GLP-2 is a 33 amino acid peptide, secreted from enteroendocrine L cells in the distal ileum and colon in a biphasic pattern, in response to nutrient ingestion including glucose, fatty acids and dietary fiber. Can J Physiol Pharmacol. 2003 Nov;81(11):1005-12. The search for the substance with intestinotrophic action seen associated with some tumours showing glucagon like immunoreactivity culminated in identification of the potential of GLP-2. GLP 2 is co-encoded with GLP-1 inside the pro-glucagon gene, and secreted in a 1:1 ratio with GLP-1 from intestinal cells. Endocrinology. 1986 Oct;119(4):1467-75.Proglucagon is metabolised in the gut to produce GLP-1 and GLP- 2 and Oxyntomodulin (in contrast to the metabolisation of Proglucagon to glucagon in the pancreas)- or in other words, tissue specific post-translational processing. Pre-proglucagon is also found in the brainstem in a small population of nerve cells in the nucleus of the solitary tract (NTS) that process the pre-propeptide as in the gut to yield GLP-1 and GLP-2.
GLP 2 (1-33) is the active form; GLP 2 (3-33) is the inactive degraded form. The half life of GLP-2 is a mere 5-7 minutes. J Clin Endocrinol Metab. 2000 Aug;85(8):2884-8 Degradation of GLP-2 is effected by Dipeptidyl peptidase IV (DPP-IV) a serine protease. Fasting plasma level of the biologically active form is 15-20 pM, which increases 2-5 fold in proportion to the size and nutrient composition of the meal ingested. Gastroenterology. 1999 Jul;117(1):99-105.
The majority of GLP-2 entering the circulation has already been inactivated by DPP-IV. Excretion is mainly effected by the kidneys and hence, GLP-2 levels increase in uraemia. J Clin Endocrinol Metab. 1992 Feb;74(2):379-84. GLP-2R (G protein coupled receptor for GLP 2) is expressed predominantly in the enteric neurones of the stomach, small bowel and colon and the brain. J Nutr. 2003 Nov;133(11):3708-11.
Actions of GLP-2
A patient with a glucagon producing tumour in the kidney developed massively enlarged small bowel and intestinal villous hyperplasia, with resolution of the defect after tumour removal. Gut. 1971 Oct;12(10):773-82 It is, in retrospect, likely that the intestinal hyperplasia might well have been mediated by GLP-2, which may have been produced in excess due to specific intra-tumoural post-translational processing. GLP-2 has been shown to increase small bowel mass in mice.Proc Natl Acad Sci U S A. 1996 Jul 23;93(15):7911-6 GLP-2 may play a role in intestinal repair after injury. Patients undergoing jejunoileal bypass exhibited increased enteroglucagon in circulation and hyperplasia in the intestinal remnant with preservation of the mucosal epithelium in the bypassed intestinal segment. Int J Obes. 1981;5(5):471-80 Circulating GLP-2 levels are increased following bowel resection or intestinal injury but not after colonic resection suggesting that an intact colon is important to increase GLP-2 production. Gut. 1982 Oct;23(10):854-61. DPP-IV inhibition concomitant with GLP-2 infusion produces even greater intestinotrophic action than GLP-2 infusion alone. Endocrinology. 2000 Nov;141(11):4013-20.
GLP-2 increases the depth of crypts in the small intestine. GLP-2 infusion intravenously prevented small bowel mucosal villous hypoplasia from developing in rats maintained on parenteral nutrition. Despite its short half life, once daily injections were sufficient to sustain intestinal weight increase in rats, suggesting that intermittent rise in GLP-2 levels are enough for the intestinotrophic actions. Am J Physiol. 1997 Jul;273(1 Pt 1):E77-84. Rats given GLP-2 were relatively protected against Indomethacin induced intestinal ulcerations; Am J Physiol. 1999 Nov;277(5 Pt 1):E937-47 The protective effect is likely to be due to enhanced repair of gut mucosa through crypt cell proliferation and suppression of apoptosis in the crypts.Gastroenterology. 2002 Feb;122(2):531-44 Similar protective effects on the intestinal epithelium with GLP-2 has been demonstrated in rats with ischemic gut, induced by superior mesenteric artery occlusion. J Pediatr Surg. 2000 Feb;35(2):357-9.
