The Effects of Zinc Supplementation Combined with Metformin on Liver Lipid Metabolism in Mice with Type 2 Diabetes

Hepatic complications, particularly non-alcoholic fatty liver disease, are highly prevalent in T2DM and are driven by dysregulated lipid metabolism and inflammation. Current therapies, including metformin, offer limited hepatic protection. This study investigated whether zinc supplementation synergizes with metformin can alleviate T2DM-associated liver damage. A T2DM mouse model was established using a high-fat high-sugar diet combined with low-dose streptozotocin, followed by a 6-week intervention with metformin, zinc sulfate, or their combination. The combined therapy most effectively restored hepatic zinc homeostasis and reduced serum liver injury markers, including ALT, AST, and ALP, while profoundly ameliorating hepatic steatosis, inflammatory infiltration, and glycogen loss. Mechanistically, co-treatment markedly suppressed lipogenesis by downregulating SREBP-1c, ACC, FASN expression and enzyme activities, while enhancing fatty acid oxidation through PPARα/CPT-1 activation and inhibiting lipid transport by reducing MTTP Protein and mRNA levels. Furthermore, the combination synergistically attenuated oxidative stress by lowering ROS and MDA levels and elevating antioxidant defenses, including SOD, GSH, and CAT activities, alongside metallothionein upregulation. As excessive ROS is a well-established trigger of NF-κB activation, this redox restoration translated into potent anti-inflammatory effects, in which the combination lowered the p-IκBα/IκBα ratio and rebalanced pro- and anti-inflammatory cytokines, surpassing the effect of zinc alone. These findings demonstrate that zinc and metformin synergistically reprogram hepatic lipid metabolism and reinforce antioxidant and anti-inflammatory defenses, offering a promising multi-targeted therapeutic strategy for T2DM-related liver injury.