title: The effects of DPP-IV inhibition in NOD mice with overt diabetes.
abstract: Sitagliptin is a dipeptidyl peptidase IV (DPP-IV) inhibitor that exerts an anti-hyperglycaemic effect by preventing degradation of glucagon-like peptide 1 with subsequent β-cell stimulation and potential regeneration. We tested whether sitagliptin therapy in symptomatic non-obese diabetic (NOD) mice would lead to changes in the immune cell profile, improve β-cell survival and induce diabetes remission. Flow cytometry analysis of immune cells in the spleen and peripheral lymph nodes, immunohistology of the pancreas and DPP-IV activity were investigated in diabetic NOD mice, either treated or non-treated with sitagliptin, at 0, 7, 14 and 28 days after hyperglycaemia onset, and in non-diabetic NOD controls. While compared to diabetic controls sitagliptin prevented increase of the CD8+/CD4+ ratio in pancreatic nodes after four weeks (0.443 ± 0.067 vs. 0.544 ± 0.131; P < 0.05), the population of Tregs in lymph nodes increased from day 0 to 28 in both treated and non-treated diabetic groups (8 ± 1.76 vs. 13.45 ± 5.07 % and 8 ± 1.76 vs. 13.19 ± 5.58 %, respectively). The severity of islet infiltration was similar in both diabetic groups and decreased in parallel with β-cell loss. Surprisingly, sitagliptin blocked the DPP-IV activity only temporarily (on day 7, 277.68 ± 89.2 vs. 547.40 ± 94.04 ng/ml in the diabetic control group) with no apparent effect later on. In conclusion, sitagliptin administered after the onset of overt hyperglycaemia in NOD mice had only a marginal immunological effect and did not lead to diabetes remission. Failure to block DPP-IV over time represents an important finding that requires further explanation.
authors.affiliation: Institute for Clinical and Experimental Medicine, Prague, Czech Republic. lept@medicon.cz
authors.forename: L
authors.initials: L
authors.lastname: Vargová
authors.forename: K
authors.initials: K
authors.lastname: Zacharovová
authors.forename: E
authors.initials: E
authors.lastname: Dovolilová
authors.forename: L
authors.initials: L
authors.lastname: Vojtová
authors.forename: Z
authors.initials: Z
authors.lastname: Cimburek
authors.forename: F
authors.initials: F
authors.lastname: Saudek
mesh_terms: D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D018819:Dipeptidyl Peptidase 4 / Q000187:drug effects*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005260:Female; D007515:Islets of Langerhans / Q000276:immunology / Q000473:pathology; D008198:Lymph Nodes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D011719:Pyrazines / Q000494:pharmacology / Q000627:therapeutic use*; D000068900:Sitagliptin Phosphate; D013154:Spleen / Q000276:immunology / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D013997:Time Factors; D014230:Triazoles / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D011719:Pyrazines; D014230:Triazoles; D018819:Dipeptidyl Peptidase 4; C545245:Dpp4 protein, mouse; D000068900:Sitagliptin Phosphate