{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T05:21:42Z","timestamp":1782796902657,"version":"3.54.5"},"reference-count":36,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2023,4,22]],"date-time":"2023-04-22T00:00:00Z","timestamp":1682121600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"The National Key R&amp;D Program of China","award":["2021YFA0805903"],"award-info":[{"award-number":["2021YFA0805903"]}]},{"name":"The National Key R&amp;D Program of China","award":["32070535"],"award-info":[{"award-number":["32070535"]}]},{"name":"The National Key R&amp;D Program of China","award":["ASTIP-IAS05"],"award-info":[{"award-number":["ASTIP-IAS05"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["2021YFA0805903"],"award-info":[{"award-number":["2021YFA0805903"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32070535"],"award-info":[{"award-number":["32070535"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["ASTIP-IAS05"],"award-info":[{"award-number":["ASTIP-IAS05"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"The Agricultural Science and Technology Innovation Program","award":["2021YFA0805903"],"award-info":[{"award-number":["2021YFA0805903"]}]},{"name":"The Agricultural Science and Technology Innovation Program","award":["32070535"],"award-info":[{"award-number":["32070535"]}]},{"name":"The Agricultural Science and Technology Innovation Program","award":["ASTIP-IAS05"],"award-info":[{"award-number":["ASTIP-IAS05"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Diabetes poses a significant threat to human health. Exocrine pancreatic dysfunction is related to diabetes, but the exact mechanism is not fully understood. This study aimed to describe the pathological phenotype and pathological mechanisms of the pancreas of transgenic pigs (PIGinH11) that was constructed in our laboratory and to compare it with humans. We established diabetes-susceptible transgenic pigs and subjected them to high-fat and high-sucrose dietary interventions. The damage to the pancreatic endocrine and exocrine was evaluated using histopathology and the involved molecular mechanisms were analyzed using single-nucleus RNA-sequencing (SnRNA-seq). Compared to wild-type (WT) pigs, PIGinH11 pigs showed similar pathological manifestations to type 2 diabetes patients, such as insulin deficiency, fatty deposition, inflammatory infiltration, fibrosis tissue necrosis, double positive cells, endoplasmic reticulum (ER) and mitochondria damage. SnRNA-seq analysis revealed 16 clusters and cell-type-specific gene expression characterization in the pig pancreas. Notably, clusters of Ainar-M and Endocrine-U were observed at the intermediate state between the exocrine and endocrine pancreas. Beta cells of the PIGinH11 group demonstrated the dysfunction with insulin produced and secret decreased and ER stress. Moreover, like clinic patients, acinar cells expressed fewer digestive enzymes and showed organelle damage. We hypothesize that TXNIP that is upregulated by high glucose might play an important role in the dysfunction of endocrine to exocrine cells in PIGinH11 pigs.<\/jats:p>","DOI":"10.3390\/ijms24097701","type":"journal-article","created":{"date-parts":[[2023,4,24]],"date-time":"2023-04-24T04:01:23Z","timestamp":1682308883000},"page":"7701","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["SnRNA-Seq of Pancreas Revealed the Dysfunction of Endocrine and Exocrine Cells in Transgenic Pigs with Prediabetes"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9725-8117","authenticated-orcid":false,"given":"Huanqi","family":"Peng","sequence":"first","affiliation":[{"name":"State Key Laboratory of Animal Nutrition, Ministry of Agriculture Key Laboratory of Animal Genetics Breeding and Reproduction, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaiyi","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Animal Nutrition, Ministry of Agriculture Key Laboratory of Animal Genetics Breeding and Reproduction, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiakun","family":"Miao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Animal Nutrition, Ministry of Agriculture Key Laboratory of Animal Genetics Breeding and Reproduction, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Yang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Animal Nutrition, Ministry of Agriculture Key Laboratory of Animal Genetics Breeding and Reproduction, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuang","family":"Xu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Animal Nutrition, Ministry of Agriculture Key Laboratory of Animal Genetics Breeding and Reproduction, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianwen","family":"Wu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Animal Nutrition, Ministry of Agriculture Key Laboratory of Animal Genetics Breeding and Reproduction, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cong","family":"Tao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Animal Nutrition, Ministry of Agriculture Key Laboratory of Animal Genetics Breeding and Reproduction, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanfang","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Animal Nutrition, Ministry of Agriculture Key Laboratory of Animal Genetics Breeding and Reproduction, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1511-2286","authenticated-orcid":false,"given":"Shulin","family":"Yang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Animal Nutrition, Ministry of Agriculture Key Laboratory of Animal Genetics Breeding and Reproduction, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Galicia-Garcia, U., Benito-Vicente, A., Jebari, S., Larrea-Sebal, A., Siddiqi, H., Uribe, K.B., Ostolaza, H., and Martin, C. (2020). Pathophysiology of type 2 diabetes mellitus. