Sitagliptin, a dipeptidyl peptidase-4 inhibitor, suppresses CXCL5 and SDF-1 and does not accelerate intestinal neoplasia formation in ApcMin/+ mice fed a high-fat diet

Fujiwara,Kaori; Inoue,Takuya; Henmi,Yujiro; Hirata,Yoshimasa; Naka,Yutaka; Hara,Azusa; Kakimoto,Kazuki; Nouda,Sadaharu; Okada,Toshihiko; Kawakami,Ken; Takeuchi,Toshihisa; Higuchi,Kazuhide

doi:10.3892/ol.2017.6698

Sitagliptin, a dipeptidyl peptidase-4 inhibitor, suppresses CXCL5 and SDF-1 and does not accelerate intestinal neoplasia formation in ApcMin/+ mice fed a high-fat diet

Authors:
- Kaori Fujiwara
- Takuya Inoue
- Yujiro Henmi
- Yoshimasa Hirata
- Yutaka Naka
- Azusa Hara
- Kazuki Kakimoto
- Sadaharu Nouda
- Toshihiko Okada
- Ken Kawakami
- Toshihisa Takeuchi
- Kazuhide Higuchi
View Affiliations

Affiliations: Second Department of Internal Medicine, Osaka Medical College, Takatsuki, Osaka 569‑8686, Japan
Published online on: August 1, 2017 https://doi.org/10.3892/ol.2017.6698
Pages: 4355-4360

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The relationship between type 2 diabetes mellitus and intestinal neoplasia has been shown epidemiologically. A high-fat diet (HFD) is also known to promote insulin resistance, which is a risk factor for intestinal neoplasia. Dipeptidyl peptidase‑4 (DPP‑4) inhibitors are used in the clinic for the treatment of type 2 diabetes and also to prolong the effects of glucagon‑like peptide‑1 (GLP‑1). However, since the intestinotrophic hormone GLP‑2 and chemokines, such as CXCL5 and stromal cell‑derived factor‑1 (SDF‑1), are also substrates of DPP‑4, DPP‑4 inhibitors may increase the risk of intestinal carcinogenesis. In this study, we evaluated the impact of a DPP‑4 inhibitor on intestinal tumorigenesis in ApcMin/+ mice fed a HFD. Six‑week‑old male ApcMin/+ mice were randomized to either a normal diet (10 kcal% fat) group, a HFD (60 kcal% fat) group, or a HFD group treated with sitagliptin (STG). The mice were euthanized nine weeks after the start of treatment. Daily treatment with STG did not increase number of intestinal tumors in the HFD group; however, this increase was not statistically significant. The mucosal concentration of total GLP‑2 was significantly increased in the HFD group. The chemokine protein array showed elevated plasma concentrations of CXCL5 and SDF‑1 in the HFD group. The administration of STG significantly suppressed the levels of plasma CXCL5 and SDF‑1 in mice fed a HFD. Since CXCL5 expression is increased in patients with type 2 diabetes, and GLP‑2, CXCL5 and SDF‑1 are associated with tumor progression, DPP‑4 inhibition may have potential as an agent for decreasing the risk of cancer in obese or diabetic patients.

