Isoliquiritigenin alleviates diabetic symptoms via activating AMPK and inhibiting mTORC1 signaling in diet-induced diabetic mice

To determine the effects of isoliquiritigenin (ISL), a chalcone compound isolated from licorice, on type 2 diabetes mellitus (T2DM). 8-week-old C7BL/6 mice were used to establish the T2DM animal model by feeding with high-fat-high-glucose diet (HFD) combined with intraperitoneal injection of streptozotocin. The animals were treated with ISL for 3 weeks. Blood glucose levels, oral glucose tolerance, and insulin tolerance were examined, serum parameters were determined, histologic sections were prepared, activities of enzymes related to glucolipid metabolism were analyzed, and the mitochondrial function was investigated to evaluate effects of ISL on metabolism. The underlying mechanisms of ISL alleviating insulin resistance and restoring metabolic homeostasis were analyzed in HepG2 and INS-1 cells. ISL exhibits a potent activity in relieving hyperglycemia of type 2 diabetic mice. It alleviates insulin resistance and restores metabolic homeostasis without obvious adversary effects in HFD-induced diabetic mice. The metabolic benefits of ISL treatment include promoting hepatic glycogenesis, inhibiting hepatic lipogenesis, reducing hepatic steatosis, and sensitizing insulin signaling. Mechanistically, ISL activates adenosine monophosphate-activated protein kinase (AMPK) and inhibits mammalian target of rapamycin complex 1 (mTORC1). It also suppresses mitochondrial function and reduces ATP production. Our findings demonstrate that ISL is able to significantly reduce blood glucose level and alleviate insulin resistance without obvious side effects in diabetic mice, hence uncovering a great potential of ISL as a novel drug candidate in prevention and treatment of T2DM.