PMID- 22989472 OWN - NLM STAT- MEDLINE DCOM- 20130322 LR - 20191210 IS - 1873-1686 (Electronic) IS - 0167-0115 (Linking) VI - 179 IP - 1-3 DP - 2012 Nov 10 TI - Glucagon-like peptide-1 (GLP-1) receptor agonism or DPP-4 inhibition does not accelerate neoplasia in carcinogen treated mice. PG - 91-100 LID - S0167-0115(12)00232-7 [pii] LID - 10.1016/j.regpep.2012.08.016 [doi] AB - INTRODUCTION: Glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2) are secreted in parallel from the intestinal endocrine cells after nutrient intake. GLP-1 is an incretin hormone and analogues are available for the treatment of type 2 diabetes mellitus (T2DM). GLP-2 is an intestinal growth hormone and is shown to promote growth of colonic adenomas in carcinogen treated mice. Both peptides are degraded by dipeptidyl peptidase-4 (DPP-4) into inactive metabolites. DPP-4 inhibitors are therefore also in use for treatment of T2DM. It is possible that DPP-4 inhibition by enhancing the exposure of endogenous GLP-2 to the intestinal epithelia also might mediate growth and promote neoplasia. We investigated the intestinal growth effect of the GLP-1 receptor agonists (GLP-1 RAs) (liraglutide and exenatide) and DPP-4 inhibition (sitagliptin) in healthy mice. We also investigated the potential tumour promoting effect of liraglutide and sitaglitin in the colon of carcinogen treated mice. We used GLP-2 as a positive control. METHODS: For the growth study we treated healthy CD1 mice with liraglutide (300 mugx2), exenatide (12.5 mugx2) or vehicle subcutaneously and sitagliptin (8mgx2) or water by oral gavage for 10 or 30 days. We measured intestinal weight, cross sectional area, villus height and crypt depth. For the tumour study we treated carcinogen treated mice (1,2 dimethylhydrazine 21 mg/kg/week for 12 weeks) with liraglutide (300 mugx2), Gly2-GLP-2 (25 mugx2) or vehicle subcutaneously and sitagliptin (8 mgx2) or water by oral gavage for 45 days. We counted aberrant crypt foci (ACF), mucin depleted foci (MDF) and adenomas in the colon. Using COS-7 cells transfected with a GLP-2 receptor, we tested if liraglutide or exenatide could activate the receptor. RESULTS: In the 10 days experiment the relative small intestinal weight was increased with 56% in the liraglutide group (p<0.001) and 26% in the exenatide group (p<01) compared with vehicle treated mice. After 30 days of treatment, liraglutide did also increase the colonic weight (p<0.01). By morphometry the growth pattern mimicked that of GLP-2. Sitagliptin treatment had only a minor effect. In the carcinogen treated mice we found no increase of ACF in any of the groups, the numbers of MDF and adenomas after liraglutide and sitagliptin treatments were similar to their respective control groups. Neither liraglutide nor exenatide stimulated cAMP release from GLP-2 receptor transfected cells. CONCLUSION: Both GLP-1 analogues were potent growth stimulators of the healthy mouse intestine. No agonism was found for GLP-1 RAs at the GLP-2 receptor. Despite of the growth effect, liraglutide did not promote dysplasia in the colon. Sitagliptin did not show any tumour promoting effects, and non considerable growth effects. CI - Copyright (c) 2012 Elsevier B.V. All rights reserved. FAU - Kissow, Hannelouise AU - Kissow H AD - Department of Biomedical Sciences, and The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. kissow@sund.ku.dk FAU - Hartmann, Bolette AU - Hartmann B FAU - Holst, Jens Juul AU - Holst JJ FAU - Viby, Niels-Erik AU - Viby NE FAU - Hansen, Laerke Schmidt AU - Hansen LS FAU - Rosenkilde, Mette Marie AU - Rosenkilde MM FAU - Hare, Kristine Juul AU - Hare KJ FAU - Poulsen, Steen Seier AU - Poulsen SS LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20120915 PL - Netherlands TA - Regul Pept JT - Regulatory peptides JID - 8100479 RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 0 (Glp1r protein, mouse) RN - 0 (Glucagon-Like Peptide-1 Receptor) RN - 0 (Glucagon-Like Peptide-2 Receptor) RN - 0 (Hypoglycemic Agents) RN - 0 (Peptides) RN - 0 (Pyrazines) RN - 0 (Receptors, Glucagon) RN - 0 (Triazoles) RN - 0 (Venoms) RN - 7M19191IKG (teduglutide) RN - 839I73S42A (Liraglutide) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 9P1872D4OL (Exenatide) RN - E0399OZS9N (Cyclic AMP) RN - EC 3.4.14.5 (Dipeptidyl Peptidase 4) RN - EC 3.4.14.5 (Dpp4 protein, mouse) RN - IX068S9745 (1,2-Dimethylhydrazine) RN - TS63EW8X6F (Sitagliptin Phosphate) SB - IM MH - 1,2-Dimethylhydrazine/administration & dosage/*adverse effects MH - Aberrant Crypt Foci/pathology MH - Adenoma/chemically induced/metabolism MH - Anatomy, Cross-Sectional MH - Animals MH - COS Cells MH - Chlorocebus aethiops MH - Colon/drug effects/metabolism/pathology MH - Colonic Neoplasms/metabolism/*pathology MH - Cyclic AMP/metabolism MH - Diabetes Mellitus, Type 2/metabolism/pathology MH - Dipeptidyl Peptidase 4/*blood MH - Dipeptidyl-Peptidase IV Inhibitors/pharmacology MH - Exenatide MH - Female MH - Glucagon-Like Peptide 1/analogs & derivatives/pharmacology MH - Glucagon-Like Peptide-1 Receptor MH - Glucagon-Like Peptide-2 Receptor MH - Hypoglycemic Agents/pharmacology MH - Intestinal Mucosa/drug effects/metabolism/pathology MH - Intestine, Small/drug effects/metabolism/pathology MH - Liraglutide MH - Mice MH - Mice, Inbred C57BL MH - Organ Size MH - Peptides/pharmacology MH - Pyrazines/pharmacology MH - Receptors, Glucagon/*agonists/genetics/metabolism MH - Sitagliptin Phosphate MH - Transfection MH - Triazoles/pharmacology MH - Venoms/pharmacology EDAT- 2012/09/20 06:00 MHDA- 2013/03/23 06:00 CRDT- 2012/09/20 06:00 PHST- 2012/03/15 00:00 [received] PHST- 2012/07/29 00:00 [revised] PHST- 2012/08/29 00:00 [accepted] PHST- 2012/09/20 06:00 [entrez] PHST- 2012/09/20 06:00 [pubmed] PHST- 2013/03/23 06:00 [medline] AID - S0167-0115(12)00232-7 [pii] AID - 10.1016/j.regpep.2012.08.016 [doi] PST - ppublish SO - Regul Pept. 2012 Nov 10;179(1-3):91-100. doi: 10.1016/j.regpep.2012.08.016. Epub 2012 Sep 15.