From the Guidelines
Glucagon-like peptide-1 (GLP-1) works by binding to specific receptors on pancreatic beta cells, stimulating insulin secretion in a glucose-dependent manner, and its mechanism of action is best described by the most recent and highest quality study 1. When blood glucose levels rise after a meal, GLP-1 enhances insulin release while simultaneously suppressing glucagon secretion from pancreatic alpha cells, which helps lower blood glucose. GLP-1 also slows gastric emptying, prolonging the time food remains in the stomach, which reduces post-meal glucose spikes. In the brain, GLP-1 acts on receptors in the hypothalamus to increase satiety and reduce appetite, leading to decreased food intake and weight loss. Additionally, GLP-1 protects beta cells by promoting their proliferation and inhibiting apoptosis, potentially preserving pancreatic function over time. These combined actions make GLP-1 and GLP-1 receptor agonists (like semaglutide, dulaglutide, and liraglutide) effective treatments for type 2 diabetes and obesity, as they improve glycemic control while supporting weight management through multiple physiological pathways, as supported by other studies 1.
Some key points about the mechanism of action of GLP-1 include:
- Stimulation of insulin secretion in a glucose-dependent manner
- Suppression of glucagon secretion
- Delayed gastric emptying
- Increased satiety and reduced appetite
- Protection of beta cells through promotion of proliferation and inhibition of apoptosis These effects contribute to the therapeutic benefits of GLP-1 and its receptor agonists in the management of type 2 diabetes and obesity.
From the FDA Drug Label
Incretins, such as glucagon-like peptide-1 (GLP-1), enhance glucose-dependent insulin secretion and exhibit other antihyperglycemic actions following their release into the circulation from the gut Exenatide is a GLP-1 receptor agonist that enhances glucose-dependent insulin secretion by the pancreatic beta-cell, suppresses inappropriately elevated glucagon secretion, and slows gastric emptying. The amino acid sequence of exenatide partially overlaps that of human GLP-1. Exenatide has been shown to bind and activate the human GLP-1 receptor in vitro This leads to an increase in both glucose-dependent synthesis of insulin, and in vivo secretion of insulin from pancreatic beta cells, by mechanisms involving cyclic AMP and/or other intracellular signaling pathways.
The mechanism of action of GLP-1 is to:
- Enhance glucose-dependent insulin secretion
- Exhibit other antihyperglycemic actions
- Suppress inappropriately elevated glucagon secretion
- Slow gastric emptying This is achieved by binding and activating the human GLP-1 receptor in vitro, leading to an increase in glucose-dependent synthesis of insulin and in vivo secretion of insulin from pancreatic beta cells, through mechanisms involving cyclic AMP and/or other intracellular signaling pathways 2.
From the Research
Mechanism of Action of GLP-1
The mechanism of action of Glucagon-like peptide-1 (GLP-1) involves several key processes:
- Stimulation of insulin secretion from pancreatic β-cells in a glucose-dependent manner 3, 4, 5
- Inhibition of glucagon secretion 3, 6
- Delay of gastric emptying and reduction of gastric acid and pancreatic exocrine secretion 3, 6
- Increase in cytoplasmic concentration of Ca2+ through Na(+)-dependent uptake of extracellular Ca2+ and release of Ca2+ from intracellular Ca2+ stores 3
- Activation of adenylate cyclase and formation of cyclic AMP 3
- Regulation of ion channels, including ATP-sensitive K(+) channels, voltage-dependent Ca(2+) channels, voltage-dependent K(+) channels, and nonselective cation channels 5
- Regulation of intracellular energy homeostasis and exocytosis 5
GLP-1 Receptor Signaling
GLP-1 exerts its actions through activating specific receptors of the seven transmembraneous domain-G-protein-coupled type with 463 amino acids 3. The GLP-1 receptor (GLP-1R) is a G protein-coupled receptor that is activated directly or indirectly by blood glucose-lowering agents currently in use for the treatment of type 2 diabetes mellitus (T2DM) 6.
Therapeutic Potential of GLP-1
The multiple actions of GLP-1, including its ability to stimulate insulin secretion, delay gastric emptying, decrease glucagon levels, and reduce appetite, make it a potential therapeutic target for the treatment of diabetes 7. GLP-1-based therapeutics, such as GLP-1R agonists and DPP-IV inhibitors, have been shown to be effective in reducing hyperglycaemia with minimal hypoglycaemia risk 4, 6.