned mice displayed impaired glucose-stimulated insulin secretion, decreased insulin hormone gene expression, oxidative stress, and increased markers of cellular senescence. Our results suggest that GSH biosynthesis is essential for normal development of the mouse pancreatic islet, and that protection from oxidative stress-induced cellular senescence might prevent abnormal islet-cell damage during embryogenesis.\n                <\/jats:p>","DOI":"10.1101\/2023.06.13.544855","type":"posted-content","created":{"date-parts":[[2023,6,14]],"date-time":"2023-06-14T12:35:12Z","timestamp":1686746112000},"source":"Crossref","is-referenced-by-count":3,"title":["Endocrine pancreas-specific\n                  <i>Gclc<\/i>\n                  gene deletion causes a severe diabetes phenotype"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1451-7735","authenticated-orcid":false,"given":"Emily A.","family":"Davidson","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1960-419X","authenticated-orcid":false,"given":"Ying","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Surendra","family":"Singh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0417-1400","authenticated-orcid":false,"given":"David J.","family":"Orlicky","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0983-2762","authenticated-orcid":false,"given":"Brian","family":"Thompson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yewei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2302-8914","authenticated-orcid":false,"given":"Georgia","family":"Charkoftaki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tristan A.","family":"Furnary","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rebecca L.","family":"Cardone","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard G.","family":"Kibbey","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Colin T.","family":"Shearn","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel W.","family":"Nebert","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David C.","family":"Thompson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2552-3118","authenticated-orcid":false,"given":"Vasilis","family":"Vasiliou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2023063009451041000_2023.06.13.544855v3.1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M504604200"},{"issue":"18","key":"2023063009451041000_2023.06.13.544855v3.2","doi-asserted-by":"crossref","first-page":"3691","DOI":"10.1016\/j.molcel.2021.08.018","article-title":"Redox metabolism: ROS as specific molecular regulators of cell signaling and function","volume":"81","year":"2021","journal-title":"Mol Cell"},{"key":"2023063009451041000_2023.06.13.544855v3.3","doi-asserted-by":"publisher","DOI":"10.1155\/2014\/360438"},{"key":"2023063009451041000_2023.06.13.544855v3.4","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0000690"},{"key":"2023063009451041000_2023.06.13.544855v3.5","doi-asserted-by":"publisher","DOI":"10.1007\/s00204-015-1520-y"},{"key":"2023063009451041000_2023.06.13.544855v3.6","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0907-12.2012"},{"key":"2023063009451041000_2023.06.13.544855v3.7","doi-asserted-by":"crossref","unstructured":"Cadet, J. and J.R. Wagner , DNA base damage by reactive oxygen species, oxidizing agents, and UV radiation. Cold Spring Harb Perspect Biol, 2013. 5(2).","DOI":"10.1101\/cshperspect.a012559"},{"key":"2023063009451041000_2023.06.13.544855v3.8","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2004.02.013"},{"key":"2023063009451041000_2023.06.13.544855v3.9","doi-asserted-by":"publisher","DOI":"10.1023\/A:1009616228304"},{"key":"2023063009451041000_2023.06.13.544855v3.10","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2007.12.017"},{"key":"2023063009451041000_2023.06.13.544855v3.11","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.2000.3930"},{"key":"2023063009451041000_2023.06.13.544855v3.12","doi-asserted-by":"publisher","DOI":"10.1002\/hep.21635"},{"issue":"7","key":"2023063009451041000_2023.06.13.544855v3.13","doi-asserted-by":"crossref","first-page":"1376","DOI":"10.1093\/hmg\/ddx040","article-title":"Gclc deficiency in mouse CNS causes mitochondrial damage and neurodegeneration","volume":"26","year":"2017","journal-title":"Hum Mol Genet"},{"issue":"6","key":"2023063009451041000_2023.06.13.544855v3.14","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1016\/j.immuni.2017.06.009","article-title":"Glutathione Primes T Cell Metabolism for Inflammation","volume":"46","year":"2017","journal-title":"Immunity"},{"key":"2023063009451041000_2023.06.13.544855v3.15","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/j.jtos.2021.08.010","article-title":"Impaired GSH biosynthesis disrupts eye development, lens morphogenesis and PAX6 function","volume":"22","year":"2021","journal-title":"Ocul Surf"},{"key":"2023063009451041000_2023.06.13.544855v3.16","doi-asserted-by":"publisher","DOI":"10.1101\/gad.184000"},{"key":"2023063009451041000_2023.06.13.544855v3.17","doi-asserted-by":"publisher","DOI":"10.1101\/gad.11.13.1662"},{"key":"2023063009451041000_2023.06.13.544855v3.18","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2004.01.040"},{"issue":"3","key":"2023063009451041000_2023.06.13.544855v3.19","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1016\/j.celrep.2019.06.058","article-title":"Mitochondrial GTP Links Nutrient Sensing to \u03b2 Cell Health, Mitochondrial Morphology, and Insulin Secretion Independent of OxPhos","volume":"28","year":"2019","journal-title":"Cell reports"},{"issue":"1","key":"2023063009451041000_2023.06.13.544855v3.20","doi-asserted-by":"crossref","first-page":"47","DOI":"10.4103\/0019-509X.12345","article-title":"Affordable image analysis using NIH Image\/ImageJ","volume":"41","year":"2004","journal-title":"Indian J Cancer"},{"issue":"7","key":"2023063009451041000_2023.06.13.544855v3.21","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","year":"2012","journal-title":"Nature