GLP-2 has been shown to exhibit promising therapeutic potential in experimental models of intestinal atrophy and injury including:
TPN-induced mucosal atrophy
Prevention of parenteral nutrition-induced gut hypoplasia by coinfusion of glucagon-like peptide-2. Am J Physiol. 1997;273 :G559-63 Intravenous GLP-2 reverses the TPN-associated mucosal villus hypoplasia in the small bowelMaintaining gut integrity during parenteral nutrition of tumor-bearing rats: effects of glucagon-like peptide 2. Nutr Cancer. 2000;37(2):215-22 GLP-2 infusion reverses mucosal atrophy in the small bowel without effects on tumor growth in tumor-bearing ratsShort bowel syndrome following major intestinal resection in rats
GLP-2 augments the adaptive response to massive intestinal resection in rat. Am J Physiol. 1998 Nov;275(5 Pt 1):G911-21 GLP-2 improves nutrient absorption and augments intestinal adaptation in rats following MSBR. Consistent with a role for endogenous GLP-2 in intestinal adaptation, the levels of circulating GLP-2 are rapidly and significantly elevated in the rat following MSBR. See Time-dependent intestinal adaptation and GLP-2 alterations after small bowel resection in rats. Am J Physiol Gastrointest Liver Physiol. 2001 Sep;281(3):G779-85. The increase in endogenous levels of GLP-2 after major small bowel resection appears to be an important component of intestinal adaptation as rats administered GLP-2 antisera exhibited diminished histological features of intestinal adaptation in the remnant ileum as shown in Glucagon-like Peptide 2 is an endogenous mediator of postresection intestinal adaptation. JPEN J Parenter Enteral Nutr. 2005 Mar-Apr;29(2):97-101
Experimental dextran sulfate-induced colitis in mice
Human [Gly2]GLP-2 reduces the severity of colonic injury in a murine model of experimental colitis Am J Physiol 1999 Jan;276(1 Pt 1):G79-91 GLP-2 markedly attenuates weight loss and reduces multiple histological parameters of intestinal injury in the colon of mice with DS colitis
Non-steroidal anti-inflammatory drug-induced enteritis in mice and rats
Administration of GLP-2 markedly decreased NSAID-induced
intestinal in mice, as shown below
Glucagon-like peptide 2 decreases mortality and reduces the severity of indomethacin-induced murine enteritis Am J Physiol 1999 Nov;277(5 Pt 1):E937-47 GLP-2, administered in a variety of regimens, reduces mortality and improves gross and microscopic indices of intestinal injury in mice with NSAID-induced enteritis
GLP-2 administration in experimental vascular ischemia
Evidence for the protective effects of GLP-2 in the setting of experimental intestinal injury is described in Glucagonlike peptide-2 analogue enhances intestinal mucosal mass after ischemia and reperfusion J Pediatr Surg. 2000 Feb;35(2):357-9. This study shows that GLP-2 promotes mucosal repair and significantly reduces mortality in rats following experimental SMA occlusion. Similarly, GLP-2 was administered prior to ischemia-reperfusion for 3 days, or prior to and following I/R, in rats. The authors concluded that treatment with GLP-2 attenuates intestinal I/R injury, reduces bacterial translocation, inhibits the release of oxygen free radicals and ET-1, and inhibitd the production of proinflammatory cytokines Protective effects of glucagon-like peptide 2 on intestinal ischemia-reperfusion rats Microsurgery. 2008 Mar 27;28(4):285-290. [Epub ahead of print]
GLP-2 and Immune-mediated IBD in rats
Treatment of inflammatory bowel disease in a rodent model with the intestinal growth factor glucagon-like peptide-2 J Pediatr Surg 2000 Jun;35(6):847-51 Administration of GLP-2 as a 14 day intravenous infusion at 50 microg/kg/d significantly reduced gross and histological intestinal mucosal damage and reduced the levels of the cytokines TNF-alpha and IFN-gamma in rats with antigen induced enteritis.
