Current and potential therapeutic targets of glucagon-like peptide-2

Current Opinion in Pharmacology

Volumn 31, Issue , 2016, Pages 13-18

  Austin, Kaori ^a   Markovic, Melanie A ^a   Brubaker, Patricia L ^a  

^a UNIVERSITY OF TORONTO   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

ELSIGLUTIDE; GLUCAGON LIKE PEPTIDE 2; GLUCAGON LIKE PEPTIDE 2 RECEPTOR; TEDUGLUTIDE; DELAYED RELEASE FORMULATION;

APOPTOSIS; CELL POPULATION; CELL PROLIFERATION; DISEASE SEVERITY; DRUG EFFECT; DRUG MECHANISM; DRUG TARGETING; DRUG USE; HUMAN; INTESTINAL STEM CELL; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; QUALITY OF LIFE; REVIEW; SHORT BOWEL SYNDROME; ADULT; ANIMAL; DELAYED RELEASE FORMULATION; INTESTINAL DISEASES; INTESTINE; INTESTINE MUCOSA; METABOLISM; PATHOLOGY;

ADULT; ANIMALS; DELAYED-ACTION PREPARATIONS; GLUCAGON-LIKE PEPTIDE 2; HUMANS; INTESTINAL DISEASES; INTESTINAL MUCOSA; INTESTINES; SHORT BOWEL SYNDROME;

EID: 84983471879     PISSN: 14714892     EISSN: 14714973     Source Type: Journal    
DOI: 10.1016/j.coph.2016.08.008     Document Type: Review

References (52)

