The intestinal endocrine L cells release a 30-amino acid hormone called Glucagon-like peptide which belongs to the glucagon-like peptide family. Scientists found GLP-1 in 1983 and fully identified its properties during cloning experiments in 1987. The 30-amino acid hormone helps control blood glucose levels and other essential health processes. Research shows GLP-1 helps treat diabetes and obesity while showing promise for heart health and brain protection.
The glucagon-like peptide family consists of important peptide hormones that work as part of the glucagon/incretin system. Its main members include glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-2) and glucagon. Peptide hormones in this class help control how energy is stored and used in the body while managing food consumption and digestive movement plus insulin release and cellular development.
Glucagon-like peptide-1 (GLP-1) is a peptide hormone secreted by intestinal L cells and belongs to the glucagon-like peptide family. It is mainly released in the intestine after food ingestion and acts in the islet β cells, thereby regulating blood sugar levels.
Glucagon-like peptide 1 structure
GLP-1 is a peptide consisting of 30 amino acids with a molecular weight of about 3.5 kDa. This peptide is produced from the precursor hormone preucagon (preproglucagon) through post-translational processing of intestinal L cells. The biologically active forms mainly include GLP-1-(7-37) and GLP-1-(7-36) NH2.
Glucagon-like peptide-2 (GLP-2) is a 33-amino acid polypeptide hormone secreted by intestinal endocrine L cells, belonging to the glucagon-like peptide family. It is produced by transcription of the proglucagon gene and has a similar structure and function to glucagon (GLP-1).
Glucagon-like peptide 2 structure
GLP-2 is a polypeptide composed of 33 amino acids with a molecular weight of about 3.3 kDa. It is encoded by the proglucagon gene and is cleaved by the glucagon precursor protease (prohormone convertase 1/3). The second amino acid of GLP-2 is alanine (Ala), which makes it susceptible to degradation by dipeptidyl peptidase-IV (DPP-IV).
Glucagon is a hormone secreted by α cells of the pancreas, whose main function is to regulate blood sugar levels, raising blood sugar by promoting the release of stored glucose by the liver. It is a polypeptide composed of 29 amino acids with a molecular weight of about 3485 daltons. In recent years, glucagon and its receptors have become an important research target for diabetes treatment. Studies have shown that insulin resistance and fat metabolism can be improved by modulating the glucagon signaling pathway.
GLP-1 (glucagon-like peptide-1) and GLP-2 (glucagon-like peptide-2) are two important increin hormones, both of which are derived from the glucagon gene, but have different physiological functions and mechanisms of action. Here are their main differences:
GLP-1 and GLP-2 are secreted by intestinal endocrine L cells, which are mainly found in the small and large intestines. Their secretion in the gut is stimulated by nutrients such as carbohydrates, fats, and dietary fiber in a 1:1 ratio.
GLP-1 and GLP-2 are both peptides composed of 33 amino acids, but their N-terminal sequences differ. The 2nd amino acid of GLP-1 is methionine (M), while the 2nd amino acid of GLP-2 is threonine (T).
GLP-1 has a short half-life in circulation (about 2 minutes) and is easily degraded to an inactive form by DPP-IV enzymes. Whereas, GLP-2 has a longer half-life (about 5-7 minutes) and is therefore more stable in the intestine.
GLP-1 activates a variety of signaling pathways by binding to GLP-1R, and exerts insulin secretion stimulation, glucagon secretion inhibition, gastrointestinal motility regulation, and metabolic regulation independent of GLP-1R. Together, these mechanisms maintain glycemic balance and provide important targets for diabetes treatment.
Table.1 Mechanism of action of glucagon-like peptides.
| Mechanism/Effect | Description |
| Stimulation of insulin secretion | GLP-1 activates cAMP-PKA signaling in pancreatic β cells, promoting insulin gene expression and secretion in response to elevated blood glucose. Its effect diminishes when glucose levels are normal. |
| Inhibition of glucagon secretion | GLP-1 inhibits glucagon secretion from islet α cells, reducing glycogenolysis and gluconeogenesis in the liver, which lowers blood sugar levels. |
| Regulation of gastrointestinal motility and appetite | GLP-1 delays gastric emptying and suppresses appetite by activating receptors in the enteric nervous system and central nervous system, promoting satiety. |
| Independent of GLP-1R | In addition to the effects mediated by GLP-1R, GLP-1 exhibits some biological effects independent of GLP-1R. For example, studies have shown that GLP-1 can exert insulin-like effects by regulating metabolic pathways such as oxidative stress, fatty acid oxidation, and glycolysis through mitochondrial function. |
| Role in other organs | GLP-1 exerts protective effects in tissues like the heart, liver, and kidneys, enhancing calcium currents in the heart and inhibiting oxidative stress in the liver. |
| Metabolic regulation and antidiabetic effects | GLP-1 reduces blood glucose, improves metabolic health, promotes weight loss, and has cardiovascular and anti-inflammatory effects, helping manage diabetes. |
| Degradation & Recycling | GLP-1 has a short half-life of under 2 minutes, rapidly degraded by DPP-IV. Clinical use often involves DPP-IV inhibitors or GLP-1 analogues to extend its action. |
Fig.1 The main physiological functions of GLP-1 1,2.GLP-1 is a multifunctional peptide hormone, whose main functions include regulating blood glucose, promoting insulin secretion, inhibiting glucagon secretion, delaying gastric emptying, increasing satiety, and regulating lipid metabolism. In addition, it plays an important role in the central nervous system, immune system, and bone health, among others. These properties make GLP-1 an important target in the treatment of diabetes and obesity management, and it has shown a wide range of potential applications in research.
