What Is Glucagon-Like Peptide-1?

Glucagon-like peptide-1 (GLP-1) is a brain-gut peptide secreted by ileal endocrine cells and is currently used as a target for type 2 diabetes drugs. Since GLP-1 can inhibit gastric emptying and reduce bowel movements, it helps control food intake and reduce weight. In a prospective placebo-controlled, randomized, double-blind, crossover trial in 19 obese patients, subcutaneous GLP-1 administration increased patient satiety and reduced the average meal intake by 15 %. However, since GLP-1 is a polypeptide, its inability to be administered orally is a major drawback.

Glucagon-like peptide-1

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Glucagon-like peptide-1 (

The most rapid development of this class of drugs is the GLP-1 receptor agonist Exenatide (a 39-amino acid peptide) synthesized by Amylin Pharmaceuticals. Amylin Pharmaceuticals announced in November 2003 the results of three key phase III clinical trials of Exe-natide for type 2 diabetes, all of which reached the end of diabetes treatment. The high-dose group (10 micrograms, 3 times a day) can reduce the patient's weight by an average of 2 kg, which is significant compared with the control group. In April 2005, the FDA approved Exenatide for the treatment of type 2 diabetes.

As early as the 1960s, McIntyre and Elrick et al.

What are the biological characteristics of GLP-1? How to exert the hypoglycemic effect?

Studies have confirmed that incretin promotes insulin secretion from islet cells in a glucose concentration-dependent manner and reduces the secretion of glucagon by islet cells, thereby lowering blood glucose. After meals in normal people, incretins begin to secrete, which in turn promotes insulin secretion to reduce fluctuations in blood sugar after a meal. However, in patients with type 2 diabetes, the "incretin effect" is impaired, and the increase in GLP-1 concentration after meals is less than that in normal people. However, its role in promoting insulin secretion and lowering blood glucose is not. Obviously, GLP-1 and its analogs can be an important target for the treatment of type 2 diabetes.

The following aspects play a hypoglycemic effect. GLP-1 has the effect of protecting cells. GLP-1 can act on islet cells, promote the transcription of insulin genes, insulin synthesis and secretion, and can stimulate the proliferation and differentiation of islet cells and inhibit islets. Beta cell apoptosis, increase the number of islet beta cells [2-5]. In addition, GLP-1 can also act on islet alpha cells, strongly inhibit the release of glucagon, and act on islet delta cells to promote the secretion of somatostatin, which can also participate in the inhibition of pancreatic height as a paracrine hormone Glucagon secretion.

Studies have shown that GLP-1 can significantly improve the blood glucose status of type 2 diabetes animal models or patients through a variety of mechanisms. Among them, it promotes the regeneration and repair of islet cells and increases the number of islet cells. This is type 2 diabetes. The treatment offers a very good prospect.

GLP-1 has a glucose concentration-dependent hypoglycemic effect. As an enteric hormone, GLP-1 is released into the blood under the stimulation of nutrients, especially carbohydrates. Its insulin secretion-promoting effect is glucose concentration-dependent. Nauck [6] studied 10 patients with type 2 diabetes with poor glycemic control and gave patients GLP-1 or placebo on an empty stomach. The results showed that after GLP-1 infusion, the patients' insulin and C-peptide levels increased significantly, glucagon levels significantly decreased, and fasting blood glucose levels became normal after 4 hours. After the blood glucose level is normal, although the GLP-1 infusion is continued, the patient's insulin level will not increase any more, and the blood glucose level will remain stable and will not decrease further. This shows that GLP-1 has a glucose concentration-dependent hypoglycemic effect, that is, GLP-1 can only exert a hypoglycemic effect when the blood glucose level is increased, and it will not be further reduced when the blood glucose level is normal. This glucose concentration-dependent hypoglycemic property of GLP-1 is the basis and guarantee of its safety in clinical application, thereby eliminating people's concerns that existing diabetes treatment drugs and protocols may cause patients with severe hypoglycemia.

GLP-1 has the effect of reducing body weight. Zander et al. [7] showed that after 6 weeks of treatment with GLP-1, the 20 patients with type 2 diabetes who lost weight lost an average of 1.9 kg. Researchers believe that GLP-1 exerts weight-reducing effects through a variety of ways, including inhibiting gastrointestinal motility and gastric juice secretion, suppressing appetite and food intake, and delaying emptying of gastric contents. In addition, GLP-1 can also act on the central nervous system (especially the hypothalamus), which can cause the body to feel full and reduce appetite.

In addition, GLP-1 also has many other biological characteristics and functions. For example, GLP-1 may play a role in lowering lipids and blood pressure, thereby protecting the cardiovascular system; it can also enhance learning by acting on the center And memory function to protect the nerves.

However, the application of GLP-1 to the clinic also faces a problem. GLP-1 produced by the human body is easily degraded by the dipeptidyl peptidase IV (DPP-IV) in the body, and its plasma half-life is less than 2 minutes. Continuous intravenous infusion or continuous subcutaneous injection can produce efficacy, which greatly limits the clinical application of GLP-1.

In order to solve this problem, scholars have proposed two schemes. One is to develop GLP-1 analogues, so that they not only retain the efficacy of GLP-1, but also resist degradation; the second is to develop DPP-IV inhibitors to make the body itself The secreted GLP-1 is not degraded. At present, both aspects of research have made some progress. It is believed that with the deepening of the research on GLP-1 signaling system, more new targets will be found, and more new drugs for the treatment of diabetes will be developed to benefit patients with diabetes.