## 1 Introduction  
T2 DM is a chronic metabolic disorder characterized by insulin resistance and impaired insulin secretion, leading to elevated blood glucose levels [1; 2]. It is one of the most prevalent chronic diseases worldwide, contributing to significant morbidity and mortality due to its complications, including cardiovascular disease, neuropathy, retinopathy, and nephropathy. The management of T2 DM often involves lifestyle modifications, such as diet and exercise, as well as pharmacological interventions. Several classes of drugs have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of T2 DM [3; 4], each targeting different aspects of glucose regulation. These include alpha-glucosidase inhibitors, which slow down carbohydrate absorption in the intestines; sulfonylurea, which stimulate insulin secretion from pancreatic \(\beta\) cells; GLP-1 receptor agonists, which enhance insulin secretion and suppress glucagon release; dipeptidyl peptidase-4 (DPP4) inhibitors, which prolong the action of incretin hormones; AMPK activators, which improve insulin sensitivity; PPAR-\(\gamma\) activators, which enhance glucose uptake in the adipose tissue; and SGLT2 inhibitors, which promote glucose excretion through urine. Among these, AMPK plays a critical role in maintaining cellular energy homeostasis. AMPK is activated in response to low-energy states, such as during exercise or caloric restriction, and functions to restore energy balance by promoting ATP-generating processes while inhibiting ATP-consuming pathways. In the context of T2 DM, AMPK activation improves insulin sensitivity, enhances glucose uptake in muscle and adipose tissue, and reduces hepatic glucose production. Metformin, one of the most widely prescribed drugs for T2 DM, exerts its glucose-lowering effects primarily through the activation of AMPK, highlighting the therapeutic potential of targeting this pathway [5,6]. The advantages of AMPK activators include their ability to target multiple aspects of glucose metabolism and their potential benefits in reducing inflammation and oxidative stress, both of which are associated with T2 DM. AMPK not only regulates energy homeostasis but also plays a critical role in modulating inflammation and oxidative stress, both of which are implicated in the pathogenesis of T2 DM. AMPK activation inhibits the activity of nuclear factor-\(\kappa\)B (NF-\(\kappa\)B), a key transcription factor involved in the inflammatory response, thereby reducing the production of pro-inflammatory cytokines such as TNF-\(\alpha\) and IL-6 [7,8]. In addition, AMPK plays a critical role in regulating oxidative stress, particularly in the context of fatty acid metabolism. Studies have shown that chronic exposure to fatty acids, such as palmitate, can inhibit AMPK activity in tissues like the liver and skeletal muscle, independent of AMP levels [9,10]. This inhibition is mediated through pathways involving PP2A, which is activated by the ceramide synthesis induced by fatty acids. Reduced AMPK activity under these conditions contributes to a decrease in fat oxidative capacity, which has been observed in T2 DM and in rodent models fed a high-fat diet [11]. These anti-inflammatory and antioxidant effects of AMPK suggest that its activation could have significant therapeutic benefits in mitigating the chronic low-grade inflammation and oxidative stress associated with T2 DM. To understand the potential role of natural compounds, particularly flavonoids, in T2 DM management better, it is essential to explore their ability to modulate AMPK activation. Flavonoids, as natural AMPK activators, have been shown to influence both glucose metabolism and oxidative stress regulation. This transition highlights the growing interest in these compounds as complementary therapies for T2 DM, providing a bridge between traditional pharmacotherapy and emerging natural treatments.