Combined treatment with dipeptidyl peptidase 4 (DPP4) inhibitor sitagliptin and elemental diets reduced indomethacin-induced intestinal injury in rats via the increase of mucosal glucagon-like peptide-2 concentration

Kaori Fujiwara; Takuya Inoue; Naoki Yorifuji; Munetaka Iguchi; Taisuke Sakanaka; Ken Narabayashi; Kazuki Kakimoto; Sadaharu Nouda; Toshihiko Okada; Kumi Ishida; Yosuke Abe; Daisuke Masuda; Toshihisa Takeuchi; Shinya Fukunishi; Eiji Umegaki; Yasutada Akiba; Jonathan D. Kaunitz; Kazuhide Higuchi

doi:10.3164/jcbn.14-111

Original Articles

Combined treatment with dipeptidyl peptidase 4 (DPP4) inhibitor sitagliptin and elemental diets reduced indomethacin-induced intestinal injury in rats via the increase of mucosal glucagon-like peptide-2 concentration

Kaori Fujiwara, Takuya Inoue, Naoki Yorifuji, Munetaka Iguchi, Taisuke Sakanaka, Ken Narabayashi, Kazuki Kakimoto, Sadaharu Nouda, Toshihiko Okada, Kumi Ishida, Yosuke Abe, Daisuke Masuda, Toshihisa Takeuchi, Shinya Fukunishi, Eiji Umegaki, Yasutada Akiba, Jonathan D. Kaunitz, Kazuhide Higuchi

Author information

Kaori Fujiwara
Second Department of Internal Medicine, Osaka Medical College
Takuya Inoue
Second Department of Internal Medicine, Osaka Medical College
Naoki Yorifuji
Second Department of Internal Medicine, Osaka Medical College
Munetaka Iguchi
Second Department of Internal Medicine, Osaka Medical College
Taisuke Sakanaka
Second Department of Internal Medicine, Osaka Medical College
Ken Narabayashi
Second Department of Internal Medicine, Osaka Medical College
Kazuki Kakimoto
Second Department of Internal Medicine, Osaka Medical College
Sadaharu Nouda
Second Department of Internal Medicine, Osaka Medical College
Toshihiko Okada
Second Department of Internal Medicine, Osaka Medical College
Kumi Ishida
Second Department of Internal Medicine, Osaka Medical College
Yosuke Abe
Second Department of Internal Medicine, Osaka Medical College
Daisuke Masuda
Second Department of Internal Medicine, Osaka Medical College
Toshihisa Takeuchi
Second Department of Internal Medicine, Osaka Medical College
Shinya Fukunishi
Second Department of Internal Medicine, Osaka Medical College
Eiji Umegaki
Second Department of Internal Medicine, Osaka Medical College
Yasutada Akiba
Greater Los Angeles Veterans Affairs Healthcare System and School of Medicine, Department of Medicine, University of California
Jonathan D. Kaunitz
Greater Los Angeles Veterans Affairs Healthcare System and School of Medicine, Department of Medicine, University of California
Greater Los Angeles Veterans Affairs Healthcare System and School of Medicine, Department of Surgery, University of California
Kazuhide Higuchi
Second Department of Internal Medicine, Osaka Medical College

Keywords: GLP-1, GLP-2, DPP4, DPP8, sitagliptin

JOURNAL FREE ACCESS

2015 Volume 56 Issue 2 Pages 155-162

DOI https://doi.org/10.3164/jcbn.14-111

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Abstract

The gut incretin glucagon-like peptide-1 (GLP-1) and the intestinotropic hormone GLP-2 are released from enteroendocrine L cells in response to ingested nutrients. Treatment with an exogenous GLP-2 analogue increases intestinal villous mass and prevents intestinal injury. Since GLP-2 is rapidly degraded by dipeptidyl peptidase 4 (DPP4), DPP4 inhibition may be an effective treatment for intestinal ulcers. We measured mRNA expression and DPP enzymatic activity in intestinal segments. Mucosal DPP activity and GLP concentrations were measured after administration of the DPP4 inhibitor sitagliptin (STG). Small intestinal ulcers were induced by indomethacin (IM) injection. STG was given before IM treatment, or orally administered after IM treatment with or without an elemental diet (ED). DPP4 mRNA expression and enzymatic activity were high in the jejunum and ileum. STG dose-dependently suppressed ileal mucosal enzyme activity. Treatment with STG prior to IM reduced small intestinal ulcer scores. Combined treatment with STG and ED accelerated intestinal ulcer healing, accompanied by increased mucosal GLP-2 concentrations. The reduction of ulcers by ED and STG was reversed by co-administration of the GLP-2 receptor antagonist. DPP4 inhibition combined with luminal nutrients, which up-regulate mucosal concentrations of GLP-2, may be an effective therapy for the treatment of small intestinal ulcers.

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