1. 1 Drucker, D.J., Erlich, P., Asa, S.L., Brubaker, P.L., Induction of intestinal epithelial proliferation by glucagon-like peptide 2. Proc Natl Acad Sci U S A 93 (1996), 7911–7916.
2. 2 Rowland, K.J., Brubaker, P.L., The “cryptic” mechanism of action of glucagon-like peptide-2. Am J Physiol Gastrointest Liver Physiol 301 (2011), G1–G8.
3. 3•• Drucker, D.J., Yusta, B., Physiology and pharmacology of the enteroendocrine hormone glucagon-like peptide-2. Annu Rev Physiol 76 (2014), 561–583 This excellent review covers the physiology and pathophysiology of GLP-2 with a particular emphasis on basic biology of this hormone and the results of pre-clinical studies.
4. 4•• Jeppesen, P.B., Gut hormones in the treatment of short-bowel syndrome and intestinal failure. Curr Opin Endocrinol Diabetes Obes 22 (2015), 14–20 This excellent paper reviews the results of clinical trials on teduglutide that led to its approval for use in adult patients with SBS.
5. 5 Xiao, Q., Boushey, R.P., Drucker, D.J., Brubaker, P.L., Secretion of the intestinotropic hormone glucagon-like peptide 2 is differentially regulated by nutrients in humans. Gastroenterology 117 (1999), 99–105.
6. 6 Tsai, C.H., Hill, M., Drucker, D.J., Biological determinants of intestinotrophic properties of GLP-2 in vivo. Am J Physiol Gastrointest Liver Physiol 272 (1997), G662–G668.
7. 7 Yusta, B., Holland, D., Koehler, J.A., Maziarz, M., Estall, J.L., Higgins, R., Drucker, D.J., ErbB signaling is required for the proliferative actions of GLP-2 in the murine gut. Gastroenterology 137 (2009), 986–996.
8. 8 Dube, P.E., Forse, C.L., Bahrami, J., Brubaker, P.L., Essential role of insulin-like growth factor-1 in the intestinal tropic effects of glucagon-like peptide-2 in mice. Gastroenterology 131 (2006), 589–605.
9. 9 Smither, B.R., Pang, H.Y., Brubaker, P.L., Glucagon-like peptide-2 requires a full-complement of Bmi-1 for its proliferative effects in the murine small intestine. Endocrinology 157 (2016), 2660–2670.
10. 10 Booth, C., Booth, D., Williamson, S., Demchyshyn, L.L., Potten, C.S., Teduglutide ([Gly2]GLP-2) protects small intestinal stem cells from radiation damage. Cell Prolif 37 (2004), 385–400.
11. 11 Rowland, K.J., Trivedi, S., Wan, K., Kulkarni, R.N., Holzenberger, M., Robine, S., Brubaker, P.L., Loss of glucagon-like peptide-2-induced proliferation following intestinal epithelial insulin-like growth factor-1 receptor deletion. Gastroenterology 141 (2011), 2166–2175.
12. 12• Austin, K., Imam, N.A., Pintar, J.E., Brubaker, P.L., IGF binding protein-4 is required for the growth effects of glucagon-like peptide-2 in murine intestine. Endocrinology 156 (2015), 429–436 This study demonstrated that whole-body IGFBP-4 knockout mice have an impaired intestinal proliferative response to chronic GLP-2 administration. This finding provides further support for the importance of the IGF-1 axis in the mechanism of action of GLP-2.
13. 13 Orskov, C., Hartmann, B., Poulsen, S.S., Thulesen, J., Hare, K.J., Holst, J.J., GLP-2 stimulates colonic growth via KGF, released by subepithelial myofibroblasts with GLP-2 receptors. Regul Pept 124 (2005), 105–112.
14. 14 Van Landeghem, L., Santoro, M.A., Mah, A.T., Krebs, A.E., Dehmer, J.J., McNaughton, K.K., Helmrath, M.A., Magness, S.T., Lund, P.K., IGF1 stimulates crypt expansion via differential activation of 2 intestinal stem cell populations. FASEB J 29 (2015), 2828–2842.
15. 15 Simmons, J.G., Hoyt, E.C., Westwick, J.K., Brenner, D.A., Pucilowska, J.B., Lund, P.K., Insulin-like growth factor-I and epidermal growth factor interact to regulate growth and gene expression in IEC-6 intestinal epithelial cells. Mol Endocrinol 9 (1995), 1157–1165.
16. 16 Boushey, R.P., Yusta, B., Drucker, D.J., Glucagon-like peptide 2 decreases mortality and reduces the severity of indomethacin-induced murine enteritis. Am J Physiol Endocrinol Metab 277 (1999), E937–E947.
17. 17 Boushey, R.P., Yusta, B., Drucker, D.J., Glucagon-like peptide (GLP)-2 reduces chemotherapy-associated mortality and enhances cell survival in cells expressing a transfected GLP-2 receptor. Cancer Res 61 (2001), 687–693.
18. 18 Drucker, D.J., Yusta, B., Boushey, R.P., DeForest, L., Brubaker, P.L., Human [Gly2]GLP-2 reduces the severity of colonic injury in a murine model of experimental colitis. Am J Physiol 276 (1999), G79–G91.
19. 19 Benjamin, M.A., McKay, D.M., Yang, P.C., Cameron, H., Perdue, M.H., Glucagon-like peptide-2 enhances intestinal epithelial barrier function of both transcellular and paracellular pathways in the mouse. Gut 47 (2000), 112–119.
