Your gut makes a hormone that is gone almost as soon as it arrives. In plain terms, that fact explains most of the drug story around GLP-1.
Glucagon-like peptide-1 is a peptide of 30 or 31 amino acids. Researchers identified it in 1983 as a cleavage product of proglucagon processing. L cells, the endocrine cells lining the intestine, secrete it. The pancreas contributes through its alpha cells, and a small cluster of brainstem neurons does the same. When it does its job, it nudges the pancreas to release more insulin and lowers the concentration of glucagon.
More than a sugar signal
GLP-1 does not stop at the pancreas. It slows the emptying of the stomach after a meal, reduces gastric acid secretion and tightens the pylorus, the valve at the stomach’s exit. In the brain, GLP-1 and its receptor turn up in the hypothalamic feeding centres and nearby regions that control appetite. In mouse experiments, GLP-1 injected into the brain’s ventricles cut food intake. Less hunger and slower digestion add up to weight loss, and that second effect is why a diabetes hormone ended up in the obesity conversation.
It has a cousin. GIP, made by K cells in the gut, also pushes insulin out of the pancreas in a glucose-dependent way. The pair are the incretin hormones, named for the way they amplify insulin after eating.
The problem with the natural hormone
Think of natural GLP-1 as a message written in disappearing ink. An enzyme called DPP-4 breaks it down quickly, so nobody can simply inject the real thing and expect it to last. Drug designers needed a lookalike that the body could not shred so fast.
The first answer came from an odd place. Exenatide, the first GLP-1 receptor agonist approved for type 2 diabetes, is a synthetic copy of exendin-4, a compound found naturally in the Gila monster. It mimics human GLP-1 but resists DPP-4. Its half-life is still only 2.4 hours. It blocks glucagon release, slows gastric emptying, curbs appetite and raises insulin in step with blood sugar. Later drugs such as liraglutide were engineered to stay in the blood longer; the FDA has approved liraglutide for long-term weight management.
Benefits and open questions
The practical upshot, according to a 2021 review in Frontiers in Endocrinology, is that these drugs lower fasting blood glucose and HbA1c, reduce blood pressure and body weight, and carry a low incidence of hypoglycemia. Nausea and vomiting are common side effects. The mechanism behind weight loss in obesity is still not fully settled, and a 2023 review in the same journal said more clinical evidence is needed on long-term safety and efficacy.
Cost is another sticking point. Exenatide and liraglutide are peptide preparations that are expensive to produce, and they must be injected. Small-molecule agonists could be taken by mouth instead, sparing patients the discomfort of injections.
Sources
- GLP-1 receptor agonists for the treatment of obesity: Role as a promising approach (Frontiers in Endocrinology)
- GLP-1 Receptor Agonists: Beyond Their Pancreatic Effects (Frontiers in Endocrinology)
