The dipeptidyl peptidase-4 inhibitor sitagliptin suppresses mouse colon tumorigenesis in type 2 diabetic mice

Yorifuji,Naoki; Inoue,Takuya; Iguchi,Munetaka; Fujiwara,Kaori; Kakimoto,Kazuki; Nouda,Sadaharu; Okada,Toshihiko; Kawakami,Ken; Abe,Yosuke; Takeuchi,Toshihisa; Higuchi,Kazuhide

doi:10.3892/or.2015.4429

The dipeptidyl peptidase-4 inhibitor sitagliptin suppresses mouse colon tumorigenesis in type 2 diabetic mice

Authors:
- Naoki Yorifuji
- Takuya Inoue
- Munetaka Iguchi
- Kaori Fujiwara
- Kazuki Kakimoto
- Sadaharu Nouda
- Toshihiko Okada
- Ken Kawakami
- Yosuke Abe
- Toshihisa Takeuchi
- Kazuhide Higuchi
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Affiliations: Second Department of Internal Medicine, Osaka Medical College, Takatsuki City, Osaka 569-8686, Japan
Published online on: November 16, 2015 https://doi.org/10.3892/or.2015.4429
Pages: 676-682

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Abstract

Patients with type 2 diabetes mellitus are known to have an increased risk of colorectal neoplasia. Dipeptidyl peptidase-4 (DPP-4) inhibitors have been used as a new therapeutic tool for type 2 diabetes. Since the substrates for DPP-4 include intestinotrophic hormones and chemokines such as GLP-2 and stromal cell-derived factor-1 (SDF-1), which are associated with tumor progression, DPP-4 inhibitors may increase the risk of colorectal tumors. However, the influence of DPP-4 inhibitors on colorectal neoplasia in patients with type 2 diabetes remains unknown. In the present study, we show that long-term administration of a DPP-4 inhibitor, sitagliptin (STG), suppressed colon carcinogenesis in leptin-deficient (ob/ob) C57BL/6J mice. Colonic mucosal concentrations of glucagon‑like peptide-1 (GLP-1) and GLP-2 were significantly elevated in the ob/ob mice. However, mucosal GLP concentrations and the plasma level of SDF-1 were not affected by the administration of STG. Real‑time PCR analysis revealed that colonic mucosal IL-6 mRNA expression, which was significantly upregulated in the ob/ob mice, was significantly suppressed by the long-term administration of STG. These results suggest that a DPP-4 inhibitor may suppress colon carcinogenesis in mice with type 2 diabetes in a GLP-independent manner. Since DPP-4 has multiple biological functions, further studies analyzing other factors related to colon carcinogenesis are needed.

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