GLP-2 maintains intestinal mucosal integrity with decreased likelihood of bacterial sepsis and improved survival in rats treated with chemotherapeutic agents. Cancer Res. 2001 Jan 15;61(2):687-93. GLP-2 is effective in decreasing the intestinal permeability in acute necrotising pancreatitis in rats, which has been blamed to be responsible in facilitating bacterial translocation. Am J Surg. 2001 Jun;181(6):571-5 Circulating enteroglucagon has been demonstrated to be higher in Coeliac disease and tropical sprue, with elevated levels being related to the degree of malabsorption Gut. 1984 Jun;25(6):629-35 .GLP-2 levels were also higher in crohn's and ulcerative colitis associated with reduced activity of DPP-IV enzyme, suggesting a protective mechanism initiated to facilitate bowel repair in these diseases. Am J Physiol Regul Integr Comp Physiol. 2000 Apr;278(4):R1057-63
In humans with short bowel syndrome GLP-2 administration increases both energy absorption and lean body mass and is well tolerated. Gastroenterology. 2001 Mar;120(4):806-15. GLP-2 may act to curtail fluid loss in patients with short bowel syndrome.
Increased islet and portal blood flow is another beneficial effect of GLP-2. GLP-2 delays gastric emptying but less potently than GLP-1. Scand J Gastroenterol. 2004 Apr;39(4):353-8. GLP 2 has not been shown to have any effect on food intake in humans. GLP-2 has not been shown to be critical in the development of fetal intestine, but does contribute to neonatal intestinal growth. Rats lacking GLP-2 due to a mutation, exhibited normal growth of the bowels.
Therapeutic implications of GLP-2
GLP-2 agonism may be used to protect against NSAID-induced mucosal damage and chemotherapy-associated gastrointestinal toxicity, as well as to increase intestinal absorptive surface post resective surgery? Teduglutide ([Gly2]GLP-2), a dipeptidyl peptidase (DPP-IV) resistant analogue of GLP-2, has encouragingly trophic actions on the intestine. A 3 week study with subcutaneous Teduglutide administration in patients with short bowel shows increased villus height, crypt depth, and mitotic index with increased intestinal wet weight absorption. Gut. 2005 Sep;54(9):1224-31 Teduglutide has also been shown to have protective effects on the intestine from radiation induced damage if administered prior to the procedure by modulating clonogenic stem cell survival in the small intestine. Cell Prolif. 2004 Dec;37(6):385-400. The physiological action of GLP 2 in the CNS remains to be elucidated. Metformin has been shown to increase GLP-1 levels and due to the co secretion of GLP-1 and GLP-2, it was no surprise that GLP-2 levels were also increased in rats by 2 fold using metformin .Eur J Pharmacol. 2004 Mar 19;488(1-3):213-8 A protective effect on 5FU-induced weight reduction of the small intestine of rats has been shown in that study using a combination of Metformin and a DPP-IV inhibitor (but not by either alone). DPP-IV inhibitor valine pyrrolidide (val-pyr) has been shown to potentiate the effect of exogenous GLP-2 in rodents with increased levels of active GLP-2 Endocrinology. 2000 Nov;141(11):4013-20. making it a potential agent for combination therapy with GLP-2 agonists.
GLP 2 (1-33) is the active form; GLP 2 (3-33) is the inactive degraded form. The half life of GLP-2 is a mere 5-7 minutes. J Clin Endocrinol Metab. 2000 Aug;85(8):2884-8 Degradation of GLP-2 is effected by Dipeptidyl peptidase IV (DPP-IV) a serine protease. Fasting plasma level of the biologically active form is 15-20 pM, which increases 2-5 fold in proportion to the size and nutrient composition of the meal ingested. Gastroenterology. 1999 Jul;117(1):99-105.
The majority of GLP-2 entering the circulation has already been inactivated by DPP-IV. Excretion is mainly effected by the kidneys and hence, GLP-2 levels increase in uraemia. J Clin Endocrinol Metab. 1992 Feb;74(2):379-84. GLP-2R (G protein coupled receptor for GLP 2) is expressed predominantly in the enteric neurones of the stomach, small bowel and colon and the brain. J Nutr. 2003 Nov;133(11):3708-11.
Actions of GLP-2
A patient with a glucagon producing tumour in the kidney developed massively enlarged small bowel and intestinal villous hyperplasia, with resolution of the defect after tumour removal. Gut. 1971 Oct;12(10):773-82 It is, in retrospect, likely that the intestinal hyperplasia might well have been mediated by GLP-2, which may have been produced in excess due to specific intra-tumoural post-translational processing. GLP-2 has been shown to increase small bowel mass in mice.Proc Natl Acad Sci U S A. 1996 Jul 23;93(15):7911-6 GLP-2 may play a role in intestinal repair after injury. Patients undergoing jejunoileal bypass exhibited increased enteroglucagon in circulation and hyperplasia in the intestinal remnant with preservation of the mucosal epithelium in the bypassed intestinal segment. Int J Obes. 1981;5(5):471-80 Circulating GLP-2 levels are increased following bowel resection or intestinal injury but not after colonic resection suggesting that an intact colon is important to increase GLP-2 production. Gut. 1982 Oct;23(10):854-61. DPP-IV inhibition concomitant with GLP-2 infusion produces even greater intestinotrophic action than GLP-2 infusion alone. Endocrinology. 2000 Nov;141(11):4013-20.
