Glucagon-like peptide-1 (GLP-1) is a naturally occurring hormone that plays a significant role in metabolic regulation, primarily focusing on managing blood sugar and influencing appetite. It belongs to a class of hormones called incretins, released from the gut in response to food intake. This peptide signals the brain, pancreas, and stomach that nutrients have arrived and need to be processed. Therapeutic applications of this hormone treat conditions like Type 2 Diabetes and obesity by mimicking and prolonging its natural actions.
Glucagon-like Peptide-1’s Natural Role in the Body
Glucagon-like peptide-1 is synthesized from proglucagon and secreted primarily by L-cells in the small intestine and colon following a meal. Its most recognized function is stimulating insulin release from pancreatic beta cells in a glucose-dependent manner. This means GLP-1 only significantly increases insulin secretion when blood glucose levels are elevated, which lowers the risk of hypoglycemia.
The hormone also inhibits glucagon release from pancreatic alpha cells. Since glucagon instructs the liver to release stored glucose, suppressing it helps decrease the liver’s production of new glucose after a meal. This dual action of boosting insulin and suppressing glucagon stabilizes blood glucose concentrations.
Beyond its direct effects on the pancreas, GLP-1 influences the gastrointestinal tract and the central nervous system. It delays gastric emptying, slowing the rate food moves from the stomach to the small intestine. This slowing helps prevent sharp spikes in blood sugar and contributes to an increased feeling of fullness. In the brain, GLP-1 acts on receptors in the hypothalamus, promoting satiety and reducing overall food intake.
The native GLP-1 hormone has a very short half-life in the bloodstream, typically lasting only one to two minutes. This rapid breakdown is caused by the enzyme Dipeptidyl Peptidase-4 (DPP-4), which quickly inactivates the peptide. This rapid clearance limits the duration of GLP-1’s action, necessitating the development of engineered compounds for sustained therapeutic use.
Developing Therapeutic GLP-1 Receptor Agonists
The short half-life of natural GLP-1 challenged its use as a medication, leading researchers to develop synthetic compounds called GLP-1 Receptor Agonists (GLP-1 RAs). These drugs are chemically modified to resist degradation by the DPP-4 enzyme, dramatically extending their activity in the body. The result of this modification is a much longer half-life, enabling convenient dosing schedules like once-daily, once-weekly, or longer intervals.
These long-acting analogues directly activate the GLP-1 receptors, amplifying the hormone’s natural effects. The primary therapeutic application is the management of Type 2 Diabetes, where the compounds improve glycemic control by enhancing insulin secretion and suppressing glucagon. This mechanism provides a significant advantage over many older diabetes medications, as GLP-1 RAs also promote weight loss and have a low risk of causing hypoglycemia.
GLP-1 RAs are also approved for chronic weight management, leveraging the hormone’s effects on appetite and satiety. The compounds act in the brain to reduce hunger and slow gastric emptying, thereby reducing caloric intake and promoting a negative energy balance. Delivery methods predominantly involve subcutaneous injection, though some are formulated for oral administration.
The class of GLP-1 RAs includes single agonists, such as liraglutide and semaglutide, which target only the GLP-1 receptor. A newer advancement is the development of dual agonists, such as tirzepatide, which activate both the GLP-1 receptor and the Glucose-dependent Insulinotropic Polypeptide (GIP) receptor. GIP is another incretin hormone that stimulates insulin release. This combined dual agonism offers enhanced efficacy for both blood sugar control and weight reduction compared to single agonists.
Common Adverse Effects and Safety Considerations
The most frequently reported adverse effects associated with GLP-1 RA therapy are gastrointestinal. These common symptoms include nausea, vomiting, diarrhea, and constipation, which are directly related to the drug’s effect of slowing gut motility. These effects are often most pronounced when first starting the medication or after a dose increase, but they tend to decrease in severity over time as the body adjusts.
The use of GLP-1 RAs requires adherence to specific safety considerations and contraindications. There is a small, but serious, risk of developing acute pancreatitis, which is inflammation of the pancreas. Patients are monitored for this condition, with symptoms including severe, persistent abdominal pain that may radiate to the back. Gallbladder issues, such as gallstones and inflammation, have also been reported as rare but serious adverse events.
A specific contraindication for GLP-1 RAs involves certain types of thyroid cancer. These medications are contraindicated in patients with a personal or family history of Medullary Thyroid Carcinoma (MTC) or Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). This warning is based on findings from rodent studies, although a clear causal relationship in humans has not been established. Patients with these specific risk factors should not use GLP-1 receptor agonists.