Combined Exendin-4 and Rituximab Treatment Improves β-Cell Function and Delays Disease Progression in NOD Mice

Type 1 diabetes mellitus is characterized by immune-mediated pancreatic β-cell loss and progressive impairment of insulin production. This study evaluated the effects of combined rituximab, a B-cell-directed therapy, and exendin-4, a glucagon-like peptide-1 receptor agonist, on β-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 β-cell-supportive strategies for preserving islet function and delaying disease progression in type 1 diabetes.