As early as the 1960s, McIntyre and Elrick et al. found that oral glucose had a significantly higher stimulatory effect on insulin secretion than intravenous injections, an additional effect known as the “enterotropic effect,” and further studies by Perley et al. Perley et al. further showed that this “enterotrophic effect” produced more than 50% of the total insulin after feeding. In 1986, Nauck et al. found that the effect of intestinal glucagon was diminished in patients with type 2 diabetes, suggesting that abnormalities in the intestinal glucagon system may contribute to the pathogenesis of type 2 diabetes. With the development of cellular and molecular biology, the mystery of enteroglucagon has been slowly unveiled. Studies have confirmed that enteroglucagon is an intestinal-derived hormone in human body, which can promote insulin secretion and exert glucose concentration-dependent hypoglycemic effects after feeding. Enterostatin is mainly composed of GLP-1 and glucose-dependent insulin-releasing peptide (GIP), of which GLP-1 plays a more important role in the development of type 2 diabetes. GLP-1 is expressed by the glucagonogen gene, whose main expression product is glucagon in islet alpha cells, while in L cells of the intestinal mucosa, prohormone convertase (PC1) shears glucagonogen to its carboxy-terminal peptide chain sequence, GLP-1. GLP-1 has 2 bioactive forms, GLP-1 (7-37) and GLP- 1 (7-36) amide, which differ by only one amino acid sequence, and about 80% of the circulating activity of GLP-1 is derived from GLP-1 (7-36) amide. What are the biological properties of GLP-1? How does it exert hypoglycemic effects? Studies have demonstrated that enteroglucagon lowers blood glucose by promoting insulin secretion from pancreatic β-cells and reducing glucagon secretion from pancreatic α-cells in a glucose concentration-dependent manner. In normal people, after a meal, enteroglucagon starts to be secreted, which in turn promotes insulin secretion to reduce postprandial blood glucose fluctuations. However, in patients with type 2 diabetes, the “enteroglucagon effect” is impaired, which is mainly manifested as a decrease in the increase of GLP-1 concentration after meals compared with normal people, but its role in promoting insulin secretion and lowering blood glucose is not significantly impaired, so GLP-1 and its analogues can be an important target for the treatment of type 2 diabetes. GLP-1 exerts its hypoglycemic effects mainly through the following aspects: GLP-1 has a protective effect on β cells GLP-1 can act on pancreatic β cells, promote the transcription of insulin genes, insulin synthesis and secretion, and stimulate the proliferation and differentiation of pancreatic β cells, inhibit pancreatic β cell apoptosis and increase the number of pancreatic β cells. In addition, GLP-1 can also act on islet α cells to strongly inhibit the release of glucagon and on islet δ cells to promote the secretion of growth inhibitory hormone, which in turn can participate in inhibiting the secretion of glucagon as a paracrine hormone. Studies have demonstrated that GLP-1 can significantly improve the glycemic condition of type 2 diabetes animal models or patients through various mechanisms, among which the role of promoting the regeneration and repair of pancreatic β-cells and increasing the number of pancreatic β-cells is particularly significant. GLP-1 has glucose concentration-dependent hypoglycemic effect As an enteric-derived hormone, GLP-1 is released into the blood only when stimulated by nutrients, especially carbohydrates, and its proinsulin secretory effect is glucose concentration-dependent. Nauck et al. studied 10 patients with type 2 diabetes mellitus with poor glycemic control and gave them GLP-1 or placebo, respectively, in the fasting state , the results showed that the patients’ insulin and C-peptide levels increased significantly and glucagon levels decreased significantly after GLP-1 infusion, and fasting blood glucose levels became normal after 4 hours. After the blood glucose level was normalized, although the infusion of GLP-1 continued, the patient’s insulin level did not increase again, and the blood glucose level remained stable and did not decrease further. This indicates that GLP-1 has glucose concentration-dependent hypoglycemic effect, that is, GLP-1 only exerts hypoglycemic effect when the blood glucose level is elevated, and does not further decrease when the blood glucose level is normal. GLP-1 has the potential to cause severe hypoglycemia in patients. GLP-1 has a weight-lowering effect Zander et al. showed that after 6 weeks of treatment with GLP-1, 20 patients with type 2 diabetes in the study lost an average of 1.9 kg. GLP-1 has been shown to reduce body weight through multiple pathways, including inhibition of gastrointestinal motility and gastric secretion, inhibition of appetite and feeding, and delayed gastric emptying. In addition, GLP-1 also acts on the central nervous system (especially the hypothalamus), resulting in a feeling of fullness and decreased appetite. In addition, GLP-1 has many other biological properties and functions. For example, GLP-1 may exert hypolipidemic and antihypertensive effects, which may have a protective effect on the cardiovascular system; it may also act centrally to enhance learning and memory functions and protect the nerves. What are the problems facing GLP-1? What are the future directions? However, there are problems in applying GLP-1 in the clinic, that is, GLP-1 produced by human body is very easy to be degraded by dipeptidyl peptidase IV (DPP-IV) in the body, and its plasma half-life is less than 2 minutes, so it must be continuously injected intravenously or continuously injected subcutaneously to produce efficacy, which greatly limits the clinical application of GLP-1. To address this challenge, scholars have proposed two options: the development of GLP-1 analogs that retain the efficacy of GLP-1 while resisting degradation; and the development of DPP-IV inhibitors that protect the body’s own secreted GLP-1 from degradation. At present, some progress has been made in both of these studies. It is believed that as people study the GLP-1 signaling system more deeply, more new action targets will be discovered, and thus more novel drugs for the treatment of diabetes will be developed for the benefit of diabetic patients.