View Figures

View References

1	Tsugane S and Inoue M: Insulin resistance and cancer: Epidemiological evidence. Cancer Sci. 101:1073–1079. 2010. View Article : Google Scholar : PubMed/NCBI
2	Neville SE, Boye KS, Montgomery WS, Iwamoto K, Okamura M and Hayes RP: Diabetes in Japan: A review of disease burden and approaches to treatment. Diabetes Metab Res Rev. 25:705–716. 2009. View Article : Google Scholar : PubMed/NCBI
3	Siegel R, Naishadham D and Jemal A: Cancer statistics, 2013. CA Cancer J Clin. 63:11–30. 2013. View Article : Google Scholar : PubMed/NCBI
4	Katanoda K, Matsuda T, Matsuda A, Shibata A, Nishino Y, Fujita M, Soda M, Ioka A, Sobue T and Nishimoto H: An updated report of the trends in cancer incidence and mortality in Japan. Jpn J Clin Oncol. 43:492–507. 2013. View Article : Google Scholar : PubMed/NCBI
5	Vargas AJ and Thompson PA: Diet and nutrient factors in colorectal cancer risk. Nutr Clin Pract. 27:613–623. 2012. View Article : Google Scholar : PubMed/NCBI
6	Huang XF and Chen JZ: Obesity, the PI3K/Akt signal pathway and colon cancer. Obes Rev. 10:610–616. 2009. View Article : Google Scholar : PubMed/NCBI
7	Berster JM and Göke B: Type 2 diabetes mellitus as risk factor for colorectal cancer. Arch Physiol Biochem. 114:84–98. 2008. View Article : Google Scholar : PubMed/NCBI
8	Reimer MK, Holst JJ and Ahrén B: Long-term inhibition of dipeptidyl peptidase IV improves glucose tolerance and preserves islet function in mice. Eur J Endocrinol. 146:717–727. 2002. View Article : Google Scholar : PubMed/NCBI
9	Nadkarni P, Chepurny OG and Holz GG: Regulation of glucose homeostasis by GLP-1. Prog Mol Biol Transl Sci. 121:23–65. 2014. View Article : Google Scholar : PubMed/NCBI
10	Frezza EE, Wachtel MS and Chiriva-Internati M: The multiple faces of glucagon-like peptide-1-obesity, appetite, and stress: What is next? A review. Dig Dis Sci. 52:643–649. 2007. View Article : Google Scholar : PubMed/NCBI
11	Takasaki K, Takada H, Nakajima T, Ueno K, Ushiki J and Higo K: Involvement of the active metabolites in the inhibitory activity of K579 on rat plasma dipeptidyl peptidase IV. Eur J Pharmacol. 505:237–241. 2004. View Article : Google Scholar : PubMed/NCBI
12	Takasaki K, Nakajima T, Ueno K, Nomoto Y and Higo K: Effects of combination treatment with dipeptidyl peptidase IV inhibitor and sulfonylurea on glucose levels in rats. J Pharmacol Sci. 95:291–293. 2004. View Article : Google Scholar : PubMed/NCBI
13	Dubé PE and Brubaker PL: Frontiers in glucagon-like peptide-2: Multiple actions, multiple mediators. Am J Physiol Endocrinol Metab. 293:E460–E465. 2007. View Article : Google Scholar : PubMed/NCBI
14	Drozdowski L and Thomson AB: Intestinal hormones and growth factors: Effects on the small intestine. World J Gastroenterol. 15:385–406. 2009. View Article : Google Scholar : PubMed/NCBI
15	Hartmann B, Thulesen J, Kissow H, Thulesen S, Orskov C, Ropke C, Poulsen SS and Holst JJ: Dipeptidyl peptidase IV inhibition enhances the intestinotrophic effect of glucagon-like peptide-2 in rats and mice. Endocrinology. 141:4013–4020. 2000. View Article : Google Scholar : PubMed/NCBI
16	Boushey RP, Yusta B and Drucker DJ: Glucagon-like peptide 2 decreases mortality and reduces the severity of indomethacin-induced murine enteritis. Am J Physiol. 277:E937–E947. 1999.PubMed/NCBI
17	Fujiwara K, Inoue T, Yorifuji N, Iguchi M, Sakanaka T, Narabayashi K, Kakimoto K, Nouda S, Okada T, Ishida K, et al: 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. J Clin Biochem Nutr. 56:155–162. 2015. View Article : Google Scholar : PubMed/NCBI
18	Inoue T, Higashiyama M, Kaji I, Rudenkyy S, Higuchi K, Guth PH, Engel E, Kaunitz JD and Akiba Y: 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. View Article : Google Scholar : PubMed/NCBI
19	Iakoubov R, Lauffer LM, Trivedi S, Kim YI and Brubaker PL: Carcinogenic effects of exogenous and endogenous glucagon-like peptide-2 in azoxymethane-treated mice. Endocrinology. 150:4033–4043. 2009. View Article : Google Scholar : PubMed/NCBI
