What is GLP-1? Explaining its Mechanism of Action, Drugs, and Side Effects

GLP-1 (Glucagon-like peptide-1) is one of the hormones produced in our bodies. It has gained attention, particularly as a treatment for type 2 diabetes and obesity, and you may have heard it referred to as the “weight-loss hormone.” However, few people fully understand what GLP-1 is, how it works, what types of drugs are available, and what side effects might occur.

This article will explain, in an easy-to-understand manner, everything from the basic function of GLP-1 to why it is used in the treatment of diabetes and obesity, specific types of drugs and their mechanisms of action, and potential side effects. If you want to learn more about GLP-1, please read on.

Basic Knowledge of GLP-1 (Glucagon-like peptide-1)

Definition of GLP-1 and Its Role in the Body

GLP-1 is a gut hormone secreted from the lower part of the small intestine (primarily the ileum and colon) after eating. It is a member of the incretin hormone family and plays a crucial role in regulating blood glucose levels.

Our bodies have a system to maintain blood glucose levels within a certain range to utilize carbohydrates from food as energy. Within this system, insulin, secreted from the pancreas, is the main hormone that lowers blood glucose. GLP-1 contributes to blood glucose control by promoting the secretion of insulin.

In addition to promoting insulin secretion, GLP-1 also has the effect of suppressing the secretion of glucagon, a hormone that raises blood glucose levels. By acting on both insulin and glucagon, GLP-1 helps to stabilize blood glucose levels and prevent a rapid rise in blood glucose after meals.

Furthermore, GLP-1 also has effects such as slowing down the emptying of food from the stomach into the duodenum and acting on the brain to suppress appetite. Through these diverse functions, GLP-1 is also deeply involved in regulating energy balance.

What Kind of Hormone is GLP-1?

GLP-1 is a peptide hormone produced by cleavage from a precursor protein called proglucagon. As mentioned earlier, it is mainly secreted from specific cells (L cells) in the small intestine.

GLP-1 secretion is stimulated particularly by the intake of meals containing carbohydrates and fats. When food reaches the small intestine, L cells sense it and release GLP-1 into the bloodstream. GLP-1 in the blood is transported to various parts of the body, such as the pancreas, brain, and stomach, and exerts its physiological effects by binding to their receptors.

However, GLP-1 is rapidly broken down in the body by an enzyme called DPP-4 (dipeptidyl peptidase-4). Therefore, the action time of native GLP-1 in the body is relatively short. This characteristic of being “quickly broken down” is relevant to the development of GLP-1 receptor agonists, which will be explained later.

Research suggests that GLP-1 not only regulates blood glucose but may also have beneficial effects on various organs, including neuroprotective effects on the brain, protective effects on the cardiovascular system, and protective effects on the kidneys. These multifaceted actions are why GLP-1 is expected to be applied not only as a diabetes treatment but also for obesity and other diseases.

Mechanism of Action of GLP-1

There are three main mechanisms by which GLP-1 works in our bodies:

Insulin Secretion Promotion Effect

One of the most important actions of GLP-1 is its effect on promoting insulin secretion. GLP-1 binds to GLP-1 receptors on the surface of pancreatic beta cells, strongly promoting the secretion of insulin from these cells.

A major characteristic of this insulin secretion promoting effect is that it is “glucose-dependent.” This means that it promotes insulin secretion when blood glucose levels are high, but its action weakens or is almost inactive when blood glucose levels are within the normal range or low. For this reason, GLP-1 action alone is considered unlikely to cause severe hypoglycemia. This is a significant safety advantage compared to other drugs that promote insulin secretion (such as sulfonylureas).

GLP-1 also acts on pancreatic alpha cells, suppressing the secretion of glucagon, a hormone that raises blood glucose levels. Suppressing glucagon secretion reduces glucose release from the liver, further suppressing the rise in blood glucose. It is characteristic of GLP-1 that it lowers blood glucose through both promoting insulin secretion and suppressing glucagon secretion.

Furthermore, research suggests that, as a long-term effect, GLP-1 may increase the number of pancreatic beta cells and improve their function. This holds potential for suppressing the progression of type 2 diabetes and is attracting attention.

Gastric Emptying Delay Effect

GLP-1 has the effect of suppressing stomach motility and slowing down the rate at which food empties from the stomach into the small intestine. This is called the “gastric emptying delay effect.”

When food is emptied from the stomach slowly, it helps to prevent a rapid rise in blood glucose levels after meals. This is a beneficial effect, especially for diabetic patients who experience problematic post-meal hyperglycemia.

