Introduction
Type II diabetes mellitus (T2DM) has become a global public health crisis, which poses a great threat to the health and quality of life of people in all countries, especially in developing countries (Moucheraud et al., 2019). T2DM is a chronic metabolic disease characterized by hyperglycemia and insulin resistance and accompanied by a series of clinical syndromes, including diabetic nephropathy (Tao et al., 2019), diabetic retinopathy (Dow et al., 2018; Ren et al., 2019), and cardiovascular complications (Vaidya et al., 2015). The FDA has approved several new drugs for T2DM, such as metformin (Hostalek et al., 2015; Pernicova & Korbonits, 2014), rosiglitazone (Han et al., 2016) and Dapagliflozin (Scheen, 2017; Vivian, 2015). Unfortunately, although the use of these drugs can lower blood glucose to nearly normal levels, mortality from cardiovascular disease in diabetes either increased or was not affected (Gerstein et al., 2008; Navarro-Perez et al., 2018). Given this, the discovery of new drugs with new targets or specific molecular mechanisms is still of great concern.
Sodium-dependent glucose co-transporters (SGLTs) are solute carriers (SLCs) responsible for glucose (re)absorption (Rives et al., 2017; Wright et al., 2011). SGLTs are encoded by the SLC5A genes, contains multiple isoforms, mostly, SGLT1 and SGLT2. SGLT1 and SGLT2 are expressed in the kidney, and SGLT1 expressed in the small intestine as well (Rieg & Vallon, 2018; Wood & Trayhurn, 2003). Among them, SGLT2 is a high capacity transporter responsible for 90% of glucose reuptake and tissue-specific expressed in the renal tubules of the kidney (Abdul-Ghani et al., 2012; Wang et al., 2017). SGLT2 is a promising target for the treatment of diabetes due to the inhibition on it can reduce the risk of hyperglycemia by decreasing glucose reuptake (Chao & Henry, 2010). Nowadays, eight SGLT2 inhibitors have been approved by the FDA for treating diabetes; they can increase urinary glucose excretion and display anti-hyperglycaemic effects that are primarily independent of insulin (Filippas-Ntekouan et al., 2018; Nauck, 2014; Shyangdan et al., 2016). Moreover, the efficacy and safety of SGLT2 inhibitors, especially in the prevention of cardiovascular diseases, have attracted full attention (Vaduganathan & Butler, 2019). Nevertheless, the SGLT2 inhibitors on the market now are all glycoside compounds, and it is of considerable significance to further study whether we can expand new structure types in this field. For example, finding a novel structure from natural compounds.
Astragalus Membranaceus is used as a traditional Chinese medicine with multiple bioactivities, such as anti-hyperglycemia (Liu et al., 2019), anti-inflammation (Zhou et al., 2017), anti-fibrosis (Shan et al., 2016), and remission of diabetic nephropathy (Liu et al., 2017). Several key ingredients were identified from Astragalus Membranaceus , such as astragaloside IV (AST ), a soluble lanolin alcohol-shaped tetracyclic triterpenoid saponin. AlthoughAST shows a potential for treating T2DM (Zhang et al., 2020), it possesses low bioavailability (Cheng & Wei, 2014; Ran et al., 2016). Instead, its aglycone cycloastragalol (CAG ) exhibits good bioavailability sinceCAG is the primary metabolite of AST in vivovia intestinal bacterial biotransformation (Szabo, 2014; Zhou et al., 2012). However, the effects of CAG on treating diabetes mellitus has not been reported so far. Therefore, the first purpose in the present study is to evaluate the therapeutic effect of CAG on T2DM from the perspective of the pathological feature by using the ZDF diabetic rat model. The second goal was to investigate the molecular patterns of CAG in the performance of these effects. These studies will provide some new ideas for the discovery of new anti-T2DM drugs with SGLT2 inhibitory activity.