GLP-2 has a number of actions in the intestine including:
Stimulation of mucosal growth in the small and large intestine
Inhibition of enterocyte and crypt cell apoptosis
Stimulation of enterocyte glucose transport and GLUT-2 expression
Increased nutrient absorption
Inhibition of gastric emptying and gastric acid secretion
Reduction of intestinal permeability
Stimulation of intestinal blood flow
Relaxation of intestinal smooth muscle
Moreover, GLP-2 also has actions outside the GI tract, including stimulation of cell proliferation in rat astrocyte cell cultures (Glucagon-like peptide-2 stimulates the proliferation of cultured rat astrocytes. Eur J Biochem. 2003 Jul;270(14):3001-9)
Although plasma glucose does not change following GLP-2 administration in rodents or humans, pharmacological levels of GLP-2 (~10-fold higher than normal) are associated with increased circulating levels of glucagon in the fasted and postprandial state in normal human subjects, as shown in Glucagon-like Peptide 2 stimulates glucagon secretion, enhances lipid absorption, and inhibits gastric Acid secretion in humans. Gastroenterology. 2006 Jan;130(1):44-54. Moreover, deHeer and colleagues have demonstrated GLP-2 receptor expression in rat islets by RT-PCR and have demonstrated localization of GLP-2R immunoreactive protein to α-cells in human and rat islets by immunocytochemistry. Perfused rat pancreas experiments demonstrated that 10 nM GLP-2 stimulates glucagon secretion See The alpha cell expresses glucagon-like peptide-2 receptors and glucagon-like peptide-2 stimulates glucagon secretion from the rat pancreas. Diabetologia. 2007 Aug 4; [Epub ahead of print]
GLP-2 and bone
A single injection of GLP-2 inhibited the liberation of C-terminal telopeptide region of type I collagen, a marker of bone resorption, in postmenopausal women. Similarly, the levels of urine DPD/creatinine, a marker of bone resorption, were also significantly reduced in patients receiving a single 800-microg dose of GLP-2. Hence GLP-2 pharmacologically modulates bone resorption, as outlined in Role of gastrointestinal hormones in postprandial reduction of bone resorption. J Bone Miner Res. 2003 Dec;18(12):2180-9
The effect of GLP-2 on bone turnover at different time points during the 24h cycle has been examined in part in short term studies of healthy female postmenopausal subjects. GLP-2 administration produced a dose-related reduction of s-CTX, a marker of bone resorption, and osteocalcin levels were increased. Hence, acute GLP-2 administration may have effects on bone turnover that spans both inhibition of resorption, and possibly, stimulation of bone formation. See Reduction of nocturnal rise in bone resorption by subcutaneous GLP-2. Bone. 2004 Jan;34(1):140-7. The predominant effect of GLP-2 on inhibition of bone resorption was confirmed in a 14 day study of postmenopausal women who received either 1.6 or 3.2 mg of GLP-2 as a subcutaneous injection. GLP-2 significantly inhibited bone resorption as measured by nocturnal serum and urine concentrations of fragments derived from the degradation of the C-terminal telopeptide region of collagen type I (s-CTX and u-CTX) and u-DPD. In contrast, no change in levels of bone formation, serum osteocalcin and procollagen type I N-terminal propeptide (PINP), were observed following GLP-2 treatment. See Disassociation of bone resorption and formation by GLP-2 A 14-day study in healthy postmenopausal women. Bone. 2006 Oct 31; [Epub ahead of print]
A longer and larger study examined the effects of GLP-2 administration at doses of
0.4 mg, 1.6 mg and 3.2 mg GLP-2, administered nightly
for 4 months in postmenopausal women with osteoporosis.
GLP-2 treatment reduced the nocturnal rise in the bone resorption marker
s-CTX, but had no effect on osteocalcin, a marker of bone formation.
