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This study evaluated the effects of combined rituximab, a B-cell-directed therapy, and exendin-4, a glucagon-like peptide-1 receptor agonist, on \u03b2-cell-related function and metabolic outcomes in experimental type 1 diabetes. Pancreatic islets isolated from NOD-scid mice were used for in vitro assessment of viability, metabolic activity, insulin secretion under high-glucose conditions, and gene expression. Female NOD mice were assigned to control, exendin-4, rituximab, or combination treatment groups and treated for approximately 20 weeks. Combined treatment showed the greatest increases in insulin-related responses in vitro. In vivo, it was associated with more stable fasting blood glucose levels, improved oral glucose tolerance, delayed progression to hyperglycemia, increased circulating insulin and C-peptide levels, and reduced glucagon, HbA1c, and LDL levels. Histological and molecular analyses further demonstrated reduced pancreatic inflammatory damage, reduced apoptosis-associated changes, and increased BrdU- and cytokeratin-18-associated signals within insulin-positive islet regions. These findings support further investigation of combined B-cell-directed and \u03b2-cell-supportive strategies for preserving islet function and delaying disease progression in type 1 diabetes.<\/jats:p>","DOI":"10.3390\/biology15171472","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T01:05:26Z","timestamp":1788224726000},"page":"1472","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Combined Exendin-4 and Rituximab Treatment Improves \u03b2-Cell Function and Delays Disease Progression in NOD Mice"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-8103-4529","authenticated-orcid":false,"given":"Yongbin","family":"Wang","sequence":"first","affiliation":[{"name":"School of Health Science and Engineering, University of Shanghai for Science and Technology, South Campus of Jun Gong Road, Yangpu District, Shanghai 200093, 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