{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T12:27:07Z","timestamp":1785414427857,"version":"3.56.0"},"reference-count":40,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T00:00:00Z","timestamp":1782172800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000090","name":"Congressionally Directed Medical Research Programs (CDMRP), Department of Defence, USA","doi-asserted-by":"publisher","award":["W81XWH-22-1-0017"],"award-info":[{"award-number":["W81XWH-22-1-0017"]}],"id":[{"id":"10.13039\/100000090","id-type":"DOI","asserted-by":"publisher"}]},{"award":["W81XWH-22-1-0017"],"award-info":[{"award-number":["W81XWH-22-1-0017"]}],"id":[{"id":"https:\/\/ror.org\/03g2zjp07","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Variants in the human PAX4 gene are associated with both monogenic and complex forms of diabetes, yet their pathogenic effects remain difficult to define in models that accurately mimic human islet architecture and neonatal metabolic transitions. Here, we created a porcine PAX4 loss-of-function model using CRISPR\/Cas9 cytidine deaminase base editing to introduce a premature stop codon in the PAX4 coding sequence. PAX4 knockout piglets developed severe hyperglycemia within 24 h of birth, followed by rapid postnatal clinical deterioration and uniform death by day 3. Biochemical analysis showed significant diabetic decompensation, including electrolyte imbalances, hyperosmolality, azotemia, dyslipidemia, and metabolic acidosis. Gross and histological examinations revealed notable pancreatic hypoplasia with preservation of exocrine tissue. Single-nucleus RNA sequencing and immunohistochemistry demonstrated an almost complete loss of insulin- and somatostatin-producing \u03b2- and \u03b4-cells, respectively, with relative preservation of glucagon-expressing \u03b1-cells. Overall, these results establish PAX4 as a crucial factor in pancreatic endocrine development and postnatal glucose regulation in a large-animal model. This platform offers a human-relevant system for studying diabetes-associated PAX4 variants and for testing regenerative and gene-based therapies for insulin-deficient diabetes.<\/jats:p>","DOI":"10.3390\/ijms27135651","type":"journal-article","created":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T03:09:17Z","timestamp":1782270557000},"page":"5651","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Functional Inactivation of PAX4 Results in Disrupted Endocrine Pancreas Development and Neonatal Diabetes in Pigs"],"prefix":"10.3390","volume":"27","author":[{"given":"Ravikanthreddy","family":"Poonooru","sequence":"first","affiliation":[{"name":"Division of Animal Sciences, University of Missouri, 920 E. Campus Drive, 105 ASRC, Columbia, MO 65211, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ki-Eun","family":"Park","sequence":"additional","affiliation":[{"name":"Division of Animal Sciences, University of Missouri, 920 E. Campus Drive, 105 ASRC, Columbia, MO 65211, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda","family":"Schmelzle","sequence":"additional","affiliation":[{"name":"Division of Animal Sciences, University of Missouri, 920 E. Campus Drive, 105 ASRC, Columbia, MO 65211, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7288-7750","authenticated-orcid":false,"given":"Bhanu P.","family":"Telugu","sequence":"additional","affiliation":[{"name":"Division of Animal Sciences, University of Missouri, 920 E. Campus Drive, 105 ASRC, Columbia, MO 65211, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,23]]},"reference":[{"key":"ref_1","first-page":"23","article-title":"Basic Concepts of Diabetics Mellitus for the Welfare of General Patients","volume":"2","author":"Devajit","year":"2023","journal-title":"Stud. Soc. Sci. Humanit."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1093\/ndt\/gfaf177","article-title":"IDF Diabetes Atlas 11th edition 2025: Global prevalence and projections for 2050","volume":"41","author":"Duncan","year":"2025","journal-title":"Nephrol. Dial. 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