## 3 Pharmacological Properties of GP
### Hypoglycemic Effect  
Diabetes mellitus is a chronic metabolic disease caused by genetic and environmental factors for a long time, which has become the third category of diseases seriously endangering human health. At present, the existing oral hypoglycemic drugs in China, such as metformin and sulfonylurea, could cause serious adverse effects [114]. The long-term use of insulin will lead to decreased insulin receptor sensitivity of the body, insulin resistance, and finally aggravate the disease. Therefore, it was urgent to seek new, safe, and effective oral hypoglycemic drugs. In recent years, natural medicine has attracted more and more attention because of its long-lasting effect and fewer side effects. Researchers had made great progress in searching for anti-diabetic components from traditional Chinese medicine resources, including GP. At present, the research on anti-diabetes mainly focused on GPS, GPP, and crude extracts (Table 6) [115]. GPS, as the main active ingredient, had been reported for its hypoglycemic effects. Phanoside, a novel dammarane-type saponin with a molecular mass of 914.5 Da, was isolated from ethanol extract, and four stereoisomers differing in configurations at positions 21 and 23 were identified, each of which was found to stimulate insulin release from isolated rat pancreatic islets [122]. Phanoside-induced insulin release might be mediated via the K-ATP channel and L-type Ca\({}^{2+}\) channel [123]. However, it could dose-dependently stimulate insulin release at both low and high glucose levels (3.3 mM and 16.7 mM), suggesting that its insulin secretory effect was not glucose-dependent, which could potentially induce severe hypoglycemia and was similar to that of the well-known antidiabetic drug sulfonylurea. Gylongiposide I, which was identified in screening the active components of GP, was  
different from Phanoside and displayed unique abilities to stimulate insulin release at high glucose levels (16.7 mM) but limited effects at a low glucose concentration (3.3 mM) [124]. In vitro studies had shown [125] that GP exerted stronger inhibitory \(\alpha\)-glucosidase activity with IC50 (42.8 \(\upmu\)g/mL) as compared with acarbose (IC50 at 53.9 \(\upmu\)g/mL). Based on this, GP could be developed as a novel anti-diabetic drug taken to reduce postprandial blood glucose. Compared with the traditional oral hypoglycemic drugs that had no obvious protective effect on the kidney, GPS displayed a protective effect on the kidney while lowering blood glucose a well as significantly improving renal tubule congestion and renal tubule epithelial edema in diabetic mice [116]. AMPK was a key regulator of glucose and lipid metabolism. Activated AMPK decreases blood glucose levels by increasing the glucose uptake and glycogen synthesis, stimulating the translocation of glucose transporter 4 (GluT4) to the cell membrane as well as up-regulating GluT4 expression. Therefore, AMPK activators were considered promising candidates for type-2 diabetes mellitus. Two novel dammarane-type saponins named damulin A and B isolated from GP could stimulate glucose uptake via AMPK activation in L6 myotube cells [117]. Protein tyrosine phosphatase 1B (PTP1B), a negative regulator of the insulin-signaling pathway, could inhibit or terminate the insulin signaling pathway transduction and further regulate negatively insulin sensitivity. Therefore, inhibition of PTP1B was an effective therapeutic approach to treatment type-2 diabetes mellitus. In a recent study conducted by [PERSON] et al. that aimed to find the hypoglycemic active components in GP, 12 compounds and their hydrolysis products were isolated and identified from GPS, and 11 compounds exerted inhibitory activity against PTP1B [126]; these results were in line with previous studies [127]. It was reported that insulin sensitivity could be affected by inflammation.