Dose‐Dependent Protective Effects of Agmatine on Sublingual Gland Dysfunction and Pancreatic Damage in Experimental Diabetes: Evidence From Histological, Biochemical, and Immunohistochemical Analyses

Diabetes mellitus (DM) induces endocrine and exocrine dysfunction, including salivary gland impairment. While the sublingual gland (SLG) contributes to saliva production, its involvement in diabetes remains understudied. Agmatine (AGM), a naturally occurring polyamine, exhibits antioxidant and anti-inflammatory properties; however, its protective effects on the SLG and pancreas in diabetes have remained largely uninvestigated. This study introduces new insights into SLG injury in diabetes and the dose-dependent protective benefits of AGM through multi-level analysis. Male Wistar rats were rendered diabetic by a single intraperitoneal STZ injection (65 mg/kg) and treated with either low-dose (40 mg/kg) or high-dose (100 mg/kg) AGM for two weeks. SLGs and the pancreas were analyzed by histological, immunohistochemical, and biochemical methods. Mucin secretion (MUC-5B) was measured, oxidative stress markers and pro-inflammatory cytokines were quantified, and structural changes were evaluated using H&E, Alcian Blue/PAS, and Mallory's trichrome staining. Immunohistochemistry included α-SMA and CK17 for SLG and insulin receptor for the pancreas. STZ-induced diabetes resulted in a substantial reduction in MUC-5B, increased oxidative stress and pro-inflammatory markers, damage to acinar and myoepithelial cells, and injury to pancreatic β-cells. Agmatine administration enhanced these parameters in a dose-dependent manner, with high-dose treatment reinstating mucin secretion, regulating oxidative and inflammatory indicators, and maintaining histological and immunohistochemical integrity in both the sublingual gland and pancreas. AGM confers dose-dependent protection against SLG dysfunction and pancreatic damage in diabetic rats via antioxidant, anti-inflammatory, and cytoprotective mechanisms. These findings highlight the therapeutic potential of AGM in preventing salivary gland dysfunction and maintaining pancreatic function in diabetes.