20. 20 McConnell, R.E., Benesh, A.E., Mao, S., Tabb, D.L., Tyska, M.J., Proteomic analysis of the enterocyte brush border. Am J Physiol Gastrointest Liver Physiol 300 (2011), G914–G926.
21. 21 Brubaker, P.L., Izzo, A., Hill, M., Drucker, D.J., Intestinal function in mice with small bowel growth induced by glucagon-like peptide-2. Am J Physiol 272 (1997), E1050–E1058.
22. 22 Scott, R.B., Kirk, D., MacNaughton, W.K., Meddings, J.B., GLP-2 augments the adaptive response to massive intestinal resection in rats. Am J Physiol Gastrointest Liver Physiol 275 (1998), G911–G921.
23. 23• Iturrino, J., Camilleri, M., Acosta, A., O'Neill, J., Burton, D., Edakkanambeth Varayil, J., Carlson, P.J., Zinsmeister, A.R., Hurt, R., Acute effects of a glucagon-like peptide 2 analogue, teduglutide, on gastrointestinal motor function and permeability in adult patients with short bowel syndrome on home parenteral nutrition. JPEN J Parenter Enteral Nutr, 2015 pii: 0148607115597644 Human patients with SBS treated with teduglutide for one-week demonstrated an increase in gut transit time. This clinical study shows a beneficial effect of GLP-2 that is non-growth related.
24. 24 Hsieh, J., Longuet, C., Maida, A., Bahrami, J., Xu, E., Baker, C.L., Brubaker, P.L., Drucker, D.J., Adeli, K., Glucagon-like peptide-2 increases intestinal lipid absorption and chylomicron production via CD36. Gastroenterology 137 (2009), 997–1005.
25. 25 Hsieh, J., Trajcevski, K.E., Farr, S.L., Baker, C.L., Lake, E.J., Taher, J., Iqbal, J., Hussain, M.M., Adeli, K., Glucagon-like peptide 2 (GLP-2) stimulates postprandial chylomicron production and postabsorptive release of intestinal triglyceride storage pools via induction of nitric oxide signaling in male hamsters and mice. Endocrinology 156 (2015), 3538–3547.
26. 26• Dash, S., Xiao, C., Morgantini, C., Connelly, P.W., Patterson, B.W., Lewis, G.F., Glucagon-like peptide-2 regulates release of chylomicrons from the intestine. Gastroenterology 147 (2014), 1275–1284 This study demonstrated that GLP-2 infusion into human subjects results in an acute and transient increase in the triglyceride-rich lipoprotein, apoB-48, in the plasma. This study is the first to show that GLP-2 improves intestinal chylomicron production in humans, consistent with other studies illustrating increased fat absorption in response to GLP-2 treatment.
27. 27 Cheeseman, C.I., Upregulation of SGLT-1 transport activity in rat jejunum induced by GLP-2 infusion in vivo. Am J Physiol Regul Integr Comp Physiol 273 (1997), R1965–R1971.
28. 28 Au, A., Gupta, A., Schembri, P., Cheeseman, C.I., Rapid insertion of GLUT2 into the rat jejunal brush-border membrane promoted by glucagon-like peptide 2. Biochem J 367 (2002), 247–254.
29. 29 Bremholm, L., Hornum, M., Andersen, U.B., Hartmann, B., Holst, J.J., Jeppesen, P.B., The effect of glucagon-like peptide-2 on mesenteric blood flow and cardiac parameters in end-jejunostomy short bowel patients. Regul Pept 168 (2011), 32–38.
30. 30 Guan, X., Karpen, H.E., Stephens, J., Bukowski, J.T., Niu, S., Zhang, G., Stoll, B., Finegold, M.J., Holst, J.J., Hadsell, D., Nichols, B.L., et al. GLP-2 receptor localizes to enteric neurons and endocrine cells expressing vasoactive peptides and mediates increased blood flow. Gastroenterology 130 (2006), 150–164.
31. 31 Cani, P.D., Possemiers, S., Van de, W.T., Guiot, Y., Everard, A., Rottier, O., Geurts, L., Naslain, D., Neyrinck, A., Lambert, D.M., Muccioli, G.G., et al. Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability. Gut 58 (2009), 1091–1103.
32. 32 Dong, C.X., Zhao, W., Solomon, C., Rowland, K.J., Ackerley, C., Robine, S., Holzenberger, M., Gonska, T., Brubaker, P.L., The intestinal epithelial insulin-like growth factor-1 receptor links glucagon-like peptide-2 action to gut barrier function. Endocrinology 155 (2014), 370–379.
33. 33 Sigalet, D.L., Wallace, L.E., Holst, J.J., Martin, G.R., Kaji, T., Tanaka, H., Sharkey, K.A., Enteric neural pathways mediate the anti-inflammatory actions of glucagon-like peptide 2. Am J Physiol Gastrointest Liver Physiol 293 (2007), G211–G221.
34. 34 Nakame, K., Kaji, T., Mukai, M., Shinyama, S., Matsufuji, H., The protective and anti-inflammatory effects of glucagon-like peptide-2 in an experimental rat model of necrotizing enterocolitis. Peptides 75 (2016), 1–7.
35. 35 Tappenden, K.A., Intestinal adaptation following resection. JPEN J Parenter Enteral Nutr 38 (2014), 23S–31S.
36. 36 Lim, D.W., Wales, P.W., Turner, J.M., Bigam, D.L., Brubaker, P.L., On the horizon: trophic peptide growth factors as therapy for neonatal short bowel syndrome. Expert Opin Ther Targets 20 (2016), 819–830.
