title: Glucagon-like peptide-1 (GLP-1) receptor agonism or DPP-4 inhibition does not accelerate neoplasia in carcinogen treated mice.
abstract: BACKGROUND
  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 μg×2), exenatide (12.5 μg×2) or vehicle subcutaneously and sitagliptin (8mg×2) 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 μg×2), Gly2-GLP-2 (25 μg×2) or vehicle subcutaneously and sitagliptin (8 mg×2) 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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
authors.forename: Hannelouise
authors.initials: H
authors.lastname: Kissow
authors.forename: Bolette
authors.initials: B
authors.lastname: Hartmann
authors.forename: Jens Juul
authors.initials: JJ
authors.lastname: Holst
authors.forename: Niels-Erik
authors.initials: NE
authors.lastname: Viby
authors.forename: Lærke Schmidt
authors.initials: LS
authors.lastname: Hansen
authors.forename: Mette Marie
authors.initials: MM
authors.lastname: Rosenkilde
authors.forename: Kristine Juul
authors.initials: KJ
authors.lastname: Hare
authors.forename: Steen Seier
authors.initials: SS
authors.lastname: Poulsen
mesh_terms: D019813:1,2-Dimethylhydrazine / Q000008:administration & dosage / Q000009:adverse effects*; D058739:Aberrant Crypt Foci / Q000473:pathology; D000236:Adenoma / Q000139:chemically induced / Q000378:metabolism; D019412:Anatomy, Cross-Sectional; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology*; D000242:Cyclic AMP / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000473:pathology; D018819:Dipeptidyl Peptidase 4 / Q000097:blood*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology; D000077270:Exenatide; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives / Q000494:pharmacology; D000067757:Glucagon-Like Peptide-1 Receptor; D000067758:Glucagon-Like Peptide-2 Receptor; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000069450:Liraglutide; D051379:Mice; D008810:Mice, Inbred C57BL; D009929:Organ Size; D010455:Peptides / Q000494:pharmacology; D011719:Pyrazines / Q000494:pharmacology; D018027:Receptors, Glucagon / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D000068900:Sitagliptin Phosphate; D014162:Transfection; D014230:Triazoles / Q000494:pharmacology; D014688:Venoms / Q000494:pharmacology
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D000067758:Glucagon-Like Peptide-2 Receptor; D007004:Hypoglycemic Agents; D010455:Peptides; D011719:Pyrazines; D018027:Receptors, Glucagon; D014230:Triazoles; D014688:Venoms; C494910:teduglutide; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide; D000242:Cyclic AMP; D018819:Dipeptidyl Peptidase 4; C545245:Dpp4 protein, mouse; D019813:1,2-Dimethylhydrazine; D000068900:Sitagliptin Phosphate