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

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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.

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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

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Acknowledgments

We thank Coleen and Bea Palileo for their assistance with manuscript preparation. Supported by the Department of Veterans Affairs Merit Review Award, NIH-NIDDK R01 DK54221 (J. Kaunitz), and the animal core of NIH-NIDDK P30 DK0413 (J.E. Rozengurt).

Conflict of interest

None.

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Authors and Affiliations

  1. Greater Los Angles Veterans Affairs Healthcare System, Los Angeles, CA, USA

    Sergiy Rudenkyy, Paul H. Guth, Jonathan D. Kaunitz & Yasutada Akiba

  2. Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA

    Takuya Inoue, Masaaki Higashiyama, Izumi Kaji, Jonathan D. Kaunitz & Yasutada Akiba

  3. Department of Biomathematics, University of California, Los Angeles, Los Angeles, CA, USA

    Eli Engel

  4. Brentwood Biomedical Research Institute, Los Angeles, CA, 90073, USA

    Jonathan D. Kaunitz & Yasutada Akiba

  5. The Second Department of Internal Medicine, Osaka Medical College, Osaka, Japan

    Takuya Inoue & Kazuhide Higuchi

  6. West Los Angeles VA Medical Center, Bldg. 114, Suite 217, 11301 Wilshire Blvd., Los Angeles, CA, 90073, USA

    Jonathan D. Kaunitz

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  1. Takuya Inoue
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  2. Masaaki Higashiyama
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  4. Sergiy Rudenkyy
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  7. Eli Engel
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  9. Yasutada Akiba
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Correspondence to Jonathan D. Kaunitz.

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Inoue, T., Higashiyama, M., Kaji, I. et al. Dipeptidyl Peptidase IV Inhibition Prevents the Formation and Promotes the Healing of Indomethacin-Induced Intestinal Ulcers in Rats. Dig Dis Sci 59, 1286–1295 (2014). https://doi.org/10.1007/s10620-013-3001-6

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  • DOI: https://doi.org/10.1007/s10620-013-3001-6

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