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What is a Glucagon-like Peptide?
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.
Glucagon-like Peptide Family
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.
What is Glucagon-like Peptide-1?
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.
What is Glucagon-like Peptide-2?
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).
What is Glucagon?
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:
Source and secretion
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.
Structure and degradation
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.
Regulates blood sugar
GLP-1 lowers blood sugar levels by stimulating β islet cells to secrete insulin. It enhances insulin sensitivity and inhibits glucagon secretion, thereby maintaining blood sugar stability.
GLP-1 also acts as a "postprandial insulin releaser" by delaying gastric emptying to limit the sharp rise in postprandial blood glucose.
Promotes islet β cell function
GLP-1 protects pancreatic islet β cells from apoptosis, increases the proliferation and differentiation of β cells, and thus improves insulin secretion. It also restores the sensitivity of pancreatic islet β cells to glucose, possibly by increasing the expression of GLUT2 and glucokinase.
Inhibits gastric emptying
GLP-1 delays gastric emptying by inhibiting motility and secretion in the gastrointestinal tract, thereby reducing food intake and increasing satiety. This effect makes GLP-1 a potent appetite suppressant that aids in weight management.
Regulates lipid metabolism
GLP-1 not only regulates glucose metabolism, but also participates in the regulation of lipid metabolism. It is able to improve lipid metabolism abnormalities in diabetic patients, reduce liver fat accumulation and triglyceride levels. GLP-1 promotes lipolysis and inhibits the proliferation of fat cells by activating lipolytic enzymes in the liver.
The role of the central nervous system
GLP-1 is able to cross the blood-brain barrier and function in the brain. It regulates appetite, memory function, and mood by acting on receptors in the hypothalamus and limbic system.
GLP-1 also has neuroprotective effects in the central nervous system and may have potential therapeutic value for neurological diseases such as Alzheimer's disease.
Anti-inflammatory and immunomodulatory
GLP-1 is involved in the anti-inflammatory response by regulating the function of immune cells. For example, it is able to promote the polarization of macrophages, thereby reducing the inflammatory response.
Other physiological effects
GLP-1 also has a growth-promoting effect, especially in intestinal epithelial cells.
It has also shown a potential role in bone health, possibly improving bone density by regulating bone metabolism.
Glucagon-like Peptide Receptor
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.
Cardiovascular disease (CVD) refers to diseases related to the heart or blood vessels, also known as circulatory system diseases, circulatory system diseases...
Glucagon-like Peptide Receptor Agonist
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.
Mechanism of action of GLP-1 receptor agonists
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.
A once-weekly injectable, effective in managing type 2 diabetes and obesity, promoting better patient adherence due to its extended duration of action.
Clinical application and efficacy
Treatment of diabetes: GLP-1 receptor agonists are widely used in patients with type 2 diabetes as a second-line treatment option for non-insulin hypoglycemic agents. For example, semaglutide is a long-acting GLP-1 analogue that can be injected subcutaneously once a week to control blood sugar levels. In addition, liraglutide has also been shown to reduce cardiovascular events in diabetic patients.
Obesity management: GLP-1 receptor agonists have also shown significant weight loss effects in the treatment of obesity. For example, semaglutide and liraglutide have both been shown to reduce weight and improve metabolic status.
Cardiovascular protection: Several studies have shown that GLP-1 receptor agonists may have a protective effect against cardiovascular disease. For example, semaglutide reduced the incidence of cardiovascular events in people with diabetes.
Other potential benefits: GLP-1 receptor agonists have also been found to have potential therapeutic effects on neurodegenerative diseases, diabetic retinopathy, and more.
Safety and side effects
Although GLP-1 receptor agonists have significant efficacy, they can also cause some side effects during their use. For example:
Gastrointestinal reactions: Common side effects include nausea, vomiting, diarrhea, etc.
Pancreatitis risk: Some patients may develop acute pancreatitis.
Gallbladder and biliary tract problems: Studies have shown that the use of GLP-1 receptor agonists may increase the risk of gallbladder disease.
Research progress of novel GLP-1 receptor agonists
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.
With the gradual deepening of peptide research, the clinical application of...
Glucagon-like Peptide Receptor Inhibitors
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.
The main mechanism of action of GLP-1 receptor inhibitors
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.