Treatment with GLP-2 modestly but significantly increased total hip BMD in a dose-dependent manner
Four-Month Treatment with GLP-2 Significantly Increases Hip BMD A randomized, placebo-controlled, dose-ranging study in postmenopausal women with low BMD
Bone. 2009 Nov;45(5):833-42
Gastrointestinal actions of GLP-2
What are the molecular targets for GLP-2 action? The IGF-1 system is important for GLP-2 action in mice, as GLP-2 induces the expression of IGF-1 in vitro and IGF-1-/- mice exhibit markedly impaired responses to GLP-2 in vivo. Furthermore, IGF-2-/- mice also exhibited an impairment of selective GLP-2 actions as described in The essential role of insulin-like growth factor-1 in the intestinal tropic effects of glucagon-like Peptide-2 in mice. Gastroenterology. 2006 Aug;131(2):589-605. Infusion of GLP-2 in TPN-fed rats resulted in upregulation of sucrase-isomaltase gene expression in the small bowel, but no change in the levels of cdx-2, a key transcription factor that regulates SI gene expression. Hence, the mechanism for these findings remains uncertain, but is likely related to the GLP-2-induction of a coordinated molecular program of small bowel epithelial growth. To review the data, see Am J Physiol Gastrointest Liver Physiol 2000 Mar;278(3):G425-G428 Glucagon-like peptide-2 increases sucrase-isomaltase but not caudal-related homeobox protein-2 gene expression
GLP-2 also appears to exert effects on the gut independent of IGF-1 or KGF action. GLP-2 administration in mice produces a spectrum of action comparable to that described for EGF, including stimulation of crypt cell proliferation, and both EGF and GLP-2 activate a number of common downstream targets in the small and large bowel. Moreover, GLP-2 , but not IGF-1 or KGF activates a subset of ErbB family members in the murine gut, and many of the actions of GLP-2 in the GI tract are significantly diminished or eliminated following elimination of ErbB signaling. See . ErbB signaling is required for the proliferative actions of GLP-2 in the murine gut doi:10.1053/j.gastro.2009.05.057
Of the actions in the GI tract delineated above, the most rapid effects detected following GLP-2 infusion are localized to the enterocyte, with enhanced hexose transport mediated in part by increased GLUT-2 localization to the basolateral membrane in the rat. See Upregulation of SGLT-1 transport activity in rat jejunum induced by GLP-2 infusion in vivo. Am J Physiol. 1997 Dec;273(6 Pt 2):R1965-71 and Basolateral D-glucose transport activity along the crypt-villus axis in rat jejunum and upregulation induced by gastric inhibitory peptide and glucagon-like peptide-2. Exp Physiol. 1998 Sep;83(5):605-16 and Rapid insertion of GLUT2 into rat Jejunal brush-border membrane promoted by glucagon-like peptide 2. Biochem J. 2002 Jul 3
Similarly, GLP-2 rapidly promotes absorption of enteral lipids, and increases secretion of triglyceride (TG)-rich lipoprotein (TRL)-apoB48. GLP-2 also stimulated secretion of TRL-rich particles from jejunal fragments. The actions of GLP-2 on intestinal lipid synthesis/secretion were diminished in CD36-/- mice. See Glucagon-like Peptide-2 Increases Intestinal Lipid Absorption and Chylomicron Production via CD36 Gastroenterology. 2009 May 28. [Epub ahead of print]
Does GLP-2 have a role in the maturation of the fetal or neonatal gut? The GLP-2 receptor is expressed in the fetal gut and treatment of neonatal rats, from the first day of birth, with GLP-2, promotes enhanced gut growth. Similarly, treatment of premature pigs, infused with TPN, with GLP-2, also enhanced DNA synthesis, increased villus height, reduced apoptosis and reduced proteolysis in the developing pig gut. See GLP-2 stimulates intestinal growth in premature TPN-fed pigs by suppressing proteolysis and apoptosis AJP Vol. 279, Issue 6, G1249-G1256, December 2000.
