Intricate interplay between ORMDL3, ER stress, and autophagy in the diabetic intestine

Diabetes mellitus (DM) and inflammatory bowel disease (IBD) are prevalent chronic conditions characterized by immune dysregulation and metabolic disturbances. The global incidence of both diseases is increasing, with mounting evidence highlighting the critical role of intestinal barrier dysfunction and inflammation in their pathogenesis. Although genome-wide association studies (GWAS) have implicated the orosomucoid-like protein 3 (ORMDL3), also known as ORMDL sphingolipid biosynthesis regulator 3, in susceptibility to both IBD and DM, its precise role in diabetes-associated intestinal alterations remains poorly defined. In this study, we examined intestinal changes in a Sprague Dawley rat model of experimentally induced diabetes, focusing on ORMDL3 expression and its relationship with endoplasmic reticulum (ER) stress and autophagy. Diabetic rats exhibited pronounced histopathological alterations, including villous atrophy, goblet cell depletion, inflammatory cell infiltration, and lipofuscin accumulation, indicative of compromised intestinal barrier integrity and chronic low-grade inflammation. ORMDL3 expression was significantly elevated at both the transcript and protein levels. A strong positive correlation between ORMDL3 and ATF6 suggests the activation of ER stress pathways within the diabetic intestine. Additionally, increased expression of autophagy-related genes, including NOD2, ULK1, and ATG4, was particularly evident in female diabetic rats, indicating a sex-specific modulation of autophagic responses to hyperglycemic stress. The observed molecular and histological changes reflect key mechanisms implicated in IBD, potentially indicating shared pathways driving both diabetic and inflammatory intestinal disorders. Collectively, our findings underscore a complex interplay between hyperglycemia-induced ER stress and autophagy in the diabetic intestine, positioning ORMDL3 as an orchestrator in the underlying pathogenesis and a potential therapeutic target for IBDs.