methods"},{"key":"2023063009451041000_2023.06.13.544855v3.22","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2089"},{"key":"2023063009451041000_2023.06.13.544855v3.23","doi-asserted-by":"publisher","DOI":"10.1006\/meth.2001.1262"},{"key":"2023063009451041000_2023.06.13.544855v3.24","doi-asserted-by":"publisher","DOI":"10.1023\/A:1020884312053"},{"key":"2023063009451041000_2023.06.13.544855v3.25","doi-asserted-by":"publisher","DOI":"10.3390\/metabo10020071"},{"key":"2023063009451041000_2023.06.13.544855v3.26","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.05.015"},{"key":"2023063009451041000_2023.06.13.544855v3.27","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2005.04.030"},{"key":"2023063009451041000_2023.06.13.544855v3.28","doi-asserted-by":"publisher","DOI":"10.2337\/db09-1151"},{"key":"2023063009451041000_2023.06.13.544855v3.29","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.10150"},{"key":"2023063009451041000_2023.06.13.544855v3.30","doi-asserted-by":"publisher","DOI":"10.1080\/10715760802317663"},{"key":"2023063009451041000_2023.06.13.544855v3.31","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2012.4553"},{"issue":"3","key":"2023063009451041000_2023.06.13.544855v3.32","first-page":"G199","article-title":"Postnatal development: coordination of feeding, digestion, and metabolism","volume":"241","year":"1981","journal-title":"Am J Physiol"},{"key":"2023063009451041000_2023.06.13.544855v3.33","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.02.058"},{"issue":"5 Pt 1","key":"2023063009451041000_2023.06.13.544855v3.34","first-page":"E890","article-title":"Glucose-induced insulin release in islets of young rats: time-dependent potentiation and effects of 2-bromostearate","volume":"263","year":"1992","journal-title":"Am J Physiol"},{"key":"2023063009451041000_2023.06.13.544855v3.35","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-010-2036-x"},{"issue":"8","key":"2023063009451041000_2023.06.13.544855v3.36","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1089\/ars.2014.6135","article-title":"NADPH Oxidase-Dependent Reactive Oxygen Species Stimulate \u03b2-Cell Regeneration Through Differentiation of Endocrine Progenitors in Murine Pancreas","volume":"24","year":"2016","journal-title":"Antioxid Redox Signal"},{"key":"2023063009451041000_2023.06.13.544855v3.37","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2017.7342"},{"key":"2023063009451041000_2023.06.13.544855v3.38","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.12.010"},{"key":"2023063009451041000_2023.06.13.544855v3.39","doi-asserted-by":"crossref","first-page":"101107","DOI":"10.1016\/j.redox.2019.101107","article-title":"NRF2 plays a critical role in mitigating lipid peroxidation and ferroptosis","volume":"23","year":"2019","journal-title":"Redox Biology"},{"key":"2023063009451041000_2023.06.13.544855v3.40","doi-asserted-by":"publisher","DOI":"10.1515\/BC.2009.033"},{"issue":"8","key":"2023063009451041000_2023.06.13.544855v3.41","doi-asserted-by":"crossref","first-page":"110037","DOI":"10.1016\/j.celrep.2021.110037","article-title":"Glucose metabolism and pyruvate carboxylase enhance glutathione synthesis and restrict oxidative stress in pancreatic islets","volume":"37","year":"2021","journal-title":"Cell Rep"},{"issue":"1","key":"2023063009451041000_2023.06.13.544855v3.42","doi-asserted-by":"crossref","first-page":"3994","DOI":"10.1038\/s41598-017-03873-9","article-title":"Distinct Levels of Reactive Oxygen Species Coordinate Metabolic Activity with Beta-cell Mass Plasticity","volume":"7","year":"2017","journal-title":"Scientific Reports"},{"key":"2023063009451041000_2023.06.13.544855v3.43","doi-asserted-by":"publisher","DOI":"10.1038\/s41418-022-00988-z"},{"key":"2023063009451041000_2023.06.13.544855v3.44","doi-asserted-by":"publisher","DOI":"10.3109\/03009734.2016.1154906"},{"key":"2023063009451041000_2023.06.13.544855v3.45","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.05.039"},{"key":"2023063009451041000_2023.06.13.544855v3.46","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201708092"},{"key":"2023063009451041000_2023.06.13.544855v3.47","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.19.3.2109"},{"issue":"7742","key":"2023063009451041000_2023.06.13.544855v3.48","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1038\/s41586-018-0784-9","article-title":"L1 drives IFN in senescent cells and promotes age-associated inflammation","volume":"566","year":"2019","journal-title":"Nature"},{"key":"2023063009451041000_2023.06.13.544855v3.49","doi-asserted-by":"crossref","unstructured":"Alessio, N. , et al., Different Stages of Quiescence, Senescence, and Cell Stress Identified by Molecular Algorithm Based on the Expression of Ki67, RPS6, and Beta-Galactosidase Activity. Int J Mol Sci, 2021. 22(6).","DOI":"10.3390\/ijms22063102"},{"key":"2023063009451041000_2023.06.13.544855v3.50","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-62703-239-1_5"},{"key":"2023063009451041000_2023.06.13.544855v3.51","doi-asserted-by":"publisher","DOI":"10.2337\/db20-0553"},{"issue":"1","key":"2023063009451041000_2023.06.13.544855v3.52","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1186\/s12979-020-00187-9","article-title":"Role of immune cells in the removal of deleterious senescent cells","volume":"17","year":"2020","journal-title":"Immunity & Ageing"},{"key":"2023063009451041000_2023.06.13.544855v3.53","doi-asserted-by":"publisher","DOI":"10.1172\/JCI95148"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2023.06.13.544855","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T04:46:16Z","timestamp":1768452376000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2023.06.13.544855"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,14]]},"references-count":53,"URL":"https:\/\/doi.org\/10.1101\/2023.06.13.544855","relation":{},"subject":[],"published":{"date-parts":[[2023,6,14]]},"subtype":"preprint"}}