GLP-2 increases the depth of crypts in the small intestine. GLP-2 infusion intravenously prevented small bowel mucosal villous hypoplasia from developing in rats maintained on parenteral nutrition. Despite its short half life, once daily injections were sufficient to sustain intestinal weight increase in rats, suggesting that intermittent rise in GLP-2 levels are enough for the intestinotrophic actions. Am J Physiol. 1997 Jul;273(1 Pt 1):E77-84. Rats given GLP-2 were relatively protected against Indomethacin induced intestinal ulcerations; Am J Physiol. 1999 Nov;277(5 Pt 1):E937-47 The protective effect is likely to be due to enhanced repair of gut mucosa through crypt cell proliferation and suppression of apoptosis in the crypts.Gastroenterology. 2002 Feb;122(2):531-44 Similar protective effects on the intestinal epithelium with GLP-2 has been demonstrated in rats with ischemic gut, induced by superior mesenteric artery occlusion. J Pediatr Surg. 2000 Feb;35(2):357-9.
GLP-2 maintains intestinal mucosal integrity with decreased likelihood of bacterial sepsis and improved survival in rats treated with chemotherapeutic agents. Cancer Res. 2001 Jan 15;61(2):687-93. GLP-2 is effective in decreasing the intestinal permeability in acute necrotising pancreatitis in rats, which has been blamed to be responsible in facilitating bacterial translocation. Am J Surg. 2001 Jun;181(6):571-5 Circulating enteroglucagon has been demonstrated to be higher in Coeliac disease and tropical sprue, with elevated levels being related to the degree of malabsorption Gut. 1984 Jun;25(6):629-35 .GLP-2 levels were also higher in crohn's and ulcerative colitis associated with reduced activity of DPP-IV enzyme, suggesting a protective mechanism initiated to facilitate bowel repair in these diseases. Am J Physiol Regul Integr Comp Physiol. 2000 Apr;278(4):R1057-63
In humans with short bowel syndrome GLP-2 administration increases both energy absorption and lean body mass and is well tolerated. Gastroenterology. 2001 Mar;120(4):806-15. GLP-2 may act to curtail fluid loss in patients with short bowel syndrome.
Increased islet and portal blood flow is another beneficial effect of GLP-2. GLP-2 delays gastric emptying but less potently than GLP-1. Scand J Gastroenterol. 2004 Apr;39(4):353-8. GLP 2 has not been shown to have any effect on food intake in humans. GLP-2 has not been shown to be critical in the development of fetal intestine, but does contribute to neonatal intestinal growth. Rats lacking GLP-2 due to a mutation, exhibited normal growth of the bowels.
Therapeutic implications of GLP-2
GLP-2 agonism may be used to protect against NSAID-induced mucosal damage and chemotherapy-associated gastrointestinal toxicity, as well as to increase intestinal absorptive surface post resective surgery? Teduglutide ([Gly2]GLP-2), a dipeptidyl peptidase (DPP-IV) resistant analogue of GLP-2, has encouragingly trophic actions on the intestine. A 3 week study with subcutaneous Teduglutide administration in patients with short bowel shows increased villus height, crypt depth, and mitotic index with increased intestinal wet weight absorption. Gut. 2005 Sep;54(9):1224-31 Teduglutide has also been shown to have protective effects on the intestine from radiation induced damage if administered prior to the procedure by modulating clonogenic stem cell survival in the small intestine. Cell Prolif. 2004 Dec;37(6):385-400. The physiological action of GLP 2 in the CNS remains to be elucidated. Metformin has been shown to increase GLP-1 levels and due to the co secretion of GLP-1 and GLP-2, it was no surprise that GLP-2 levels were also increased in rats by 2 fold using metformin .Eur J Pharmacol. 2004 Mar 19;488(1-3):213-8 A protective effect on 5FU-induced weight reduction of the small intestine of rats has been shown in that study using a combination of Metformin and a DPP-IV inhibitor (but not by either alone). DPP-IV inhibitor valine pyrrolidide (val-pyr) has been shown to potentiate the effect of exogenous GLP-2 in rodents with increased levels of active GLP-2 Endocrinology. 2000 Nov;141(11):4013-20. making it a potential agent for combination therapy with GLP-2 agonists.