## 3 The Role of AMPK in T2 DM
### The Role of AMPK in Skeletal Muscle  
AMPK plays a pivotal role in the regulation of glucose metabolism within skeletal muscle, particularly in the context of T2 DM. In skeletal muscle, which is a major site for glucose disposal, AMPK activation enhances glucose uptake and improves insulin sensitivity, making it a crucial target for T2 DM management. AMPK is activated in response to low-energy states, such as during exercise or caloric restriction, which leads to an increase in the AMP/ATP ratio. Once activated, AMPKpromotes the translocation of glucose transporter 4 (GLUT4) to the cell membrane, facilitating glucose uptake into muscle cells [45]. This mechanism is particularly important in overcoming insulin resistance, a common issue in DM where muscle cells fail to absorb glucose effectively due to impaired insulin signaling. Studies have shown that certain compounds can activate AMPK in skeletal muscle, thereby enhancing glucose uptake. For instance, roesmary extract has been demonstrated to induce AMPK phosphorylation, which increases GLUT4 levels and promotes glucose uptake, even in insulin-resistant muscle cells [46]. Similarly, asprosin, a hormone, has been found to activate AMPK, leading to the upregulation of GLUT4 and increased glucose uptake, highlighting its potential therapeutic effects in T2 DM [47]. Moreover, AMPK activation in skeletal muscle not only increases glucose uptake but also improves glucose metabolism by enhancing mitochondrial biogenesis and fatty acid oxidation. This dual effect helps reduce hyperglycemia and improves overall metabolic health. For example, in experiments with L6 myotubes, the compound promalabaricone B was shown to activate AMPK, leading to increased GLUT4 expression and glucose uptake, offering a protective effect against T2 DM [48]. In addition to GLUT4, AMPK also regulates GLUT1 expression in skeletal muscle, which is another glucose transporter involved in maintaining basal glucose uptake. Compounds like isonymphaeol B and 3\({}^{\prime}\)-geranyl naringenin have been reported to enhance GLUT1 levels through AMPK activation, suggesting their potential as anti-diabetic agents [49]. These findings emphasize the importance of the AMPK/GLUT axis in regulating glucose homeostasis and suggest that targeting this pathway could be beneficial in managing T2 DM. Overall, AMPK acts as a critical energy sensor in skeletal muscle, orchestrating a series of responses that enhance glucose uptake and metabolism, thereby improving insulin sensitivity. This makes AMPK a valuable target for therapeutic strategies aimed at treating or managing T2 DM, particularly in overcoming insulin resistance and enhancing glucose utilization in skeletal muscle. The therapeutic potential of AMPK activators, including natural compounds and pharmacological agents, continues to be a significant area of research for developing effective treatments for T2 DM [50]. The role of AMPK in T2 DM is illustrated in Figure 2.  
Figure 2: The role of AMPK in pancreatic beta cells and skeletal muscle. (**A**) This panel illustrates the role of AMPK in the regulation of insulin secretion within pancreatic beta cells. Under normal conditions, glucose enters the beta cells through glucose transporter 2 (GLUT2), where it undergoes metabolism, leading to an increase in the ATP/ADP ratio. This rise in ATP closes ATPase potassium channels (K_ATPs), resulting in membrane depolarization and the opening of voltage-dependent calcium channels (CaVGICs). The influx of Ca2+ triggers the exocytosis of insulin-containing vesicles. AMPK activity is inhibited in high-glucose conditions, allowing the full engagement of energy-demanding processes necessary for insulin secretion. However, when AMPK activators are present, AMPK may be activated, which can impact the insulin secretion process. (**B**) This panel demonstrates the role of AMPK in skeletal muscle cells, focusing on glucose uptake.