## 4 Plant-Derived Flavonoids That Induce AMPK Activation
These beneficial effects were primarily mediated through the activation of AMPK\(\alpha\)2, which influenced various signaling pathways, including the inhibition of the MAPK pathway and activation of the IRS1/PI3K/Akt pathway. In another study, [PERSON] and colleagues investigated the effects of quercetin, a citrus flavonoid, on glucose uptake in skeletal muscle cells (L6 myotubes) [62]. They discovered that quercetin enhances glucose uptake via the AMPK pathway and its downstream target p38 MAPK, independent of the insulin signaling pathway. This mechanism, which also involves an increase in intracellular calcium and a transient change in mitochondrial membrane potential, highlights quercetin's potential as a promising compound for managing T2 DM by improving insulin resistance through an AMPK-mediated pathway. [PERSON] and colleagues explored the effects of the soy isoflavone genistein on adipocyte differentiation and its relation to AMPK activation in 3T3-L1 cells [63]. They found that genistein significantly inhibited adipocyte differentiation and induced apoptosis in mature adipocytes through the rapid activation of AMPK, suggesting that AMPK is a critical target in the anti-obesity effects of genistein. Derrone, an isoflavone isolated from _Tetracer scandens_, was found to significantly enhance glucose uptake in L6 myotubes [64]. This effect is associated with the activation of AMPK and the overexpression of the glucose transport proteins GLUT4 and GLUT1. In addition to promoting glucose uptake, derrone also inhibited protein tyrosine phosphatase 1B (PTP1B) activity, a known negative regulator of insulin signaling, with no reported toxicity to muscle cells. These findings suggest that derrone holds potential therapeutic value for the treatment of T2 DM by improving glucose metabolism. Alpiumiumisoflavone, another isoflavone from _Tetracer scandens_, demonstrated significant glucose uptake activity in L6 myotubes under both basal and insulin-stimulated conditions [64]. This compound also activated AMPK and increased the expression of the glucose transport proteins GLUT4 and GLUT1. Additionally, alpiumiumisoflavone inhibited PTP1B activity, which plays a role in regulating insulin signaling, without exhibiting toxicity to muscle cells. These properties make alpiumisoflavone a promising candidate for the treatment of T2 DM by enhancing glucose metabolism and insulin sensitivity. [PERSON] and colleagues investigated the anti-diabetic effects of aspalathin, a primary polyphenol found in rooibos extract, with a focus on its molecular mechanisms in glucose metabolism and oxidative stress reduction [65]. Aspalathin was shown to improve glucose uptake by activating AMPK and promoting GLUT4 translocation in L6 myotubes while reducing the ROS levels in pancreatic \(\beta\) cells. In vivo studies using ob/ob mice demonstrated that aspalathin significantly lowered their fasting blood glucose levels, improved glucose intolerance, and downregulated hepatic genes involved in gluconeogenesis and lipogenesis, highlighting its potential as an anti-diabetic agent. The research findings on flavonoids regulating AMPK activation in T2 DM are summarized in Table 1.