Also, when food stays in the stomach longer, it helps maintain a feeling of fullness. This sustained feeling of fullness, combined with the appetite suppressing effect explained next, leads to a reduction in food intake.

However, this gastric emptying delay effect can also be a cause of side effects such as nausea and indigestion associated with GLP-1 receptor agonists. These side effects are more likely to occur especially when starting treatment.

Appetite Suppression Effect

GLP-1 acts on areas in the brain, such as the hypothalamus, that are involved in appetite regulation, and has the effect of suppressing appetite. Specifically, it reduces the desire to eat by enhancing satiety signals and suppressing hunger signals.

This appetite suppressing effect, combined with the gastric emptying delay effect, leads to a reduction in food intake and a decrease in snacking, resulting in reduced calorie intake. This is one of the main mechanisms by which GLP-1 receptor agonists exert a weight-loss effect.

Research suggests that GLP-1’s action on the brain may not only suppress appetite but also change preferences for certain foods (especially high-fat, high-sugar foods). This may potentially support the adoption of healthy eating habits.

These three main actions – insulin secretion promotion, gastric emptying delay, and appetite suppression – combine to allow GLP-1 receptor agonists to improve blood glucose control in diabetes and also promote weight loss.

What are GLP-1 Receptor Agonists (GLP-1 Agonists)?

GLP-1 receptor agonists are artificially synthesized drugs designed to overcome the weakness of native GLP-1, which is rapidly broken down in the body, and to maintain its physiological effects for a prolonged period. Since they bind to GLP-1 receptors and exert their effects in the same way as native GLP-1, they are called “GLP-1 receptor agonists” or simply “GLP-1 agonists.”

These drugs are designed to be resistant to breakdown by the DPP-4 enzyme, allowing them to remain stable in the body for a long time and exert their effects with less frequent administration, such as once daily or once weekly.

Types and List of GLP-1 Receptor Agonists

Currently, several types of GLP-1 receptor agonists are approved and used in Japan. These differ in their drug structure, administration method (injection or oral), and frequency of administration.

Drug Name (Generic)	Main Product Name	Administration Method	Administration Frequency	Key Features
Liraglutide	Victoza, Saxenda	Injection	Once daily	Relatively long history, extensive evidence
Exenatide	Byetta, Bydureon	Injection	Twice daily, Once weekly	One of the first GLP-1 agonists introduced
Lixisenatide	Lyxumia	Injection	Once daily	Considered particularly effective for postprandial hyperglycemia
Dulaglutide	Trulicity	Injection	Once weekly	High convenience with once-weekly administration
Semaglutide (Injection)	Ozempic	Injection	Once weekly	Tends to have strong blood glucose lowering and weight loss effects
Semaglutide (Oral)	Rybelsus	Oral	Once daily	Only oral drug, for patients who dislike injections
Dulaglutide (High Dose)	Mansaro	Injection	Once weekly	Approved for obesity treatment in addition to type 2 diabetes (in Japan)

*This is a partial list of major drugs and does not cover all products. Indications (diabetes treatment, obesity treatment, etc.) and dosages vary by drug. Always use under the prescription and guidance of a physician.

Each of these drugs has its own characteristics, so a physician selects the optimal drug considering the patient’s condition, lifestyle, and treatment goals. For example, Rybelsus, an oral drug, might be an option for those who dislike injections, while semaglutide might be considered for those expecting stronger blood glucose lowering or weight loss effects.

GLP-1 Receptor Agonists as Diabetes Treatment Drugs

GLP-1 receptor agonists are widely used as treatment drugs for type 2 diabetes. Their major advantages include:

• Excellent Blood Glucose Control: They effectively improve blood glucose levels, especially post-meal hyperglycemia, by promoting glucose-dependent insulin secretion and suppressing glucagon secretion.
• Low Hypoglycemia Risk: Because they work only when blood glucose is high, they are less likely to cause severe hypoglycemia when used alone compared to other insulin secretagogues.
• Weight Loss Effect: Due to their appetite suppressing and gastric emptying delay effects, many patients can expect weight loss. This is particularly beneficial for type 2 diabetic patients who are often obese.
• Cardiovascular Event Inhibition: Some GLP-1 receptor agonists (such as liraglutide, semaglutide, and dulaglutide) have shown in large clinical trials to reduce the risk of cardiovascular events. This is a very important advantage for diabetic patients who are at high risk of cardiovascular disease.
• Kidney Disease Progression Inhibition: Some GLP-1 receptor agonists also show potential in slowing the progression of diabetic kidney disease.