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21176275"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"109119","DOI":"10.1016\/j.diabres.2021.109119","article-title":"IDF Diabetes Atlas: Global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045","volume":"183","author":"Sun","year":"2022","journal-title":"Diabetes Res. Clin. Pr."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1172\/JCI7231","article-title":"The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus","volume":"104","author":"Weyer","year":"1999","journal-title":"J. Clin. Investig."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1016\/j.pan.2018.05.006","article-title":"Exocrine pancreatic insufficiency in type 1 and type 2 diabetes mellitus: Do we need to treat it? A systematic review","volume":"18","author":"Zsori","year":"2018","journal-title":"Pancreatology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1007\/s11892-020-01304-0","article-title":"Exocrine pancreatic insufficiency in type 1 and type 2 diabetes","volume":"20","author":"Radlinger","year":"2020","journal-title":"Curr. Diabetes Rep."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1016\/j.cmet.2016.08.018","article-title":"RNA sequencing of single human islet cells reveals type 2 diabetes genes","volume":"24","author":"Xin","year":"2016","journal-title":"Cell Metab."},{"key":"ref_7","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":"ref_8","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1016\/j.cels.2016.08.011","article-title":"A single-cell transcriptomic map of the human and mouse pancreas reveals inter- and intra-cell population structure","volume":"3","author":"Baron","year":"2016","journal-title":"Cell Syst."},{"key":"ref_9","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":"ref_10","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1101\/gr.212720.116","article-title":"Single-cell transcriptomes identify human islet cell signatures and reveal cell-type-specific expression changes in type 2 diabetes","volume":"27","author":"Lawlor","year":"2017","journal-title":"Genome Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1330","DOI":"10.1053\/j.gastro.2020.11.010","article-title":"Single-nucleus and in situ RNA-sequencing reveal cell topographies in the human pancreas","volume":"160","author":"Tosti","year":"2021","journal-title":"Gastroenterology"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Mao, X., Mao, S., Wang, L., Jiang, H., Deng, S., Wang, Y., Ye, J., Li, Z., Zou, W., and Liao, Z. (2022). Single-cell transcriptomic analysis of the mouse pancreas: Characteristic features of pancreatic ductal cells in chronic pancreatitis. Genes, 13.","DOI":"10.3390\/genes13061015"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1038\/s41574-018-0132-z","article-title":"Modelling the endocrine pancreas in health and disease","volume":"15","author":"Bakhti","year":"2019","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"11745","DOI":"10.1073\/pnas.1708420114","article-title":"Favorable outcome of experimental islet xenotransplantation without immunosuppression in a nonhuman primate model of diabetes","volume":"114","author":"Ludwig","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1007\/s00441-019-03158-9","article-title":"Porcine models for studying complications and organ crosstalk in diabetes mellitus","volume":"380","author":"Renner","year":"2020","journal-title":"Cell Tissue Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"690069","DOI":"10.3389\/fimmu.2021.690069","article-title":"CD8+ T cells involved in metabolic inflammation in visceral adipose tissue and liver of transgenic pigs","volume":"12","author":"Zhang","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1097\/MPA.0000000000000349","article-title":"Long-term high-fat high-sucrose diet promotes enlarged islets and beta-cell damage by oxidative stress in Bama Minipigs","volume":"44","author":"Zhao","year":"2015","journal-title":"Pancreas"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Benner, C., van der Meulen, T., Caceres, E., Tigyi, K., Donaldson, C.J., and Huising, M.O. (2014). The transcriptional landscape of mouse beta cells compared to human beta cells reveals notable species differences in long non-coding RNA and protein-coding gene expression. BMC Genom., 15.","DOI":"10.1186\/1471-2164-15-620"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1002\/path.4655","article-title":"Incretin actions and consequences of incretin-based therapies: Lessons from complementary animal models","volume":"238","author":"Renner","year":"2016","journal-title":"J. Pathol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1016\/j.tcb.2004.03.008","article-title":"LRH-1: An orphan nuclear receptor involved in development, metabolism and steroidogenesis","volume":"14","author":"Fayard","year":"2004","journal-title":"Trends Cell Biol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Masini, M., Marselli, L., Himpe, E., Martino, L., Bugliani, M., Suleiman, M., Boggi, U., Filipponi, F., Occhipinti, M., and Bouwens, L. (2017). Co-localization of acinar markers and insulin in pancreatic cells of subjects with type 2 diabetes. