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

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 Apc Min/+ mice fed a HFD. Six-week-old male Apc Min/+ 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.

CD26/DPP4 - a potential biomarker and target for cancer therapy

“…suppressed the levels of plasma CXCL5 and CXCL12 in mice fed a HFD which could suggest a reduction in cancer risk in obese or diabetic patients (Fujiwara et al, 2017).…”

Phytochemicals in Garlic Extract Inhibit Therapeutic Enzyme DPP-4 and Induce Skeletal Muscle Cell Proliferation: A Possible Mechanism of Action to Benefit the Treatment of Diabetes Mellitus

“…Dipeptidyl peptidase 4 (DPP-4) is a naturally occurring serine protease expressed on the cell surface and thoroughly known to regulate glucose metabolism. DPP-4 rapidly degrades glucagon-like peptide (GLP-1 and GLP-2), glucose-dependent insulin releasing polypeptide GIP [5], stromal-cell derived factor (SDF-2) [6], chemokine (C-C motif) ligand 5 (RANTES) [7], and eotaxin [8]. Among these specific substrates, incretin hormones secreted by intestinal cells are responsible for adequately controlling blood glucose levels [9].…”

Diabetes Mellitus and Colon Carcinogenesis: Expectation for Inhibition of Colon Carcinogenesis by Oral Hypoglycemic Drugs

“…We found only one clinical study conducted in 2018 on the risk of colon carcinogenesis; the study reported that there was no improvement in the risk of developing colon carcinogenesis by DPP-4 inhibitors [77,78]. In in-vitro studies conducted between 2000 and 2019, there were three reports that confirmed the tumor suppressing by DPP-4 inhibitors [79][80][81], on the contrary, one study reported that the tumor suppressing effect could not be confirmed.…”