Due to these benefits, GLP-1 receptor agonists are one of the drugs recommended for active use from the initial treatment stages in the guidelines for type 2 diabetes treatment. They are also widely used in combination therapy with other diabetes drugs such as metformin.

Weight Loss Effect and Application in Obesity Treatment

The powerful appetite suppressing and gastric emptying delay effects of GLP-1 receptor agonists have been confirmed to cause weight loss not only in diabetic patients but also in obese individuals. Particularly, high-dose liraglutide (Saxenda) and semaglutide (some versions are approved for obesity treatment overseas) have shown significant weight loss effects even in obese individuals without diabetes.

Why Does GLP-1 Contribute to Weight Loss?

The mechanisms by which GLP-1 contributes to weight loss are mainly due to the combination of the following:

• Appetite Suppression: By acting on the brain’s appetite center, they reduce feelings of hunger and enhance satiety, naturally leading to decreased food intake.
• Gastric Emptying Delay: Food stays in the stomach longer, which maintains satiety, increases the interval between meals, or reduces the amount eaten at once.
• Influence on Energy Expenditure: Some studies suggest that GLP-1 may slightly increase resting energy expenditure, but the main contribution to weight loss is thought to be the reduction in energy intake.

Through these actions, using GLP-1 receptor agonists makes it easier to reduce food intake without conscious effort, resulting in decreased calorie intake and subsequent weight loss.

Use of GLP-1 Receptor Agonists in Non-Diabetic Individuals

GLP-1 receptor agonists were originally developed as diabetes treatment drugs, but due to their strong weight loss effects, they have also attracted attention as obesity treatment drugs.

In Japan, high-dose dulaglutide (Mansaro) was recently approved for the treatment of obesity (BMI 35 or higher, or BMI 27 or higher with two or more health disorders) in addition to being a treatment drug for type 2 diabetes. This was a groundbreaking development that made GLP-1 receptor agonists available for obesity treatment under health insurance coverage.

However, many GLP-1 receptor agonists are not covered by health insurance solely for the treatment of obesity. Their use in obese individuals without diabetes, except for some drugs, is performed as self-pay medical treatment (free medical treatment). While self-pay treatment is carried out under a physician’s judgment and patient consent, it is important to understand that use outside of insurance coverage has limited public guarantees regarding safety and efficacy.

Important: Even when using GLP-1 receptor agonists for the purpose of weight loss, it is essential to consult a physician and use them under proper diagnosis, prescription, and guidance. Casual personal import or use without medical supervision poses a risk to health.

Main Side Effects of GLP-1 Receptor Agonists

GLP-1 receptor agonists are generally considered safe drugs, but they are not entirely without side effects. The main side effects are as follows:

Gastrointestinal Side Effects

The most common side effects seen with GLP-1 receptor agonists are gastrointestinal symptoms. This is related to the mechanisms of action of GLP-1, such as gastric emptying delay and appetite suppression.

Side Effect	Frequency	Characteristics	General Management
Nausea, Vomiting	Relatively high	Particularly common at the beginning of treatment or when increasing dosage.	Start at a low dose and gradually increase. Eat small, frequent meals. Use antiemetics if needed.
Diarrhea, Constipation	Relatively high	Either symptom may occur, varying from person to person.	Stay hydrated. Use probiotics, antidiarrheals, or laxatives if necessary.
Abdominal bloating, pain	Relatively high	May occur due to slowed stomach motility or changes in the gut environment.	Adjust meal portions. Use probiotics or other remedies if needed.
Indigestion, Heartburn	Relatively high	May occur due to food retention or stomach acid reflux.	Pay attention to the content, amount, and way of eating. Use antacids if needed.

These gastrointestinal symptoms often tend to improve over time with continued administration. However, if the symptoms are severe or persistent, it is necessary to consult a physician to consider dose reduction or changing the medication.