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0179398"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1007\/s11892-019-1196-4","article-title":"The beta cell in type 2 diabetes","volume":"19","author":"Christensen","year":"2019","journal-title":"Curr. Diabetes Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3305","DOI":"10.1172\/JCI65390","article-title":"Inactivation of specific beta cell transcription factors in type 2 diabetes","volume":"123","author":"Guo","year":"2013","journal-title":"J. Clin. Investig."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1146\/annurev-biochem-072909-095555","article-title":"Endoplasmic reticulum stress and type 2 diabetes","volume":"81","author":"Back","year":"2012","journal-title":"Annu. Rev. Biochem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1861","DOI":"10.1242\/jcs.00408","article-title":"The unfolded protein response","volume":"116","author":"Liu","year":"2003","journal-title":"J. Cell Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"39609","DOI":"10.1074\/jbc.M507426200","article-title":"WFS1 is a novel component of the unfolded protein response and maintains homeostasis of the endoplasmic reticulum in pancreatic beta-cells","volume":"280","author":"Fonseca","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Von Burstin, J., Reichert, M., Wescott, M.P., and Rustgi, A.K. (2010). The pancreatic and duodenal homeobox protein PDX-1 regulates the ductal specific keratin 19 through the degradation of MEIS1 and DNA binding. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0012311"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"605","DOI":"10.2337\/db13-0909","article-title":"Nrf2 protects pancreatic beta-cells from oxidative and nitrosative stress in diabetic model mice","volume":"63","author":"Yagishita","year":"2014","journal-title":"Diabetes"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1002\/jcp.10363","article-title":"Grb10 adapter protein as regulator of insulin-like growth factor receptor signaling","volume":"197","author":"Morrione","year":"2003","journal-title":"J. Cell. Physiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1733","DOI":"10.1007\/s00018-011-0899-8","article-title":"Transthyretin binds to glucose-regulated proteins and is subjected to endocytosis by the pancreatic beta-cell","volume":"69","author":"Dekki","year":"2012","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"17020","DOI":"10.1073\/pnas.0503219102","article-title":"Transthyretin constitutes a functional component in pancreatic beta-cell stimulus-secretion coupling","volume":"102","author":"Refai","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"4215","DOI":"10.1016\/j.febslet.2012.10.025","article-title":"Novel function of transthyretin in pancreatic alpha cells","volume":"586","author":"Su","year":"2012","journal-title":"FEBS Lett."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2138","DOI":"10.1016\/j.bbadis.2019.04.011","article-title":"METTL14 is essential for beta-cell survival and insulin secretion","volume":"1865","author":"Liu","year":"2019","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1111\/j.1559-4572.2008.00024.x","article-title":"Attenuation of endocrine-exocrine pancreatic communication in type 2 diabetes: Pancreatic extracellular matrix ultrastructural abnormalities","volume":"3","author":"Hayden","year":"2008","journal-title":"J. Cardiometab. Syndr."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1016\/j.dsx.2018.11.056","article-title":"Higher levels of thioredoxin interacting protein (TXNIP) in patients with prediabetes compared to obese normoglycemic subjects","volume":"13","author":"Gateva","year":"2019","journal-title":"Diabetes Metab. Syndr. Clin. Res. Rev."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1097\/MED.0000000000000391","article-title":"Diabetes pathogenic mechanisms and potential new therapies based upon a novel target called TXNIP","volume":"25","author":"Thielen","year":"2018","journal-title":"Curr. Opin. Endocrinol. Diabetes Obes."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/9\/7701\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:21:23Z","timestamp":1760124083000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/9\/7701"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,22]]},"references-count":36,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2023,5]]}},"alternative-id":["ijms24097701"],"URL":"https:\/\/doi.org\/10.3390\/ijms24097701","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,22]]}}}