In contrast, although the GLP-2 receptor is expressed in the fetal pig and rat intestine, biologically active GLP-2 (1-33) is not detected in the circulation of 98-day gestation fetuses, but is detectable by day 115. Furthermore, exogenous GLP-2 did not stimulate growth of the fetal pig gut, but was trophic to the neonatal pig intestine. These findings imply that GLP-2 is unlikely to play a major if any role in gut development. To review these elegant experiments, see GLP-2 has differential effects on small intestine growth and function in fetal and neonatal pigs. Am J Physiol Regul Integr Comp Physiol. 2001 Dec;281(6):R1986-93
Administration of GLP-2 twice daily alone or in combination with dexamethasone to rats beginning at day 11 after birth for 10 days produced selective increases in lipid absorption assessed ex vivo. Animals were analyzed at postnatal day 21 and at 7 weeks of age. Although no change in body weight was observed with GLP-2 alone, GLP-2 prevented the reduction in body weight observed with dexamethasone treatment. Similarly, GLP-2 alone had no effect on intestinal or mucosal weight. GLP-2 alone did not change lipid uptake in the jejunum or ileum of suckling or weanling rats. See Treatment of suckling rats with GLP-2 plus dexamethasone increases the ileal uptake of fatty acids in later life. Am J Physiol Gastrointest Liver Physiol. 2005 Jan;288 (1): G54-9
GLP-2 also stimulates the induction of PC2/TIS7, an immediate early gene, in both IEC cells cultured in vitro, and in the murine small bowel following exogenous [Gly2]-GLP-2 treatment in vivo. The molecular mechanisms coupling GLP-2 activated signaling pathways to induction of PC2/TIS7 expression remain to be determined. See Growth factor regulation of PC4/TIS7, an immediate early gene expressed during gut adaptation after resection. JPEN J Parenter Enteral Nutr. 2003 Mar-Apr;27(2):123-31.
GLP-2 and control of blood flow
Infusion of GLP-2 in 20 day old TPN-fed piglets to achieve pharmacological levels of GLP-2 (~ 400 pM) produces a rapid increase in portal-visceral blood flow (detectable within 10 minutes) and intestinal blood volume. GLP-2 also increased intestinal cNOS protein and activity and co-infusion of GLP-2 and L-NAME abrogated the stimulation of blood flow or intestinal glucose uptake. See GLP-2-mediated up-regulation of intestinal blood flow and glucose uptake is nitric oxide-dependent in TPN-fed piglets 1. Gastroenterology. 2003 Jul;125(1):136-147. The actions of GLP-2 to stimulate blood flow are more evident in the duodenum and jejunum but not in the distal small bowel or colon. High dose GLP-2 (2000 pmol/kg/hr) also increased pancreatic blood flow in pigs, consistent with a predominant effect localized the the superior mesenteric artery Glucagon-like peptide-2 acutely increases proximal small intestinal blood flow in TPN-fed neonatal piglets Am J Physiol Regul Integr Comp Physiol. 2006 Feb; 290(2):R283-9. The co-localization of eNOS and the GLP-2R in subsets of porcine enteric neurons, together with the detection of increased eNOS protein in porcine jejunum provide further evidence for the importance of eNOS as a downstream target for GLP-2 action GLP-2 receptor localizes to enteric neurons and endocrine cells expressing vasoactive peptides and mediates increased blood flow Gastroenterology. 2006 Jan;130(1):150-64.
GLP-2 infusion also increased SMA blood flow in anesthetized rats. Modest increases in blood flow were also seen in the carotid artery. L-NAME only partially abolished the effect of GLP-2 on blood flow and indomethacin, CCK antagonists or the GLP-1 antagonist exendin(9-39) did not attenuate the effect of GLP-2 on SMA blood flow. Mediators of glucagon-like peptide 2-induced blood flow: responses in different vascular sites Regul Pept. 2007 Jul 5;142(1-2):7-15.
The effects of GLP-2 on blood flow have also been demonstrated in healthy human subjects in the fasting state, where intravenous or s.c GLP-2 administration rapidly increased SMA blood flow, to the same extent as meal ingestion Glucagon-like peptide-2 increases mesenteric blood flow in humans Scand J Gastroenterol. 2009;44(3):314-9.
