SGLT2 Inhibition Combined with Zn Supplementation Protects the Liver-Pancreas Axis in Experimental Type 2 Diabetes

Type 2 diabetes mellitus (T2DM) is associated with chronic hyperglycemia, inflammation, and progressive hepatic and pancreatic dysfunction. Although sodium-glucose cotransporter 2 (SGLT2) inhibitors exert metabolic and organ-protective effects, their ability to preserve pancreatic architecture and attenuate diabetes-associated hepatic injury, particularly combined with nutritional interventions, remains insufficiently explored. This study investigated the protective effects of dapagliflozin (DAPA) and empagliflozin (EMPA), alone or combined with zinc (Zn), on hepatic and pancreatic alterations in experimental diabetes. Methods: Diabetes was induced in male Sprague–Dawley rats using streptozotocin (STZ) and high fat diet (HFD). Diabetic animals received DAPA, EMPA, Zn, or SGLT2 inhibitor–Zn combinations for four weeks. Hepatic biochemical parameters, lipid profile, histopathology, pancreatic morphometry, and insulin immunoreactivity were evaluated. Diabetes induced hepatic and pancreatic alterations, including elevated liver injury markers, hepatocellular degeneration, reduced islet number and β-cell density, and diminished insulin immunoreactivity. DAPA and EMPA attenuated these changes, with greater improvements following Zn combination therapy. EMPA + Zn produced the most favorable response, improving hepatic architecture, reducing VCAM-1, ICAM-1, and NF-κB expression, preserving islet morphology, increasing β-cell density, and enhancing insulin immunoreactivity. SGLT2 inhibitors attenuated diabetes-associated hepatic and pancreatic alterations in this experimental model, while Zn supplementation was associated with additional tissue-preserving effects, particularly when combined with EMPA. These findings support further investigation of combined SGLT2 inhibition and Zn supplementation as an experimental approach to diabetes-associated organ injury; however, their clinical relevance remains to be established.