Glucagon-like peptide-1 receptor (GLP-1R) is a G protein-coupled receptor that is widely expressed in pancreas, gut, and nerve tissues, and regulates cellular responses to blood glucose, insulin, and inflammatory signals, primarily by binding glucagon-like peptide-1 (GLP-1) and its analogues.
GLP-1R plays an important role in the management of diabetes and its complications. For example, GLP-1 receptor agonists (e.g., liraglutide, exenatide, etc.) have been shown to reduce blood sugar levels and improve cardiovascular health in patients with type 2 diabetes. In addition, these drugs have also shown therapeutic potential for obesity by regulating energy metabolism and appetite.
In terms of neuroprotection, GLP-1R agonists have also shown some efficacy. For example, studies have shown that GLP-1R agonists are able to alleviate cognitive impairment in Alzheimer's disease model mice and exert neuroprotective effects by modulating inflammatory pathways, such as the NF-κB signaling pathway.
It is important to note that GLP-1R not only plays a role in metabolic diseases, but also shows potential therapeutic value in other diseases. For example, GLP-1R agonists have been studied for the treatment of multiple sclerosis and neurodegenerative diseases. In addition, GLP-1R is also present in the liver, and its agonists are able to reduce hepatic fat deposits by modulating the insulin signaling pathway.
Although GLP-1R agonists have a promising role in a variety of diseases, their use still needs to consider potential side effects and risks. For example, some patients may experience gastrointestinal upset, nausea, or hypoglycemic reactions. Therefore, in clinical application, treatment needs to be individualized according to the specific situation of the patient.
As an important drug target, GLP-1R has shown significant therapeutic potential in various fields such as diabetes, obesity, and neurodegenerative diseases. Future studies will further reveal its specific mechanisms of action in different diseases and optimize its clinical application strategies.
Glucagon-like peptide-1 receptor agonists (GLP-1 receptor agonists) are a class of drugs used to treat type 2 diabetes and obesity, and their mechanism of action is mainly through the activation of glucagon-like peptide-1 (GLP-1) receptors to regulate metabolism and energy balance. These drugs have shown significant efficacy and safety in clinical studies, but there are also some potential risks and side effects.
GLP-1 receptor agonists modulate insulin secretion, inhibit gastric emptying, reduce appetite, and improve fat metabolism by mimicking the effects of endogenous GLP-1. These drugs are able to lower blood sugar levels while promoting weight loss and have some protective effect against cardiovascular disease.
Fig.2 Role of GLP1 receptor agonists (GLP1RA) 3,4. Table.2 Common GLP-1 receptor agonists.
| Product Name | Description |
|---|---|
| Liraglutide | This long-acting GLP-1 receptor agonist helps regulate blood sugar levels and supports cardiovascular health in individuals with type 2 diabetes. |
| Semaglutide | Administered once a week, this medication is effective in managing type 2 diabetes and obesity, with a proven track record for cardiovascular safety. |
| Exenatide | A GLP-1 receptor agonist for type 2 diabetes treatment, it lowers blood glucose while also promoting weight loss. |
| Lixisenatide | A rapid-acting GLP-1 receptor agonist that aids in improving blood glucose control in patients with type 2 diabetes. |
| Albiglutide | A GLP-1 receptor agonist that offers long-term control over blood sugar levels in type 2 diabetes patients, contributing to overall metabolic health. |
| Taspaglutide | A novel GLP-1 receptor agonist in development, targeting enhanced blood sugar control and potential therapeutic benefits for type 2 diabetes. |
| Dulaglutide | A once-weekly injectable, effective in managing type 2 diabetes and obesity, promoting better patient adherence due to its extended duration of action. |
Although GLP-1 receptor agonists have significant efficacy, they can also cause some side effects during their use. For example:
In recent years, scientists have developed novel GLP-1 receptor agonists to improve their bioavailability and efficacy. For example, a novel dual GLP-1/CCK receptor agonist has shown better hypoglycemic and weight-loss effects. In addition, studies have explored the potential of GLP-1 receptor agonists in kidney transplant patients.