GUT PERMEABILITY
Studies
in rodents have demonstrated that GLP-2 improves survival and decreases bacterial infection following
intestinal injury. Experiments from the lab of Mary Perdue in Hamilton now show
that GLP-2 reduces intestinal permeability via effects on the transcellular
and paracellular pathways in mice. GLP-2 increases the number of microvilli and
increases cell length. Some of the functional effects on permeability were rapid
and detected as early as 4 hours after GLP-2 administration. Subsequent studies employing a murine model of hypersensitivity
and antigen sensitization demonstrated GLP-2 reduced permeability, decreased the number of inflammatory cells, and
attenuated intestinal macromolecular uptake. See Gut 2000;47:112-119
( July ) Glucagon-like
peptide-2 enhances intestinal epithelial barrier function of both transcellular
and paracellular pathways in the mouse. Gut. 2000 Jul;47(1):112-9 and Glucagon-like
peptide-2-enhanced barrier function reduces pathophysiology in a model of food
allergy. Am J Physiol Gastrointest Liver Physiol. 2003 Jun;284(6):G905-G912. Although GLP-2 reduces gut permeability in NOD mice, it does not prevent the development of autoimmune diabetes
Glucagon like peptide-2 reduces intestinal permeability but does not modify the onset of type 1 diabetes in the non obese diabetic mouse. Endocrinology.
2009 Feb;150(2):592-9. Epub 2008 Oct 9
GLP-2 may also play a role in the development of experimental inflammation via effects on gut permeability as outlined in studies of ob:ob mice. Administration of the GLP-2 antagonist GLP-2(3-33) abolished the beneficial effects of prebiotics on inflammatory mediators in ob:ob mice, whereas treatment of ob:ob mice with GLP-2 reduced plasma levels of LPS, decreased circulating levels of inflammatory cytokines, and upregulated expression, as assessed by immunohistochemistry of tight junction proteins occludin and zonula occludens-1, and plasma levels of FTIC dextran. These findings invoke a role for endogenous and exogenous GLP-2 action in modulation of gut permeability, indirectly influencing the level of systemic inflammation in obese mice. See Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability Gut. 2009 Feb 24. [Epub ahead of print]
Does GLP-2 exert trophic effects in humans? An indirect answer to this question derives from the historical observation that a single patient with a glucagon-producing tumor presented clinically with massive small bowel enlargement, as described in Endocrine tumour in kidney affecting small bowel structure, motility, and absorptive function. Gut. 1971 Oct;12(10):773-82. To review the data on human patients with glucagonomas and intestinal growth, see GLP-2 and Human Tumors..
The most convincing evidence for GLP-2 biological actions in human subjects derives from studies of GLP-2 administration to patients with short bowel syndrome. To review the data from a human GLP-2 pilot study in patients with short bowel syndrome, see "GLP-2 Improves Nutrient Absorption and Nutritional Status in Short-Bowel Patients With No Colon" in the March 2001 issue of Gastroenterology, and the accompanying Editorial.
Does GLP-2 regulate calcium metabolism or bone turnover?
In the pilot study of GLP-2 administration to human subjects with short bowel syndrome, 400 ug GLP-2 twice daily for 5 weeks reduced stomal calcium excretion, increased bone mass and a trend to increased calcium absorption was noted in 6 patients. A F/U paper reported parameters of calcium absorption and bone turnover in more detail in these patients. GLP-2 treatment increased spinal bone mineral density (BMD), and increased calcium absorption in patients not receiving parenteral nutrition. Markers of bone turnover decreased in most of the GLP-2-treated patients. See Short-term administration of glucagon-like peptide-2. Effects on bone mineral density and markers of bone turnover in short-bowel patients with no colon. Scand J Gastroenterol. 2002 Apr;37(4):392-8
GLP-2 actions on intestinal smooth muscle
GLP-2 produces concentration-dependent relaxation of murine gastric muscle, actions that were reduced by pharmacological blockade of neuronal N-type voltage operated calcium channels, and by a VIP receptor antagonist. GLP-2 also produced direct relaxation of carbachol-precontracted muscle strips from the mouse fundus. See GLUCAGON-LIKE PEPTIDE-2 RELAXES MOUSE STOMACH THROUGH VASOACTIVE INTESTINAL PEPTIDE RELEASE. Am J Physiol Gastrointest Liver Physiol. 2009;296 G678-G684