Sueyoshi, Ryo4; Ignatoski, Kathleen M Woods4; Okawada, Manabu4; Hartmann, Bolette5; Holst, Jens Juul6; Teitelbaum, Daniel H4
1 Section of Endocrinology Research, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, Københavns Universitet2 Section for Translational Metabolic Physiology, The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, Københavns Universitet3 University of Michigan4 University of Michigan5 Section of Endocrinology Research, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, Københavns Universitet6 Section for Translational Metabolic Physiology, The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, Københavns Universitet
Glucagon-like peptide-2 (GLP-2) has been shown to be effective in patients with short bowel syndrome (SBS), but 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 SBS mouse model. Ten week old mice underwent a 50% proximal small bowel resection (SBR). Dose optimization was determined over a 3-day post-SBS period. The established optimal dose was given for 7 days, 30 days, 90 days, and 7 days followed by 23 days washout period. Adaptive response was assessed by morphology, intestinal epithelial cell (IEC) proliferation (PCNA), epithelial barrier function (transepithelial resistance), RT-PCR for intestinal transport proteins, GLP-2R, and IGF-1R, 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-2R levels, intestinal growth, and IEC proliferation. Treatment led to differential effects over time with greater absorptive function early, and enhanced proliferation at later time points. Interestingly, 7 day treatment followed by 23 days of non-treatment showed continued adaptation. DPP-IV-I enhanced IEC proliferative action up to 90-days post-resection, but this action seemed to peak by 30 days, as did GLP-2 plasma levels. Thus, use of DPP4-I treatment may prove to be a viable treatment for accelerating intestinal adaptation with SBS.
American Journal of Physiology: Gastrointestinal and Liver Physiology, 2014, Vol 307, Issue 4