Clinical application of GLP-1 receptor inhibitors
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.
A novel GLP-1 and glucagon receptor co-agonist with significant effects on weight management in obesity treatment, improving glycemic control and reducing appetite.
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.
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.
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.
Advantages and limitations of GLP-1 receptor inhibitors
Advantage:
Multiple mechanisms of action: GLP-1 receptor inhibitors not only improve glycemic control, but also reduce body weight by delaying gastric emptying and reducing appetite.
Cardiovascular protection: Some GLP-1 receptor inhibitors have demonstrated potential benefit in reducing the risk of cardiovascular events.
High safety profile: GLP-1 receptor inhibitors have a lower incidence of hypoglycemia compared with traditional hypoglycemic drugs.
Limitations:
Injectable administration: Most GLP-1 receptor inhibitors need to be administered by injection, which may affect patient compliance.
Individual differences: Responses to GLP-1 receptor inhibitors vary among patients, and some patients may experience side effects such as gastrointestinal upset.
Application of Glucagon-like Peptide
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 for Diabetes
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:
Inhibits glucagon secretion: Reduces gluconeogenesis in the liver and further lowers blood sugar.
Delays gastric emptying: Slows down the rate at which food moves through the gastrointestinal tract, thereby reducing postprandial blood sugar fluctuations.
Improve the function of pancreatic islet β cells: GLP-1 can stimulate the proliferation and differentiation of pancreatic islet β cells, while inhibiting their apoptosis, thereby improving the function of pancreatic islet β cells.
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.
Diabetes mellitus (DM) is a common endocrine and metabolic disease. Its basic pathological characteristics are absolute or...
GLP-1 for Weight Loss
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:
Appetite suppression: GLP-1 helps with weight loss by acting on the central nervous system, and reducing food intake.
Delays gastric emptying: Slows down the emptying of gastric contents, increases satiety, and reduces hunger.
Promotes lipolysis: GLP-1 promotes the thermogenesis of brown adipose tissue and accelerates lipolysis.
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.
GLP-1 has no direct evidence supporting benefits for lymphedema, but its effects on metabolism may indirectly help.
3. What are GLP-1 medications?
GLP-1 medications are drugs that mimic or enhance the effects of GLP-1 to improve blood sugar control in diabetes.
4. Why is hydration important for GLP-1?
Hydration is crucial as GLP-1 therapy can cause dehydration through increased urination, affecting kidney and overall function.
5. What does GLP-1 do to the brain?
GLP-1 helps regulate appetite, enhance satiety, and may improve cognitive function by influencing brain signaling pathways.
References
Image retrieved from Figure 1 "Via mTOR-dependent HIF-1 alfa activation, GLP-1R signaling impacts glucose metabolism in beta cells" Kalinkova et al., 2023, used under [CC BY 4.0] (https://creativecommons.org/licenses/by/4.0/). The title was changed to "The main physiological functions of GLP-1”.
Kalinkova, Mariya, et al., Pharmacogenetics of Glucagon-like-peptide-1 receptor in diabetes management. Pharmacia 70 (2023): 383-390.
Image retrieved from Figure 1 " The dichotomous effects of GLP1 receptor agonists (GLP1RA)" Wilbon et al., 2023, used under [CC BY 4.0] (https://creativecommons.org/licenses/by/4.0/). The title was changed to "Role of GLP1 receptor agonists (GLP1RA)".
Wilbon, Sydney S., and Mikhail G. Kolonin. GLP1 receptor Agonists—effects beyond obesity and diabetes. Cells 13.1 (2023): 65.
Image retrieved from Figure 1 " Physiological roles of different GLP‐1 receptor (GLP‐1R) signalling effectors" Jones et al., 2022, used under [CC BY 4.0] (https://creativecommons.org/licenses/by/4.0/). The title was changed to "Physiological effects of different GLP-1 receptor (GLP-1R) signaling effectors”.
Jones, Ben. The therapeutic potential of GLP‐1 receptor biased agonism. British Journal of Pharmacology 179.4 (2022): 492-510.
Fig.1 The main physiological functions of GLP-1 1,2.
Fig.2 Role of GLP1 receptor agonists (GLP1RA) 3,4. 
Fig.3 Physiological effects of different GLP-1 receptor (GLP-1R) signaling effectors 5,6.