Other Side Effects to Note

In addition to gastrointestinal symptoms, the following rare side effects have also been reported:

• Pancreatitis: Although very rare, acute pancreatitis has been reported as a serious side effect. If you experience persistent severe abdominal pain (especially in the upper abdomen), back pain, nausea, or vomiting, seek medical attention immediately. The causal relationship with GLP-1 receptor agonists is still debated, but it is important to understand that the risk is not zero.
• Gallstones/Cholecystitis: Rapid weight loss has been associated with an increased risk of developing gallstones and cholecystitis.
• Hypoglycemia: Severe hypoglycemia is rare with GLP-1 receptor agonists used alone, but the risk increases when used in combination with other blood glucose-lowering drugs such as sulfonylureas or insulin. If using combination therapy, be aware of the symptoms of hypoglycemia (cold sweats, palpitations, hand tremors, hunger) and take appropriate measures such as consuming sugar if necessary.
• Thyroid-related reports: Some animal studies (in rats and mice) have suggested an increased risk of thyroid C-cell tumors (medullary thyroid carcinoma in humans) with some GLP-1 receptor agonists, particularly overseas. While a clear conclusion on the risk in humans has not been reached, individuals with a history of medullary thyroid carcinoma or a family history, or those with multiple endocrine neoplasia type 2 (MEN2), should avoid using GLP-1 receptor agonists. If you notice a lump or swelling in your neck or hoarseness, consult a physician.
• Injection site reactions: When using injectable drugs, the injection site may become red, swollen, or itchy. This is usually mild and temporary.

The risk of these side effects varies depending on the type and dose of the drug, the patient’s constitution, and underlying medical conditions. When using GLP-1 receptor agonists, it is crucial to receive a full explanation from your doctor, ask any questions you may have, and be aware of the early signs of side effects.

Relationship Between Diet and GLP-1 Secretion

Native GLP-1 in the body is secreted in response to food intake. Knowing what nutrients and foods are more likely to promote GLP-1 secretion can potentially be helpful for blood glucose control and weight management in daily life.

Foods That Promote GLP-1 Secretion

GLP-1 secretion is primarily stimulated by nutrients sensed in the lower small intestine. Foods containing the following components are thought to promote GLP-1 secretion:

• Dietary Fiber: Soluble dietary fiber, which is easily fermented in the intestines, is said to particularly stimulate GLP-1 secretion strongly.
  • Examples: Seaweed (wakame, kelp), mushrooms (shiitake, enoki), vegetables (burdock, spinach), legumes (soybeans, kidney beans), fruits (apples, bananas), konjac, oatmeal
• Protein: Some reports suggest that plant-based protein promotes GLP-1 secretion more effectively than animal protein.
  • Examples: Meat, fish, eggs, dairy products, tofu, natto, and other soy products
• Fats: Unsaturated fatty acids, especially oleic acid, are said to stimulate GLP-1 secretion.
  • Examples: Olive oil, nuts, avocado, fish (mackerel, sardines, etc.)

By incorporating these foods into your diet in a balanced manner, you can expect to promote the secretion of GLP-1 after meals, helping to suppress the rapid rise in blood glucose and make it easier to feel full.

However, the effect of dietary GLP-1 secretion promotion is limited compared to the effect of GLP-1 receptor agonists. It is recommended to include these foods as part of a healthy eating habit. Also, it is important to consume a variety of foods for balanced nutrition rather than excessively consuming specific foods.

Frequently Asked Questions about GLP-1 (Q&A)

Here are some common questions that people considering using GLP-1 receptor agonists or wanting to know about GLP-1 often ask.

