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This study aimed to investigate the pancreatic molecular mechanisms involved in cellular stress, inflammation, mitogenesis, and apoptosis in metabolic disease induced by high\u2010fructose diet. Here, we used biochemical, histopathological, Western blot, and immunohistochemistry methods to determine the metabolic and pancreatic alterations in male <jats:italic>Wistar<\/jats:italic> rats fed 20% fructose in drinking water for 15 weeks. High\u2010fructose consumption in rats increased the immunopositivity and protein expression of glucose transporter 2 (GLUT2) and insulin in the pancreatic tissue, in association with abdominal adiposity, hyperglycemia, and hypertriglyceridemia. The expressions of cellular stress markers, glucose\u2010regulated protein\u201078 (GRP78) and PTEN\u2010induced putative kinase 1 (PINK1), were increased in the pancreas. The levels of interleukin (IL)\u20106, nuclear factor kappa B (NF\u03baB), tumor necrosis factor \u03b1 (TNF\u03b1), and IL\u20101\u03b2 and components of the Nod\u2010like receptor protein 3 (NLRP3) inflammasome were elevated. Excess fructose intake stimulated the activation of mitogenic extracellular signal\u2010regulated kinases 1\/2 (ERK1\/2), p38, and c\u2010Jun N\u2010terminal kinase (JNK)1 as well as the apoptotic p53 and Fas pathways in the pancreas of rats. There was also an increase in caspase\u20108 and caspase\u20103 cleavage. Our findings revealed that dietary high\u2010fructose in the pancreas causes hyperinsulinemia due to the upregulation of GLUT2 together with cellular stress and inflammatory markers, thereby stimulates mitogenic mitogen\u2010activated protein kinase (MAPK) and apoptosis pathways, resulting in a complex pathological situation.<\/jats:p>","DOI":"10.1002\/mnfr.70048","type":"journal-article","created":{"date-parts":[[2025,3,30]],"date-time":"2025-03-30T20:48:53Z","timestamp":1743367733000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Excess Fructose Intake Activates Hyperinsulinemia and Mitogenic MAPK Pathways in Association With Cellular Stress, Inflammation, and Apoptosis in the Pancreas of Rats"],"prefix":"10.1002","volume":"69","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3267-2886","authenticated-orcid":false,"given":"Ceren","family":"Guney","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Faculty of Pharmacy Gazi University  Ankara Turkey"},{"name":"Department of Pharmacology, Faculty of Pharmacy D\u00fczce University  D\u00fczce Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5165-5854","authenticated-orcid":false,"given":"Mehmet Eray","family":"Alcigir","sequence":"additional","affiliation":[{"name":"Department of Pathology, Faculty of Veterinary Medicine K\u0131r\u0131kkale University  K\u0131r\u0131kkale Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5432-0304","authenticated-orcid":false,"given":"Fatma","family":"Akar","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Pharmacy Gazi University  Ankara Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,3,28]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.metabol.2018.12.001"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-nutr-062220-025831"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/ijpo.12759"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2020.118235"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.heliyon.2023.e18896"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1080\/10408363.2019.1711360"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.29228\/jrp.357"},{"key":"e_1_2_11_9_1","first-page":"8","author":"Burgos\u2010Moron E.","year":"2019","journal-title":"Journal of Clinical Medicine"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41574-021-00510-4"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-006-0590-z"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature05485"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.52.3.812"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2008-0396"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cca.2012.03.021"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201602089"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00461.2017"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/icb.2014.4"},{"key":"e_1_2_11_19_1","first-page":"10","article-title":"Impact of Conventional and Atypical MAPKs on the Development of Metabolic Diseases","author":"Kassouf T.","year":"2020","journal-title":"Biomolecules"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1530\/JME-15-0146"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1080\/14756366.2018.1477138"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature01137"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.4103\/0971-5916.200887"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2022.976465"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11010-016-2828-5"},{"key":"e_1_2_11_26_1","volume-title":"Manual of Histologic Staining Methods of the Armed Forces Institute of Pathology","author":"Luna L. 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