37. 37 Jeppesen, P.B., Hartmann, B., Thulesen, J., Graff, J., Lohmann, J., Hansen, B.S., Tofteng, F., Poulsen, S.S., Madsen, J.L., Holst, J.J., Mortensen, P.B., Glucagon-like peptide 2 improves nutrient absorption and nutritional status in Short-Bowel patients with no colon. Gastroenterology 120 (2001), 806–815.
38. 38 Jeppesen, P.B., Lund, P., Gottschalck, I.B., Nielsen, H.B., Holst, J.J., Mortensen, J., Poulsen, S.S., Quistorff, B., Mortensen, P.B., Short bowel patients treated for two years with glucagon-like peptide 2 (GLP-2): compliance, safety, and effects on quality of life. Gastroenterol Res Pract 2009 (2009), 425751–425759.
39. 39 Jeppesen, P.B., Lund, P., Gottschalck, I.B., Nielsen, H.B., Holst, J.J., Mortensen, J., Poulsen, S.S., Quistorff, B., Mortensen, P.B., Short bowel patients treated for two years with glucagon-like peptide 2: effects on intestinal morphology and absorption, renal function, bone and body composition, and muscle function. Gastroenterol Res Pract 2009 (2009), 616051–616054 616012.
40. 40 Jeppesen, P.B., Gilroy, R., Pertkiewicz, M., Allard, J.P., Messing, B., O'Keefe, S.J., Randomised placebo-controlled trial of teduglutide in reducing parenteral nutrition and/or intravenous fluid requirements in patients with short bowel syndrome. Gut 60 (2011), 902–914.
41. 41 Jeppesen, P.B., Pertkiewicz, M., Forbes, A., Pironi, L., Gabe, S.M., Joly, F., Messing, B., Loth, S., Youssef, N.N., Heinze, H., Berghofer, P., Quality of life in patients with short bowel syndrome treated with the new glucagon-like peptide-2 analogue teduglutide — analyses from a randomised, placebo-controlled study. Clin Nutr 32 (2013), 713–721.
42. 42 Madsen, K.B., Askov-Hansen, C., Naimi, R.M., Brandt, C.F., Hartmann, B., Holst, J.J., Mortensen, P.B., Jeppesen, P.B., Acute effects of continuous infusions of glucagon-like peptide (GLP)-1, GLP-2 and the combination (GLP-1+GLP-2) on intestinal absorption in short bowel syndrome (SBS) patients. A placebo-controlled study. Regul Pept 184 (2013), 30–39.
43. 43 Iakoubov, R., Lauffer, L.M., Trivedi, S., Kim, Y.-I., Brubaker, P.L., Carcinogenic effects of exogenous and endogenous glucagon-like peptide-2 in azoxymethane-treated mice. Endocrinology 150 (2009), 4033–4043.
44. 44 Trivedi, S., Wiber, S.C., El-Zimaity, H.M., Brubaker, P.L., Glucagon-like peptide-2 increases dysplasia in rodent models of colon cancer. Am J Physiol Gastrointest Liver Physiol 302 (2011), G840–G849.
45. 45 Suri, M., Turner, J.M., Sigalet, D.L., Wizzard, P.R., Nation, P.N., Ball, R.O., Pencharz, P.B., Brubaker, P.L., Wales, P.W., Exogenous glucagon-like peptide-2 improves outcomes of intestinal adaptation in a distal-intestinal resection neonatal piglet model of short bowel syndrome. Pediatr Res 76 (2014), 370–377.
46. 46•• Sigalet, D.L., Brindle, M., Boctor, D., Casey, L., Dicken, B., Butterworth, S., Lam, V., Karnik, V., de Heuvel, E., Hartmann, B., Holst, J., A safety and dosing study of glucagon-like peptide 2 in children with intestinal failure. JPEN J Parenter Enteral Nutr, 2015, 10.1177/0148607115609566 This open-label trial showed that teduglutide is safe and well-tolerated in parenteral nutrition-dependent children with SBS, and that it may have beneficial effects on nutrition and gut growth. This is the first study to examine the use of teduglutide in non-adult patients with SBS.
47. 47 Buchman, A.L., Katz, S., Fang, J.C., Bernstein, C.N., Abou-Assi, S.G., Teduglutide, a novel mucosally active analog of glucagon-like peptide-2 (GLP-2) for the treatment of moderate to severe Crohn's disease. Inflamm Bowel Dis 16 (2010), 962–973.
48. 48 Cameron, H.L., Perdue, M.H., Stress impairs murine intestinal barrier function: improvement by glucagon-like peptide-2. J Pharmacol Exp Ther 314 (2005), 214–220.
49. 49 Liu, X., Murali, S.G., Holst, J.J., Ney, D.M., Enteral nutrients potentiate the intestinotrophic action of glucagon-like peptide-2 in association with increased insulin-like growth factor-I responses in rats. Am J Physiol Regul Integr Comp Physiol 295 (2008), R1794–R1802.
50. 50 Rishi, A.R., Rubio-Tapia, A., Murray, J.A., Refractory celiac disease. Expert Rev Gastroenterol Hepatol 10 (2016), 537–546.
51. 51 Overeem, A.W., Posovszky, C., Rings, E.H., Giepmans, B.N., van, I.S.C., The role of enterocyte defects in the pathogenesis of congenital diarrheal disorders. Dis Model Mech 9 (2016), 1–12.
52. 52 Thomson, A.B., Small intestinal disorders in the elderly. Best Pract Res Clin Gastroenterol 23 (2009), 861–874.