The GLP-2 receptor is defined as a specific receptor primarily located in the gut and brain, through which the gastrointestinal hormone glucagon-like peptide-2 (GLP-2) exerts its effects on intestinal morphology, function, and energy metabolism.
Glucagon-like peptide-2 is produced with GLP-1 and also increases crypt cell proliferation and decreases enterocyte apoptosis in rats and mice. Glucagon-like peptide-2 decreases mucosal injury in indomethacin-induced colitis and chemical-induced inflammatory bowel disease. In premature pigs sustained by parenteral nutrition, GLP-2 stimulates intestinal growth. In patients with short bowel syndrome, GLP-2 increased villus height and crypt depth and improved nutrient absorption and nutritional status. Immunoneutralization of endogenous GLP-2 reduces the adaptive intestinal growth in diabetic rats. Glucagon-like peptide-2 administration in rodents increases small intestine weight, mucosal crypt, and villus height. The GLP-2-induced increase in small intestine weight and mucosal thickness is due, in part, to the stimulation of crypt cell proliferation, resulting expansion of the crypt compartment, and a lengthening of the villi. Together, these data suggest that GLP-2 is an important regulator of intestinal growth.
The GLP-2 receptor, GPCR, is expressed predominantly in the GI tract localized to enteroendocrine cells. In the mouse, GLP-2 stimulates proliferation of columnar but not mucous progenitor cells. Increased proliferation is associated with activation of c -fos in crypt cells that do not express GLP-2 receptors, suggesting the involvement of an unidentified downstream mediator.
The glucagon-like peptide-2 receptor is expressed in the gastrointestinal tract and directly inhibits apoptosis and maintains mucosal integrity by stimulating cell proliferation in response to ligand activation. The GLP2R modulates the stable association with β-arrestin2 and is required for G protein-coupled signaling, homologous desensitization, and receptor endocytosis. Interestingly, the GLP2R carboxy-terminus, which contains the PDZ-recognition sequence, ESEI, tethers the unbound receptor at the plasma membrane and directs intracellular trafficking of internalized receptors. The interacting proteins responsible for this activity remain to be identified.
Glucagon-like peptide-2 (GLP-2) is an enterotrophic hormone and a member of the pituitary adenylate cyclase activating peptide glucagon superfamily. GLP-2 is synthesized in enteroendocrine L cells of the distal ileum and proximal colon. Within this 33–amino acid protein, the second amino acid in the sequence is alanine, which makes the hormone sensitive to degradation by the exopeptidase dipeptidyl peptidase-4. Substitution of glycine for alanine at position 2 makes a synthetic analog of GLP-2 (teduglutide) that is resistant to enzymatic degradation and significantly extends its half-life.
GLP 2 exerts its effects through the GLP-2 receptor, which has been identified on intestinal enteroendocrine cells, enteric neurons, and subepithelial myofibroblasts. Secretion of GLP-2 by intestinal L cells is driven by both direct stimulation of nutrients in the distal bowel and vagally mediated pathways, which are activated by the presence of nutrients in the proximal bowel. Ingestion of nutrients, particularly long-chain fatty acids, plays a major role in GLP-2 secretion. In patients with short-bowel syndrome, the presence of a colon in continuity with the small intestine is important for nutrient-stimulated increases in GLP-2. This finding may help explain why the presence of the colon reduces the likelihood that
