Combination of Metformin and Magnesium Citrate Reduces TNF-α, NF-κB p65, IL-6, CD4, and MMP-9 Expressions in Diabetic Model Rats

Abstract

BACKGROUND: Diabetes, which causes various complications, involves pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), nuclear factor kappa B p65 (NF-κB p65), interleukin-6 (IL-6), cluster of differentiation 4 (CD4), and matrix metalloproteinase-9 (MMP-9). Magnesium has demonstrated anti-diabetic properties, but its anti-inflammatory effects in preventing cardiovascular complications remain unclear. This study aimed to evaluate the anti-inflammatory effects of magnesium citrate, alone and in combination with metformin, by measuring TNF-α, NF-κB p65, IL-6, CD4, and MMP-9 expression in diabetic model rats. METHODS: Thirty male Wistar rats were divided into five groups: normal control, diabetes control, metformin (treated with 9 mg/200 g/day metformin), magnesium citrate (treated with 3.6 mg/200 g/day magnesium citrate), and combination therapy (treated with 4.5 mg/200 g/day metformin + 1.8 mg/200 g/day magnesium citrate). Diabetes was induced in all groups except the normal control group using streptozotocin (STZ) and nicotinamide (NA). TNF-α, NF-κB p65, IL-6, CD4, and MMP-9 expression levels were measured using enzyme-linked immunosorbent assay (ELISA). RESULTS: Significant differences in TNF-α, NF-κB p65, IL-6, CD4, and MMP-9 expression levels were observed across all groups (p<0.001). The combination therapy group demonstrated the most significant reduction in all parameters compared to the diabetic control group (p<0.001) and other therapy groups. Both metformin and magnesium citrate monotherapies showed moderate reductions in cytokine levels but were less effective than combination therapy. CONCLUSION: Combination therapy with metformin and magnesium citrate exhibited the most potent anti-inflammatory effects, significantly reducing TNF-α, NF-κB p65, IL-6, CD4, and MMP-9 expressions in diabetic Wistar rats. This combination has potential as a therapeutic approach for managing diabetes and its complications. KEYWORDS: diabetes mellitus, inflammation, cytokines, metformin, magnesium citrate