Glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2) are hormone-like substances, both originating from specialized cells within the gut. These peptides are released into the bloodstream primarily in response to food intake, acting as chemical messengers that facilitate communication between the digestive system and other parts of the body. Their discovery has significantly advanced the understanding of how the intestine functions as a dynamic endocrine organ, influencing a broad spectrum of physiological processes beyond digestion. Both GLP-1 and GLP-2 contribute to maintaining overall physiological balance in the body.
Understanding Glucagon-Like Peptide-1 (GLP-1)
Glucagon-like peptide-1 is an incretin hormone, a class of gut-derived hormones that enhance glucose-dependent insulin secretion. It is primarily synthesized and released by enteroendocrine L-cells, which are located predominantly in the ileum and colon, secreted rapidly after nutrient ingestion. One of GLP-1’s main actions is to stimulate the pancreatic beta cells, prompting them to release insulin only when blood glucose levels are elevated. This glucose-dependent mechanism prevents hypoglycemia and effectively lowers post-meal blood sugar concentrations.
Beyond its role in insulin release, GLP-1 also suppresses the secretion of glucagon from the pancreatic alpha cells. Glucagon is a hormone that raises blood glucose by signaling the liver to produce more glucose. By enhancing insulin and inhibiting glucagon, GLP-1 contributes to stable blood sugar regulation. The hormone also slows gastric emptying. This delayed transit prevents rapid surges in blood glucose after eating, allowing for a more gradual and sustained absorption of nutrients into the bloodstream.
GLP-1 interacts with specific receptors located in various parts of the brain, particularly those involved in regulating hunger and satiety. This interaction promotes a feeling of fullness and reduces appetite, which can contribute to a decrease in overall food intake and support weight management. GLP-1 has a very short half-life due to rapid degradation by the enzyme dipeptidyl peptidase-4 (DPP-4). This rapid inactivation led to the pharmaceutical development of GLP-1 analogs designed for prolonged therapeutic action.
Understanding Glucagon-Like Peptide-2 (GLP-2)
Glucagon-like peptide-2 is a peptide that, like GLP-1, is secreted by the intestinal L-cells in response to nutrients. Its core physiological functions are centered on maintaining and enhancing the structural and functional integrity of the gastrointestinal tract itself. GLP-2 acts as a potent intestinotrophic factor, promoting the growth and regeneration of the intestinal lining. This involves stimulating crypt cell proliferation and inhibiting the programmed cell death (apoptosis) of existing enterocytes.
This regenerative effect increases the surface area of the intestinal mucosa, enhancing the gut’s capacity for nutrient and fluid absorption. GLP-2 also plays a role in improving the integrity of the gut barrier, a protective layer that prevents harmful bacteria, toxins, and undigested food particles from passing into the bloodstream. It can increase mesenteric blood flow, ensuring efficient delivery of absorbed nutrients. These combined actions contribute to a robust and efficient digestive system, beneficial in conditions where the gut lining may be damaged.
Distinctions and Shared Foundations
Glucagon-like peptide-1 and GLP-2, despite their distinct physiological roles, share a common origin from a single precursor protein known as proglucagon. This single gene encodes this larger protein, which undergoes differential enzymatic processing depending on the specific cell type where it is expressed. In the pancreatic alpha cells, proglucagon is cleaved by prohormone convertase 2 to yield glucagon. Conversely, in the intestinal L-cells, a different enzyme, prohormone convertase 1/3 (PC1/3), is responsible for processing proglucagon into GLP-1 and GLP-2.
This tissue-specific enzymatic cleavage allows the body to generate two distinct hormones with specialized functions from the same initial genetic blueprint. While both GLP-1 and GLP-2 are secreted from the gut in response to nutrient signals, their primary targets and downstream signaling pathways are different. GLP-1 influences systemic metabolic control, particularly glucose regulation and appetite, by acting on receptors in the pancreas, brain, and stomach. GLP-2, conversely, exerts its main effects directly on the intestinal epithelium, promoting its growth, repair, and overall barrier function through its distinct G protein-coupled receptor.
Medical Uses
The distinct physiological actions of GLP-1 and GLP-2 have been leveraged to develop targeted medical therapies for various health conditions. For GLP-1, synthetic analogs are widely prescribed for the management of type 2 diabetes. These medications, which include semaglutide, liraglutide, dulaglutide, and exenatide, are designed to mimic the natural hormone’s ability to stimulate glucose-dependent insulin release and suppress glucagon to lower blood sugar levels. Most of these GLP-1 receptor agonists are administered as subcutaneous injections, though an oral tablet form of semaglutide is available.
Beyond diabetes, some GLP-1 receptor agonists, specifically semaglutide and liraglutide, have received approval for chronic weight management in individuals with obesity or those who are overweight with related health problems. They achieve weight reduction by slowing gastric emptying and promoting a feeling of fullness, leading to reduced calorie intake. Clinical studies have shown significant weight loss in both diabetic and non-diabetic individuals using these medications.
For GLP-2, the synthetic analog teduglutide is used to treat short bowel syndrome (SBS), a severe condition resulting from surgical removal of a significant portion of the small intestine. Patients with SBS often suffer from malabsorption and depend on intravenous parenteral nutrition. Teduglutide works by stimulating the growth and adaptation of the remaining intestinal tissue, enhancing its absorptive capacity for fluids and nutrients. This therapy can significantly reduce or eliminate the need for parenteral nutrition, improving the independence and quality of life for both adult patients and pediatric patients over one year of age.