Glabridin Alleviates Metabolic Disorders in Diet‐Induced Diabetic Mice

Glabridin (GLD) is a flavonoid derived from licorice. This study aims to evaluate GLD's therapeutic potential in ameliorating type 2 diabetes mellitus (T2DM) and elucidate its underlying mechanisms of action. A T2DM model was established using male C57BL/6J mice fed a high-fat, high-glucose diet. GLD was administered via intraperitoneal injection at doses of 10, 20, and 30 mg/kg BW, with MET (200 mg/kg BW) as a positive control. Fasting blood glucose levels, glucose tolerance, insulin tolerance, pyruvate tolerance, and serum parameters were analyzed, along with key markers of glycogen synthesis, gluconeogenesis, lipid metabolism, mitochondrial function, and endoplasmic reticulum (ER) stress. GLD significantly lowered blood glucose levels in the diabetic mice. It suppressed gluconeogenesis by inhibiting PEPCK and G6P, while promoting glycogen synthesis by activating GCK and inhibiting GSK-3β. Additionally, GLD enhanced insulin signaling by increasing IRS1 and IRS2 levels and promoting AKT phosphorylation, thereby improving insulin sensitivity. In lipid metabolism, GLD reduced hepatic steatosis and lipid accumulation by downregulating lipogenesis-related genes (SREBP1c, FAS, ACC1, and SCD1) and upregulating lipolysis-related genes (PPARα and LCAD). In energy metabolism, GLD increased mitochondrial membrane potential, reduced reactive oxygen species levels, and enhanced the expression of genes associated with mitophagy (PINK1 and Parkin) and mitochondrial biogenesis (PGC-1α, SIRT1, and TFAM). Moreover, GLD mitigated ER stress by decreasing GRP78 and CHOP levels, suppressing PERK phosphorylation, and inhibiting key stress response genes. GLD improves insulin sensitivity and exerts antidiabetic effects by ameliorating metabolic disorders, supporting its potential as a therapeutic agent for T2DM.