Increased levels of GLP-2 likely mediate small bowel villus
hyperplasia in experimental diabetes
Treatment of rats with insulin reverses the villus hyperplasia (left panel compared to right) and reduces circulating levels of GLP-2 See Intestinal growth is associated with elevated levels of glucagon-like peptide 2 in diabetic rats. Am J Physiol 1997 273: E815-20
GLP-2 effects in premature pigs
GLP-2 administration 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
GLP-2 and cancer
Does GLP-2 exert its intestinotrophic actions in the setting of neoplasia? Treatment of tumor-bearing rats with TPN alone, versus TPN plus co-administered GLP-2 demonstrated that the trophic effects of GLP-2 on the small intestinal mucosa were maintained in tumor-bearing rats. In contrast, no significant effects of GLP-2 were noted in the colon. GLP-2 did not reduce tumor-bearing immunosuppression, and GLP-2 had no effect on tumor growth, whereas bacterial translocation was modestly reduced in GLP-2-treated animals. See Maintaining gut integrity during parenteral nutrition of tumor-bearing rats: effects of glucagon-like peptide 2. Nutr Cancer. 2000;37(2):215-22
In contrast, studies in mice administered the cancer inducing methylating carcinogen 1,2-dimethylhydrazine (DMH) demonstrated that concomitant GLP-2 administration for 10 or 30 days increased the number of colonic polyps, although no effect of GLP-2 treatment on survival was detected, See Glucagon-like peptide 2 (GLP-2) accelerates the growth of colonic neoplasms in mice. Gut. 2004 Aug;53 (8): 1145-50.
GLP-2 and chemotherapy
GLP-2 administration prevents chemotherapy-induced apoptosis. How does GLP-2 receptor activation in the gut endocrine cell reduce apoptosis in the
gastrointestinal epithelium, leading to increased survival in experimental
chemotherapy- induced mucositis? Review the data in Glucagon-like
Peptide (GLP)-2 Reduces Chemotherapy-associated Mortality and Enhances
Cell Survival in Cells Expressing a Transfected GLP-2 Receptor Cancer Res 2001 61: 687-693
A similar correlation between increased levels of GLP-2 and protection from chemotherapy-induced enteritis has been demonstrated in mice treated with 5-FU and either GLP-2 alone or both metformin and Val-Pyr, which enhances the levels of circulating GLP-2. See The combination of metformin and a dipeptidyl peptidase IV inhibitor prevents 5-fluorouracil-induced reduction of small intestine weight. Eur J Pharmacol. 2004 Mar 19;488(1-3):213-8
GLP-2 in experimental burn injury
GLP-2 infusion in burned rats prevented loss of gut protein and enhanced immune function. Glucagon-like peptide-2 stimulates gut mucosal growth and immune response in burned rats. J Burn Care Rehabil. 2001 Mar-Apr; 22(2):136-43.
GLP-2 in acute necrotizing pancreatitis
The effects of a GLP-2 analog, ALX-0600, have been examined in the setting of experimental necrotizing pancreatitis induced in Sprague-Dawley rats. Treatment with ALX-0600 for 3 days significantly reduced intestinal permeability, with a trend to reduction of bacterial translocation in viscera and mesenteric lymph nodes. See The effect of glucagon-like peptide 2 on intestinal permeability and bacterial translocation in acute necrotizing pancreatitis. Am J Surg. 2001 Jun;181(6):571-5.
GLP-2 in acute radiation-induced injury
The Therapeutic Actions of GLP-2 in Human Subjects
GLP-2 exerts potent trophic and anti-apoptotic effects in the GI tract of rodents and enhances nutrient absorption in mice and rats following small bowel resection. Does GLP-2 exert the same effects in human patients with short bowel syndrome? Review the data in the first human study "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.
Similar results were obtained in a 21 day pilot study of Teduglutide, a degradation-resistant GLP-2 anaolog, in 16 human subjects with short bowel syndrome, with and without a colon in continuity. Teduglutide improved energy absorption, in association with expansion of mucosal crypt plus villus height in the small bowel, as outlined in Teduglutide (ALX-0600), a dipeptidyl peptidase IV resistant glucagon-like peptide 2 analogue, improves intestinal function in short bowel syndrome patients. Gut. 2005 Sep;54(9):1224-31
Analysis of bone density in eight short bowel patients treated with synthetic human GLP-2, 400 ug sc twice daily for 5 weeks demonstrated significant increases in spinal bone mineral density in 7/8 patients, with an increase in ionized calcium detected in 5/8 patients. The mechanism for these findings remains unclear, but may be due in part to increased calcium absorption. 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 (Teduglutide) is currently being developed by NPS Pharmaceuticals through its Canadian subsidiary NPS Allelix Corp as a potential therapeutic agent for human subjects with intestinal diseases characterized by insufficient repair of intestinal mucosa and/or compromised nutrient absorption