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Usage

Uses

Used in Pharmaceutical Industry:
GLP-2 (HUMAN) is used as a therapeutic agent for promoting intestinal epithelial proliferation and maintaining the growth and absorptive function of the intestinal mucosal villus epithelium. It is particularly useful in treating conditions that involve intestinal damage or malabsorption, such as short bowel syndrome.
Used in Research Applications:
GLP-2 (HUMAN) is used as a research tool for studying the mechanisms of intestinal epithelial proliferation and the role of GLP-2 in maintaining intestinal health. It aids in understanding the biological role of GLP-2 and its potential as a therapeutic target for various gastrointestinal disorders.
Used in Drug Development:
GLP-2 (HUMAN) is used in the development of agonists and antagonists for targeting the GLP-2 receptor. Long-acting agonists, such as [Glycine2]-GLP-2, and protease-resistant analogs like Teduglutide, are being developed to enhance the therapeutic potential of GLP-2 in treating intestinal disorders. Additionally, antagonists like GLP-2(11–33) and GLP-2(3–33) are being studied to understand their effects on GLP-2 receptor activity.

Structure

GLP-2 is a 33-aa peptide hormone, and has high sequence homology as a member of the glucagon family. The N-terminal two aa residues are cleaved off by dipeptidyl peptidase 4 (DPP-4). The N-terminal truncated GLP-2 fragment, GLP-2(3–33), acts as a competitive antagonist of the GLP-2 receptor, inhibiting nutrient- and GLP-2-induced mucosal growth in rodents. Phylogenetic analyses suggest that GLP-2 sequences have diversified most rapidly among the members of the glucagon family.?Human GLP-2: Mr 3766.1, theoretical pI 4.17. GLP-2 is soluble in 5% NH4OH (-1mg/mL). GLP-2 is inactivated by DPP-4.

Gene, mRNA, and precursor

The human proglucagon gene, GCG, location 2q36– q37, spans approximately 9.4 kb and comprises six exons and five introns. It encodes a preproglucagon of 180 aa residues that contains glucagon, GLP-1, and GLP-2.?The expression of proglucagon has been detected in the pancreatic α cells, intestinal L cells, and brain.

Synthesis and release

Glucagon, GLP-1, and GLP-2 are processed from proglucagon in pancreatic α cells and intestinal L cells in a tissue-specific manner. Prohormone convertases (PCs) are responsible for the tissue-specific processing. In pancreatic α cells, the major bioactive hormone is glucagon cleaved by PC2, whereas in the intestinal L cells, PC1/3 liberates GLP-1 and GLP-2 as bioactive hormones. As a result, GLP-1 and GLP-2 are coreleased from intestinal L cells in a 1:1 ratio following nutrient ingestion. GLP-2 secretion is also regulated by GIP and somatostatin, a gastrin-releasing peptide, and neural stimuli in a species-specific manner.

Receptors

The receptor of GLP-2 (GLP2R) is a seventransmembrane GPCR that belongs to a subclass of the family B. The human GLP-2 receptor gene, GLP2R, is located on chromosome 17 (17p13.3), and the human and rat GLP-2 receptor cDNAs were cloned from the intestine and hypothalamus in 1999. The GLP-2 receptor is highly specific to GLP-2, with increased cAMP production (EC50=0.58 nM), but not to related members of the glucagon peptide family.?GLP-2 activates cAMP production in rodent and human cells transfected with the rat or human GLP-2 receptor.

Biological functions

Compared with GLP-1 and glucagon receptors, GLP-2 receptor expression is more restricted, occurring predominantly in the gastrointestinal tract, brain, and lung. In the rat, the GLP-2 receptor is most abundant in the jejunum, followed by the duodenum, ileum, colon, and stomach, and at very low levels in several other tissues including the central nervous system. The gastrointestinal tract, from the stomach to the colon, is the principal target for GLP-2 action. It has been suggested that GLP-2 may exert diverse actions involved mainly in the control of gastrointestinal growth and function (for example, epithelial integrity, motility, and secretion; local blood flow; and nutrient uptake and utilization). A stimulatory effect of GLP-2 on glucagon secretion from the human pancreas has also been reported. However, the GLP-2 receptor is not localized to the known target cells of GLP-2 tropic action, but to scattered enteroendocrine cells, enteric neurons, and subepithelial myofibroblasts. These results suggest that paracrine and/or neural pathways may mediate the intestinal tropic actions of GLP-2. It has been reported that GLP-2 acts through a neural pathway to affect intestinal crypt cell c-fos expression, and through a nitric oxide-dependent mechanism to affect intestinal blood flow. For GLP-2-induced epithelial growth, KGF and IGF-1, secreted from subepithelial myofibroblasts, act as essential mediators in response to GLP-2. GLP-2 receptor mRNA expression has also been found in the normal human cervix, but its functional relevance is not yet known. The GLP-2 receptor is also expressed in?the central nervous system including the hypothalamus. Central GLP-2 is expected to be related to the regulation of feeding behavior. Several studies suggest that GLP2 exerts beneficial effects on glucose metabolism, especially in conditions related to the increased uptake of energy, such as obesity, at least in the animal model.

Clinical Use

The pharmacological application of GLP-2 has been recognized and assessed in preclinical and clinical investigations to prevent or treat a number of intestinal diseases, including short bowel syndrome, Crohn’s disease, inflammatory bowel disease, chemotherapyinduced intestinal mucositis, colon carcinogenesis, and small bowel enteritis. The US Food and Drug Administration has accepted Teduglutide, an analog of GLP-2, for use in adult patients with short bowel syndrome.