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In this study, we investigated the effects of sustained hyperglycemia on intestinal inflammation, endoplasmic reticulum (ER) stress, and autophagy in a translational porcine model of diabetes. Diabetes was induced in Yucatan mini pigs using a high-fat, high-carbohydrate\/fructose diet (HFHFD) followed by streptozotocin administration. Intestinal tissues from the terminal ileum and sigmoid colon were analyzed using histological evaluation, quantitative real-time PCR, and immunohistochemistry. Histological analysis revealed structural alterations in diabetic animals, including villous degeneration, crypt depletion, goblet-cell loss, and increased inflammatory-cell infiltration. Gene expression analysis revealed significant upregulation of inflammatory mediators (NF-\u03baB, TNF-\u03b1, IL-6, IL-1\u03b2), inflammasome components (NLRP3), and macrophage markers (CD68, CD86, CD163). In parallel, ER stress-related genes (ORMDL3, ATF6) and autophagy-associated genes (NOD2, ULK1, ATG4a) were significantly elevated in diabetic pigs. At the protein level, increased expression of ER stress markers was confirmed in both intestinal regions, while autophagy-related proteins showed less consistent changes and did not fully reflect the observed transcriptional patterns, suggesting a potential disconnect between transcriptional activation and downstream autophagy-related protein expression under diabetic conditions. Chronic hyperglycemia is associated with intestinal inflammation and disruption of cellular stress pathways, including ER stress and autophagy, in a porcine model. These findings provide mechanistic insight into how chronic hyperglycemia contributes to intestinal dysfunction through coordinated alterations in inflammatory signaling, ER stress, and autophagy pathways, identifying these processes as potential targets for therapeutic intervention in diabetes-associated gastrointestinal disease.<\/jats:p>","DOI":"10.1007\/s11010-026-05659-y","type":"journal-article","created":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T07:48:39Z","timestamp":1784706519000},"page":"4241-4254","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Metabolically induced intestinal inflammation: the role of ER stress and autophagy in a porcine model of diabetes"],"prefix":"10.1007","volume":"481","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-7649-186X","authenticated-orcid":false,"given":"Ugljesa","family":"Malicevic","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6643-1781","authenticated-orcid":false,"given":"Ranko","family":"Skrbic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5445-0013","authenticated-orcid":false,"given":"Devendra K.","family":"Agrawal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,22]]},"reference":[{"issue":"4","key":"5659_CR1","doi-asserted-by":"publisher","first-page":"616","DOI":"10.1053\/j.gastro.2016.07.008","volume":"151","author":"AC Luissint","year":"2016","unstructured":"Luissint AC, Parkos CA, Nusrat A (2016) Inflammation and the intestinal barrier: leukocyte\u2013epithelial cell interactions, cell junction remodeling, and mucosal repair. 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