Study on the hypoglycemic effect and mechanism of total alkaloids in Sophora alopecuroides
Diabetes is a group of metabolic diseases characterized by hyperglycemia and ultimate diabetes caused by insulin secretion or insulin function defects. According to the research data, the number of diabetes patients worldwide in 2017 was 851 million, and more than 90% of them were type 2 diabetes (T2DM). T2DM is a complex metabolic disorder characterized by chronic hyperglycemia and varying degrees of insulin resistance (IR). One of the reasons for IR is the dysregulation of the expression and function of glucose transporter 4 (GLUT4) protein. Insulin can stimulate glucose uptake in skeletal muscle, mainly by inducing GLUT4 to move from the intracellular storage location to the plasma membrane. The transport defect of GLUT4 to the cell surface is a key feature of insulin resistance in type 2 diabetes. Therefore, understanding the translocation and expression mechanism of GLUT4 is extremely important for the prevention and treatment of diabetes, which also indicates that it is a potential drug target for diabetes treatment.

Sophora alopecuroides L., as a perennial herbaceous plant of the Sophora genus in the legume family, is widely distributed in various provinces in northwest China and Central Asian countries. It has the effects of clearing heat, detoxifying, dispelling wind, and quenching thirst, and has become a commonly used ethnic medicine in the northwest region. Alkaloids are one of the main chemical components in Sophora alopecuroides, and most chemical and pharmacological studies revolve around the alkaloid components in Sophora alopecuroides. Most of the alkaloids in Sophora alopecuroides belong to quinazolidine alkaloids, which are derivatives of piperidine or pyridine. They have important pharmacological activities and application prospects in anti-inflammatory, antiarrhythmic, anti-tumor, and immune regulation fields. In recent years, studies have shown that total alkaloids extracted from Sophora alopecuroides can have a protective effect on DSS induced colitis mice, alleviate colon damage, prevent intestinal microbiota imbalance, and regulate bile acid metabolism. There are few studies on the total alkaloids of Sophora alopecuroides in diabetes. Therefore, this experiment studies its hypoglycemic effect and related action pathways by extracting the total alkaloids of Sophora alopecuroides, with a view to making full use of the medicinal resource value of Sophora alopecuroides, and providing a new way of thinking for the research of anti diabetes drugs.

Type 2 diabetes (T2DM) is a complex chronic disorder of glucose metabolism, and its incidence rate has been on the rise. At present, the traditional drugs for the treatment of type 2 diabetes are mainly metformin, insulin, sulfonylurea drugs and other oral hypoglycemic drugs, while the new hypoglycemic drugs mainly include glucagon like peptide 1 (GLP-1) receptor agonist, dipeptidyl peptidase 4 inhibitor (DPP-4i), etc. These drugs have more or less side effects. Traditional medicine extracted from natural plants has been proved to be more economical than modern medicine, with good clinical efficacy and relatively few side effects. Therefore, it has become increasingly important to seek relatively safe medicinal plants in the treatment of diabetes.
According to the chemical structure, the main components of traditional Chinese medicine in the treatment of diabetes can be divided into alkaloids, polysaccharides, saponins, flavonoids and other categories. Studies have shown that berberine, a natural alkaloid with significant hypoglycemic activity, can enhance insulin induced glucose uptake and GLUT4 translocation, improving insulin resistance. Piperidine alkaloids, such as piperine alkaloids, activate the upstream pathway of AMPK in L6 cells, thereby phosphorylating AMPK and inducing GLUT4 translocation to the plasma membrane. The total alkaloids of Sophora alopecuroides are alkaloids extracted from the medicinal plant Sophora alopecuroides, which is the general name of a variety of alkaloids including sophocarpine, sophoridine, matrine, etc. The existing research shows that the total alkaloids of Sophora alopecuroides play a certain pharmacological role in anti-tumor, anti microbial, blood pressure lowering, etc., but there are few reports on the study of diabetes. Therefore, this experiment extracted total alkaloids from the aboveground parts of Sophora alopecuroides to study its hypoglycemic effect.
The membrane translocation of GLUT4 cells in the body is influenced by multiple signaling pathways, and an important pathway that affects GLUT4 translocation is the insulin mediated signaling effect pathway. Insulin can bind to the insulin receptor (IR) and regulate glycogen synthesis, glucose uptake, and degradation through the phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) pathway, thereby exerting a regulatory effect on blood glucose. This experiment focused on L6 cells and found no significant change in AKT phosphorylation levels after TASA treatment, indicating that TASA’s hypoglycemic effect does not affect the AKT pathway. Skeletal muscle glucose uptake can also be activated and utilized through the insulin independent AMPK pathway. The mechanism is that AMPK activation causes phosphorylation of TBC1D1, which in turn upregulates the expression of downstream signaling molecule GLUT4 and promotes its transport from the cell to the cell membrane, increasing the absorption and utilization of glucose by the cell. PKC can be divided into various kinase subtypes, including typical PKC (PKC – α PKC-β、PKC-γ) ， The research results of novel PKC (PKC – ε, PKC – η, PKC – θ) and atypical PKC (PKC – Zeta, PKC – λ) show that the use of PKC – Zeta inhibitors inhibits glucose transport under insulin stimulation, while the activation of PKC – Zeta can increase glucose transport. This experiment investigated the effects of TASA on the AMPK and PKC pathways in cells and found that the phosphorylation levels of AMPK and PKC were both elevated, suggesting that TASA may further upregulate GLUT4 expression by activating the AMPK and PKC pathways.
In summary, based on GLUT4 as the target, this experiment focused on the expression and translocation of GLUT4 by TASA. The results showed that TASA could effectively increase glucose uptake and GLUT4 translocation and expression in L6 skeletal muscle cells. Further mechanism studies revealed that TASA promotes GLUT4 protein expression through two signaling pathways, AMPK and PKC. These results reveal the potential of TASA in the treatment of diabetes. However, this study still lacks the relevant experiments of TASA at the living level. Later studies will observe the effect of TASA on the blood glucose and related indicators of the living model through its action on the type 2 diabetes mouse model.