Forsythoside A attenuates metabolic dysfunction in type 2 diabetic mice by inhibiting the MAPK and activating the Nrf2 signalling pathways

Forsythoside A, a natural phenylethanoid glycoside extracted from the weeping forsythia (Forsythia suspensa), exhibits a wide range of pharmacological activity, including antibacterial, hepatoprotective, antioxidant, neuroprotective, antiviral, and anti-inflammatory. The aim of this study was to determine its anti-hyperglycaemic and antioxidative effects in a diabetic mouse model (created by administering high-fat diet alongside successive low doses of streptozotocin) by measuring fasting blood glucose levels, body weight, food and water intake, oxidative stress, and histopathological changes. Diabetic mice received either forsythoside A (30 or 60 mg/kg bw) or metformin (150 mg/kg) as standard type 2 diabetes medication for comparison. After four weeks of administration, forsythoside A significantly increased body weight and reduced food and water intake at both doses, while the higher, 60 mg/kg dose also significantly reduced fasting blood glucose and had a similar effect on all these parameters as metformin. The higher, 60 mg/kg dose also had similar antioxidative effects as metformin in lowering malondialdehyde (MDA) and reactive oxygen species (ROS) and in elevating the antioxidant superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) levels. Moreover, at 60 mg/kg forsythoside A attenuated lipid accumulation in diabetic mice by elevating high-density lipoprotein cholesterol (HDL-C) and lowering total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C), showing comparable effect to metformin. Similar improvements were observed by histopathological changes in the liver. Forsythoside A also lowered insulin levels in diabetic mice by up-regulating p-IRS-1 and inhibited the mitogen-activated protein kinase (MAPK) pathway by lowering the expressions of the p-p38 and p-JNK proteins. At the same time, it promoted the Nrf2 pathway by increasing Nrf2 and HO-1 expressions relative to untreated diabetic mice. In conclusion, forsythoside A demonstrated therapeutic effects akin to those of 150 mg/kg metformin and may be a promising candidate for clinical application.