title: Stimulation of intestinal growth and function with DPP4 inhibition in a mouse short bowel syndrome model.
abstract: Glucagon-like peptide-2 (GLP-2) has been shown to be effective in patients with short bowel syndrome (SBS), but it is rapidly inactivated by dipeptidyl peptidase IV (DPP4). We used an orally active DPP4 inhibitor (DPP4-I), MK-0626, to determine the efficacy of this approach to promote adaptation after SBS, determined optimal dosing, and identified further functional actions in a mouse model of SBS. Ten-week-old mice underwent a 50% proximal small bowel resection. Dose optimization was determined over a 3-day post-small bowel resection period. The established optimal dose was given for 7, 30, and 90 days and for 7 days followed by a 23-day washout period. Adaptive response was assessed by morphology, intestinal epithelial cell (IEC) proliferation (proliferating cell nuclear antigen), epithelial barrier function (transepithelial resistance), RT-PCR for intestinal transport proteins and GLP-2 receptor, IGF type 1 receptor, and GLP-2 plasma levels. Glucose-stimulated sodium transport was assessed for intestinal absorptive function. Seven days of DPP4-I treatment facilitated an increase in GLP-2 receptor levels, intestinal growth, and IEC proliferation. Treatment led to differential effects over time, with greater absorptive function at early time points and enhanced proliferation at later time points. Interestingly, adaptation continued in the group treated for 7 days followed by a 23-day washout. DPP4-I enhanced IEC proliferative action up to 90 days postresection, but this action seemed to peak by 30 days, as did GLP-2 plasma levels. Thus DPP4-I treatment may prove to be a viable option for accelerating intestinal adaptation with SBS.
authors: Section of Pediatric Surgery, Department of Surgery, University of Michigan, Ann Arbor, Michigan; and.
authors: Ryo
authors: R
authors: Sueyoshi
authors: Section of Pediatric Surgery, Department of Surgery, University of Michigan, Ann Arbor, Michigan; and.
authors: Kathleen M
authors: KM
authors: Woods Ignatoski
authors: Section of Pediatric Surgery, Department of Surgery, University of Michigan, Ann Arbor, Michigan; and.
authors: Manabu
authors: M
authors: Okawada
authors: Department of Biomedical Sciences, University of Copenhagen, The Panum Institute, Copenhagen, Denmark.
authors: Bolette
authors: B
authors: Hartmann
authors: Department of Biomedical Sciences, University of Copenhagen, The Panum Institute, Copenhagen, Denmark.
authors: Jens
authors: J
authors: Holst
authors: Section of Pediatric Surgery, Department of Surgery, University of Michigan, Ann Arbor, Michigan; and dttlbm@umich.edu.
authors: Daniel H
authors: DH
authors: Teitelbaum
mesh_terms: D000222:Adaptation, Physiological; D000681:Amylases / Q000097:blood; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D004195:Disease Models, Animal; D053767:Glucagon-Like Peptide 2 / Q000378:metabolism; D000067758:Glucagon-Like Peptide-2 Receptor; D007408:Intestinal Absorption / Q000187:drug effects; D007413:Intestinal Mucosa / Q000166:cytology; D007583:Jejunum / Q000187:drug effects / Q000648:ultrastructure; D008297:Male; D051379:Mice; D017526:Receptor, IGF Type 1 / Q000096:biosynthesis; D018027:Receptors, Glucagon / Q000096:biosynthesis; D012778:Short Bowel Syndrome / Q000378:metabolism*; D051269:Sodium-Glucose Transporter 1 / Q000096:biosynthesis; D014230:Triazoles / Q000627:therapeutic use; D015854:Up-Regulation
chemical_list: D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; D053767:Glucagon-Like Peptide 2; D000067758:Glucagon-Like Peptide-2 Receptor; C570834:MK0626; D018027:Receptors, Glucagon; C495675:Slc5a1 protein, mouse; D051269:Sodium-Glucose Transporter 1; D014230:Triazoles; D017526:Receptor, IGF Type 1; D000681:Amylases; D018819:Dipeptidyl Peptidase 4; C545245:Dpp4 protein, mouse
keywords: dipeptidyl peptidase IV; intestinal epithelial cell; proliferation; short bowel syndrome; sodium-glucose transport protein-1