In high fat diet-induced obese mice, the flavonoid derivative of tiliroside, Fla-CN, has antihyperglycemic effects, can improve insulin sensitivity, ameliorate metabolic lipid disorders, and benefits certain disorders characterized by insulin resistance. Fla-CN is a novel lead compound to discovery anti-diabetic and anti-obesity drugs. The present study reported the optimization of Fla-CN to obtain a new derivative, 10b, which has improved glucose consumption at the nanomolar level (EC50 = 0.3 nM) in insulin resistant (IR) HepG2 cells. 10b also increased the glycogen content and glucose uptake, and concurrently inhibited gluconeogenesis in HepG2 cells. Western blotting showed that 10b markedly enhanced the phosphorylation of AMPK (AMP-activated protein kinase) and AS160 (protein kinase B substrate of 160 kDa) and reduced the levels of the gluconeogenesis key enzymes PEPCK (phosphoenolpyruvate carboxykinase) and G6P (glucose 6-phosphatase) in HepG2 cells. The potential molecular mechanism of 10b may be activation of the AMPK/AS160 and AMPK/PEPCK/G6P pathways. We concluded that 10b might be a valuable candidate to discover anti-diabetic drugs.
Keywords: AMPK pathway; Flavonoids; Glucose metabolism disorders; Ratio of AMP/ATP; Structure-activity relationship.
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