Glucagon-like peptide-1 receptor inhibitors (GLP-1 receptor inhibitors) are a class of drugs used for the treatment of type 2 diabetes and obesity, and their mechanism of action mainly regulates insulin secretion, delays gastric emptying, reduces appetite and increases satiety by mimicking the action of endogenous glucagon-like peptide-1 (GLP-1). These include multiple types, such as GLP-1 receptor agonists and GLP-1/glucagon receptor co-agonists, which have demonstrated significant efficacy in the management of metabolic and cardiovascular diseases.
GLP-1 receptor inhibitors effectively lower blood glucose levels by activating GLP-1 receptors on β cells of the pancreas, promoting insulin secretion and inhibiting glucagon secretion. In addition, they can help with weight control by slowing the rate of stomach emptying and reducing food intake. These drugs also have certain cardiovascular protective effects, such as reducing the risk of major cardiovascular events such as myocardial infarction and stroke.
Fig.3 Physiological effects of different GLP-1 receptor (GLP-1R) signaling effectors 5,6.Diabetes management: GLP-1 receptor inhibitors are widely used in the treatment of patients with type 2 diabetes, especially those who require combination therapy to improve glycemic control. For example, semaglutide, a once-weekly injection, has been shown to be effective in lowering HbA1c. In addition, drugs such as liraglutide and lixisenatide have also shown good efficacy in clinical trials.
Obesity treatment: The use of GLP-1 receptor inhibitors in the treatment of obesity has also been widely studied. For example, tirzepatide, a novel co-agonist that acts on both GLP-1 and glucagon receptors, has shown significant effects on weight management.
Cardiovascular disease management: Several studies have shown that GLP-1 receptor inhibitors have a potential cardiovascular protective effect in patients with cardiovascular disease. For example, risinatide did not significantly improve the incidence of major adverse cardiovascular events in patients with diabetes, but its safety profile was high. In addition, GLP-1 receptor agonists have been studied to reduce the risk of atrial fibrillation recurrence.
Table.3 GLP-1 receptor inhibitors related products.
| Product Name | Description |
| Tirzepatide | A novel GLP-1 and glucagon receptor co-agonist with significant effects on weight management in obesity treatment, improving glycemic control and reducing appetite. |
| Glucagon | A hormone used in the treatment of severe hypoglycemia, it acts to raise blood glucose levels by promoting the release of glucose from liver stores. |
| Retatrutide | Next-generation GLP-1/glucagon co-agonist in development for the treatment of obesity and type 2 diabetes, aiming to improve weight loss and metabolic control with a dual mechanism. |
| Exendin (9-39) Acetate | A GLP-1 receptor antagonist that inhibits GLP-1 receptor activity, often used in research to study the physiological roles of GLP-1 in glucose regulation and appetite control. |
| GLP-2, human | Naturally occurring peptide that stimulates the growth and repair of the intestinal lining, promoting gastrointestinal health and nutrient absorption. |
| GLP-1/Glucagon-Like Peptide, human | A synthetic form of GLP-1, often used in research or therapeutic development to mimic the actions of endogenous GLP-1 in regulating insulin secretion, gastric emptying, and appetite. |
Glucagon-like peptide-1 has a variety of physiological functions, including regulating blood glucose, promoting insulin secretion, inhibiting glucagon secretion, delaying gastric emptying, and enhancing satiety. These properties make GLP-1 and its analogues show important application potential in the treatment of diabetes and obesity.
GLP-1 and its analogues can significantly improve glycemic control in patients with type 2 diabetes by mimicking the effects of endogenous GLP-1. Specific mechanisms include:
Because of these effects, GLP-1's analogues (e.g., liraglutide, lixisenatide, dulaglutide, etc.) are widely used in the treatment of diabetes and are often used as basic therapy or in combination with other hypoglycemic drugs. For example, studies have shown that GLP-1 analogues can effectively reduce HbA1c levels without causing weight gain.
In addition to diabetes treatment, GLP-1 and its analogues have also attracted attention for their significant effects on weight management. Its mechanism of action mainly includes:
Clinical studies have shown that GLP-1 analogues (such as albiglutide, exenatide, etc.) show significant weight loss in obese patients. For example, a systematic review and randomized controlled trial showed significant weight loss in obese patients treated with GLP-1 receptor agonists. In addition, these drugs may confer cardiovascular protection.
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