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.
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.
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.
[Glycine2]-GLP-2 (a long-acting agonist), Teduglutide
(a protease-resistant analog of GLP-2). There are no high-affinity specific GLP-2 receptor
antagonists but GLP-2(11–33) and GLP-2(3–33) are
known as antagonists.
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.
GLP-2 is cosecreted with GLP-1 in response to nutrient
ingestion. The principal role of GLP-2 appears to be the
maintenance of the growth and absorptive function of the
intestinal mucosal villus epithelium. GLP-2 was first identified as a novel peptide following
the cloning of the proglucagon gene in the early 1980s,
and subsequently the biosynthesis and release of GLP-2
were confirmed by isolation and characterization from
the porcine and human small intestine. The biological
role of GLP-2 as a stimulator of intestinal epithelial proliferation was first demonstrated in 1996.
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.