20	Lim JB and Chung HW: Serum ENA78/CXCL5, SDF-1/CXCL12, and their combinations as potential biomarkers for prediction of the presence and distant metastasis of primary gastric cancer. Cytokine. 73:16–22. 2015. View Article : Google Scholar : PubMed/NCBI
21	Johnson RL and Fleet JC: Animal models of colorectal cancer. Cancer Metastasis Rev. 32:39–61. 2013. View Article : Google Scholar : PubMed/NCBI
22	Yorifuji N, Inoue T, Iguchi M, Fujiwara K, Kakimoto K, Nouda S, Okada T, Kawakami K, Abe Y, Takeuchi T and Higuchi K: The dipeptidyl peptidase-4 inhibitor sitagliptin suppresses mouse colon tumorigenesis in type 2 diabetic mice. Oncol Rep. 35:676–682. 2016. View Article : Google Scholar : PubMed/NCBI
23	Sakanaka T, Inoue T, Yorifuji N, Iguchi M, Fujiwara K, Narabayashi K, Kakimoto K, Nouda S, Okada T, Kuramoto T, et al: The effects of a TGR5 agonist and a dipeptidyl peptidase IV inhibitor on dextran sulfate sodium-induced colitis in mice. J Gastroenterol Hepatol. 30:(Suppl 1). S60–S65. 2015. View Article : Google Scholar
24	Chavey C and Fajas L: CXCL5 drives obesity to diabetes, and further. Aging (Albany NY). 1:674–677. 2009. View Article : Google Scholar : PubMed/NCBI
25	Nunemaker CS, Chung HG, Verrilli GM, Corbin KL, Upadhye A and Sharma PR: Increased serum CXCL1 and CXCL5 are linked to obesity, hyperglycemia, and impaired islet function. J Endocrinol. 222:267–276. 2014. View Article : Google Scholar : PubMed/NCBI
26	Kim D, Kim J, Yoon JH, Ghim J, Yea K, Song P, Park S, Lee A, Hong CP, Jang MS, et al: CXCL12 secreted from adipose tissue recruits macrophages and induces insulin resistance in mice. Diabetologia. 57:1456–1465. 2014. View Article : Google Scholar : PubMed/NCBI
27	Blogowski W, Serwin K, Budkowska M, Salata D, Dolegowska B, Lokaj M, Prowans P and Starzynska T: Clinical analysis of systemic and adipose tissue levels of selected hormones/adipokines and stromal-derived factor-1. J Biol Regul Homeost Agents. 26:607–615. 2012.PubMed/NCBI
28	Kitahara CM, Trabert B, Katki HA, Chaturvedi AK, Kemp TJ, Pinto LA, Moore SC, Purdue MP, Wentzensen N, Hildesheim A and Shiels MS: Body mass index, physical activity, and serum markers of inflammation, immunity, and insulin resistance. Cancer Epidemiol Biomarkers Prev. 23:2840–2849. 2014. View Article : Google Scholar : PubMed/NCBI
29	Yazbeck R, Howarth GS and Abbott CA: Dipeptidyl peptidase inhibitors, an emerging drug class for inflammatory disease? Trends Pharmacol Sci. 30:600–607. 2009. View Article : Google Scholar : PubMed/NCBI
30	Busso N, Wagtmann N, Herling C, Chobaz-Péclat V, Bischof-Delaloye A, So A and Grouzmann E: Circulating CD26 is negatively associated with inflammation in human and experimental arthritis. Am J Pathol. 166:433–442. 2005. View Article : Google Scholar : PubMed/NCBI
31	Nakagami H, Pang Z, Shimosato T, Moritani T, Kurinami H, Koriyama H, Tenma A, Shimamura M and Morishita R: The dipeptidyl peptidase-4 inhibitor teneligliptin improved endothelial dysfunction and insulin resistance in the SHR/NDmcr-cp rat model of metabolic syndrome. Hypertens Res. 37:629–635. 2014. View Article : Google Scholar : PubMed/NCBI
32	Li CL, Zhao LJ, Zhou XL, Wu HX and Zhao JJ: Review on the effect of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors for the treatment of non-alcoholic fatty liver disease. J Huazhong Univ Sci Technolog Med Sci. 35:333–336. 2015. View Article : Google Scholar : PubMed/NCBI
33	Wang JH, Inoue T, Higashiyama M, Guth PH, Engel E, Kaunitz JD and Akiba Y: Umami receptor activation increases duodenal bicarbonate secretion via glucagon-like peptide-2 release in rats. J Pharmacol Exp Ther. 339:464–473. 2011. View Article : Google Scholar : PubMed/NCBI
34	Inoue T, Wang JH, Higashiyama M, Rudenkyy S, Higuchi K, Guth PH, Engel E, Kaunitz JD and Akiba Y: Dipeptidyl peptidase IV inhibition potentiates amino acid- and bile acid-induced bicarbonate secretion in rat duodenum. Am J Physiol Gastrointest Liver Physiol. 303:G810–G816. 2012. View Article : Google Scholar : PubMed/NCBI
35	Baldassano S, Amato A, Cappello F, Rappa F and Mulè F: Glucagon-like peptide-2 and mouse intestinal adaptation to a high-fat diet. J Endocrinol. 217:11–20. 2013. View Article : Google Scholar : PubMed/NCBI