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.

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.