Abstract
Given the multifactorial nature of diabetes and limitations of conventional monotherapies, combination therapies involving natural bioactive compounds offer a complementary strategy for more effective management. This study investigated the antidiabetic potential of chlorogenic acid (CGA) and gallic acid (GA), individually and in combination, using in silico, in vitro and in vivo approaches. Pharmacokinetic and molecular docking analyses were conducted to assess drug-likeness and target interactions. Antioxidant activity and α-amylase inhibition were evaluated in vitro, while therapeutic efficacy was assessed in streptozotocin-nicotinamide-induced (STZ-NA) diabetic mice. In silico analysis revealed favorable ADMET profiles and strong binding affinities of CGA and GA to key diabetic targets, including α-amylase, DPP4, PPARγ, TNF-α and IL-6, surpassing metformin. The combination showed enhanced antioxidant and α-amylase enzyme inhibitory activity compared to individual compounds. In vivo findings using an STZ-NA-induced type II diabetic mouse model demonstrated a significant reduction in blood glucose (p < 0.0001) and improvement in lipid profile upon oral supplementation. Both compounds showed a decline in gene expression of TNF-α, TGF-β and IL-6 while enhancing the level of PPARγ. Additionally, hepatic markers (ALT, AST and ALP) were significantly reduced (p < 0.05), suggesting hepatoprotective effects. Histological analysis revealed restoration of pancreatic and liver tissues. Notably, the combination of both compounds exhibited a greater antidiabetic effect than the individual compounds and the standard antidiabetic drug (metformin). Given their favorable pharmacokinetic profile, affinity for multiple antidiabetic targets and synergistic antidiabetic activities both in vitro and in vivo, CGA-GA combination may offer a safer alternative to current therapies. These findings warrant further investigation of this combination strategy for more effective diabetes management.