• Q: How long does it take for the effects of GLP-1 receptor agonists to appear?
  A: The blood glucose lowering effect usually starts to appear within a few days to about a week after starting treatment with most drugs. The weight loss effect varies from person to person but typically appears gradually over several weeks to months. Especially for the purpose of weight loss, continuous use for several months or longer is often required.
• Q: How much weight can I lose with GLP-1 receptor agonists?
  A: The extent of weight loss varies greatly from person to person. It depends on factors such as initial weight, lifestyle (diet and exercise), the type and dose of the drug used, etc. In clinical trials using standard doses for diabetes treatment, an average weight loss of several kilograms has been reported. When using high doses for obesity treatment, greater weight loss (around 5-15% of initial body weight) may be expected in some cases. However, the effects are not guaranteed for everyone.
• Q: Will I regain weight if I stop taking GLP-1 receptor agonists?
  A: Yes, there is a possibility of weight regain (rebound) if you stop taking the medication. Weight loss from GLP-1 receptor agonists is a result of the drug’s effects on appetite suppression and metabolism. When the medication is stopped, these effects cease, and your appetite and food intake may return to their previous levels, potentially leading to weight regain. To maintain weight loss, it is crucial to continue healthy eating habits and exercise routines even after discontinuing the medication.
• Q: If I use GLP-1 receptor agonists, do I still need to exercise and diet?
  A: Yes, absolutely. GLP-1 receptor agonists are medications that support treatment. To maximize their effects and manage weight healthily, it is recommended to combine them with a balanced diet and regular exercise. Improving lifestyle habits in conjunction with medication is essential for long-term health maintenance.
• Q: How are GLP-1 receptor agonists different from insulin injections?
  A: Both are medications that lower blood glucose, but they have different mechanisms of action. Insulin directly lowers blood glucose by supplementing the insulin produced by the pancreas, while GLP-1 receptor agonists work indirectly by “promoting” the body’s own insulin secretion (in a glucose-dependent manner). Therefore, a key difference is that GLP-1 receptor agonists are less likely to cause hypoglycemia when used alone. Also, GLP-1 receptor agonists have weight loss effects and cardiovascular protective effects, which differ from insulin.
• Q: Which is better, the oral type (Rybelsus) or the injectable types?
  A: The difference in effectiveness and likelihood of side effects is primarily due to the specific drug, rather than the administration method itself. Which is better depends on the patient’s preference (dislike of injections), the drug’s characteristics, and the physician’s judgment. Oral drugs have the advantage of not requiring injections, but they need to be taken with attention to the method of administration (on an empty stomach with plenty of water, and avoiding food/drink for a certain period afterwards). Injectable drugs offer more flexibility in administration timing, among other benefits.
• Q: How much do GLP-1 receptor agonists cost?
  A: The cost varies significantly depending on the type and dose of the drug, the frequency of administration, and whether it is covered by health insurance or self-pay medical treatment.
  • Under Health Insurance: If used for the treatment of type 2 diabetes or specific types of obesity, it is covered by health insurance. The cost of the medication is determined by the patient’s co-payment rate (10%, 20%, or 30%) based on income and age. Since it is a relatively expensive medication, the monthly cost can range from several thousand yen to tens of thousands of yen. It may also be eligible for the High-Cost Medical Expense Benefit System.
  • Self-Pay Medical Treatment: If used for purposes not covered by insurance, such as obesity without concurrent diabetes (except for newly approved indications), it is considered self-pay medical treatment. In this case, in addition to the medication cost, consultation fees and other expenses are fully borne by the patient, and costs are set freely by the medical institution. Monthly costs of several tens of thousands of yen or more are common.

  For accurate costs, please directly inquire with the medical institution you are considering visiting.

• Q: Where can I get a prescription for GLP-1 receptor agonists?
  A: GLP-1 receptor agonists are prescription-only medical drugs that require a doctor’s prescription. For diabetes treatment purposes, you can get a prescription from a hospital or clinic with a diabetes specialist or internal medicine physician. For obesity treatment purposes, if the specific conditions for insurance coverage are met, it may be prescribed under health insurance at a medical institution with internal medicine or an obesity clinic. Various medical institutions, including internal medicine clinics, cosmetic clinics, and obesity clinics, offer prescriptions as self-pay medical treatment outside of insurance coverage.
  In any case, it is extremely important to always receive a medical examination, accurately disclose your health status, medical history, and current medications to the doctor, and get a proper prescription. Casual personal import poses a very high risk of counterfeit products and health damage, so it should be absolutely avoided. Some medical institutions offer prescriptions through online consultations, but it is crucial to choose a trustworthy medical institution.

Summary: About GLP-1 and Its Therapeutic Applications

GLP-1 is a gut hormone that plays important roles in our bodies, such as regulating blood glucose and suppressing appetite. GLP-1 receptor agonists, which utilize its actions, are excellent treatment drugs for type 2 diabetes and have also gained attention as treatment drugs for obesity. They are medications that can offer many benefits, including improved blood glucose control, weight loss, and inhibition of cardiovascular events.

However, when using GLP-1 receptor agonists, there are risks of side effects such as gastrointestinal symptoms like nausea, and although rare, the risk of serious side effects like pancreatitis. Also, the diseases and conditions for which they are covered by health insurance are specified, and use for other purposes (e.g., weight loss for cosmetic reasons) is generally considered self-pay medical treatment.

GLP-1 receptor agonists are drugs that should be used under proper diagnosis, prescription, and management by a physician. Please consult sufficiently with your doctor about whether it is appropriate for your health condition and purpose, what kind of drug is suitable, and what risks and side effects are possible before considering its use. Absolutely avoid casual self-judgment or obtaining the medication from unreliable sources.

This article is for informational purposes only and does not recommend the use of specific drugs or medical procedures. If you are considering treatment with GLP-1 receptor agonists, please consult a specialist physician at a medical institution.