The current work studied the mechanism(s) and ability by which date palm (Phoenix dactylifera L.) fruit extract (DPE) inspired a glucose-lowering impact in rats suffering from diabetes. Forty-eight albino rats were divided into six various experimental treatments after induction of diabetes by intraperitoneal infusion of streptozotocin (45 mg/kg bwt) as follows: normal control, DPE, diabetic control, diabetic glibenclamide (GLI), diabetic DPE, and diabetic GLI plus DPE-treated groups. In animals euthanized after 8 weeks, blood and pancreatic tissue samples were assembled to assess different biochemical and histopathological changes. The expressions of insulin, B cell lymphoma-2 (Bcl-2), and cysteine aspartate-specific protease-3 (caspase-3) in islet β cells were also evaluated using immunohistochemical assessment. Diabetic rats exhibited hyperglycemia; increment of pancreatic malondialdehyde (lipid peroxidation biomarker), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β); and decrement of plasma insulin and pancreatic antioxidants: glutathione, superoxide dismutase, and catalase values. Also, the pancreatic islets exhibited histopathological and morphometric alternations associated with weak positive insulin and Bcl-2 immunoreactivity and strong positive caspase-3 immunoreactivity. DPE and/or GLI, an anti-diabetic drug, improved the pancreatic histoarchitecture and improved β cell function and structure, which increased insulin levels and improved the insulin, Bcl-2, and caspase-3 immunoreactivity in diabetic rats. Nevertheless, the combined DPE and GLI therapy revealed a significant recovery and restoration of β cells' structure and function. The date palm fruit has anti-apoptotic, anti-inflammatory, and antioxidant activities and hypoglycemic effects, which in turn play a pivotal role in avoiding the progression of diabetes mellitus. Moreover, it could potentiate the glucose-lowering activity of anti-diabetic drugs.

Keywords: Cytokines; Date palm (Phoenix dactylifera L.); Diabetes mellitus; Endocrine disruption; Histopathology; Immunohistochemistry.