Glucagon-like peptide-2 (GLP-2) is a 33-amino acid peptide hormone that acts as a signaling molecule in the digestive system. It originates primarily from the gut lining in response to food intake. Its main purpose is to maintain and promote the health of the gastrointestinal tract, ensuring efficient digestion and nutrient absorption.
How GLP-2 is Produced
GLP-2 is released from specialized enteroendocrine L-cells, located predominantly in the lower small intestine and the colon. These cells monitor the contents passing through the gut after a meal. The release of GLP-2 is closely tied to the ingestion of food, particularly fats and carbohydrates, which stimulate the L-cells to secrete the hormone.
The peptide is created through the differential processing of a larger precursor molecule, proglucagon. In the intestine, enzymes cleave proglucagon into several distinct hormones, including GLP-2 and the widely known GLP-1. Both hormones are released simultaneously following a meal, regulating different aspects of digestion and metabolism. However, native GLP-2 is rapidly broken down by the enzyme dipeptidyl peptidase IV (DPP-IV), giving it a very short half-life in the bloodstream.
The Trophic Effects on the Intestine
The most well-established function of GLP-2 is its “trophic” effect, acting as a growth and maintenance factor for the intestinal lining. This action is important because the cells lining the gut, known as enterocytes, are constantly shed and replaced. GLP-2 promotes the growth of the intestinal mucosa by stimulating the proliferation of cells within the crypts, the stem cell niches of the gut.
This growth increases both the height of the villi and the depth of the crypts, expanding the surface area available for nutrient and fluid absorption. By promoting cell growth and inhibiting the programmed death of existing cells, GLP-2 helps repair and regenerate the gut lining.
GLP-2 enhances the intestinal barrier function by tightening the junctions between epithelial cells to reduce gut permeability. This strengthening of the barrier helps prevent the passage of harmful substances from the gut lumen into the bloodstream.
The hormone also influences the mechanics of digestion by regulating gut motility and blood flow. GLP-2 slows down the movement of food through the digestive tract and decreases the secretion of gastric acid. This deceleration allows more time for the intestinal lining to absorb nutrients and fluids efficiently. Additionally, GLP-2 increases blood flow to the intestine, ensuring the enhanced absorptive surface receives the necessary resources to process and transport absorbed nutrients.
Clinical Use in Short Bowel Syndrome
The powerful trophic effects of GLP-2 have made it the basis for a targeted treatment for Short Bowel Syndrome (SBS), a condition resulting from the surgical removal or malfunction of a large part of the small intestine. Patients with SBS often experience severe malabsorption, requiring intravenous feeding, known as parenteral support (PS).
Teduglutide, marketed under names like Revestive or Gattex, is a synthetic, modified version of GLP-2 designed to resist the rapid breakdown by the DPP-IV enzyme. This modification extends the half-life of the drug, allowing for once-daily subcutaneous administration. By activating the GLP-2 receptor, teduglutide stimulates the remaining intestinal tissue to undergo adaptation, promoting mucosal growth and increasing the functional surface area.
The drug’s action helps the intestine absorb more fluids and nutrients, significantly reducing the patient’s reliance on PS. Clinical studies show that teduglutide leads to a measurable reduction in the volume of intravenous fluid needed, improving the quality of life and reducing complications associated with long-term PS use. This therapeutic application represents a major advance in SBS treatment, shifting the focus from supportive care to functional restoration of the remaining gut.
Beyond Intestinal Growth
While its primary role is in gut function, research is uncovering systemic effects of GLP-2 that extend beyond the digestive tract. One area of interest is the hormone’s potential involvement in bone metabolism. Studies suggest that GLP-2 may play a role in the “gut-bone” axis, influencing the balance between bone formation and resorption.
GLP-2 administration has been associated with a reduction in markers of bone resorption and a modest increase in spinal bone mineral density in some patient populations. This effect may be indirectly mediated by improved intestinal calcium absorption or by influencing parathyroid hormone (PTH) levels.
Furthermore, GLP-2 exhibits anti-inflammatory properties within the gut, which may offer therapeutic potential for inflammatory conditions like Crohn’s disease, separate from its growth-promoting actions.
The hormone also has connections to energy homeostasis and glucose regulation, particularly through its interaction with the central nervous system. GLP-2 can suppress food intake and gastric emptying by acting on receptors in the brain. These secondary and systemic actions indicate that GLP-2 is a pleiotropic hormone with a wider array of functions in maintaining overall metabolic health.