Digestive Diseases and Sciences

, Volume 59, Issue 6, pp 1286–1295

Dipeptidyl Peptidase IV Inhibition Prevents the Formation and Promotes the Healing of Indomethacin-Induced Intestinal Ulcers in Rats

  • Takuya Inoue
  • Masaaki Higashiyama
  • Izumi Kaji
  • Sergiy Rudenkyy
  • Kazuhide Higuchi
  • Paul H. Guth
  • Eli Engel
  • Jonathan D. Kaunitz
  • Yasutada Akiba
Original Article

DOI: 10.1007/s10620-013-3001-6

Cite this article as:
Inoue, T., Higashiyama, M., Kaji, I. et al. Dig Dis Sci (2014) 59: 1286. doi:10.1007/s10620-013-3001-6

Abstract

Backgrounds and Aims

We studied the intestinotrophic hormone glucagon-like peptide-2 (GLP-2) as a possible therapy for non-steroidal anti-inflammatory drug (NSAID)-induced intestinal ulcers. Luminal nutrients release endogenous GLP-2 from enteroendocrine L cells. Since GLP-2 is degraded by dipeptidyl peptidase IV (DPPIV), we hypothesized that DPPIV inhibition combined with luminal administration of nutrients potentiates the effects of endogenous GLP-2 on intestinal injury.

Methods

Intestinal injury was induced by indomethacin (10 mg/kg, sc) in fed rats. The long-acting DPPIV inhibitor K579 was given intragastrically (ig) or intraperitoneally (ip) before or after indomethacin treatment. l-Alanine (l-Ala) and inosine 5′-monophosphate (IMP) were co-administered ig after the treatment.

Results

Indomethacin treatment induced intestinal ulcers that gradually healed after treatment. Pretreatment with ig or ip K579 given at 1 mg/kg reduced total ulcer length, whereas K579 at 3 mg/kg had no effect. Exogenous GLP-2 also reduced intestinal ulcers. The preventive effect of K579 was dose-dependently inhibited by a GLP-2 receptor antagonist. Daily treatment with K579 (1 mg/kg), GLP-2, or l-Ala + IMP after indomethacin treatment reduced total ulcer length. Co-administration (ig) of K579 and l-Ala + IMP further accelerated intestinal ulcer healing.

Conclusion

DPPIV inhibition and exogenous GLP-2 prevented the formation and promoted the healing of indomethacin-induced intestinal ulcers, although high-dose DPPIV inhibition reversed the preventive effect. Umami receptor agonists also enhanced the healing effects of the DPPIV inhibitor. The combination of DPPIV inhibition and luminal nutrient-induced GLP-2 release may be a useful therapeutic tool for the treatment of NSAIDs-induced intestinal ulcers.

Keywords

Glucagon-like peptide-2 NSAIDs Taste receptor 

Abbreviations

DPPIV

Dipeptidyl peptidase-IV

IMP

Inosine 5′-monophosphate

IND

Indomethacin

l-Ala

l-alanine

l-Glu

l-glutamate

GLP

Glucagon-like peptide

GLP-2R

GLP-2 receptor

PV

Portal venous

T1R

Taste receptor type 1

Copyright information

© Springer Science+Business Media New York (Outside the USA) 2013

Authors and Affiliations

  • Takuya Inoue
    • 2
    • 5
  • Masaaki Higashiyama
    • 2
  • Izumi Kaji
    • 2
  • Sergiy Rudenkyy
    • 1
  • Kazuhide Higuchi
    • 5
  • Paul H. Guth
    • 1
  • Eli Engel
    • 3
  • Jonathan D. Kaunitz
    • 1
    • 2
    • 4
    • 6
  • Yasutada Akiba
    • 1
    • 2
    • 4
  1. 1.Greater Los Angles Veterans Affairs Healthcare SystemLos AngelesUSA
  2. 2.Department of MedicineUniversity of California, Los AngelesLos AngelesUSA
  3. 3.Department of BiomathematicsUniversity of California, Los AngelesLos AngelesUSA
  4. 4.Brentwood Biomedical Research InstituteLos AngelesUSA
  5. 5.The Second Department of Internal MedicineOsaka Medical CollegeOsakaJapan
  6. 6.West Los Angeles VA Medical CenterLos AngelesUSA

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