Fol. Biol. 2013, 59, 116-122

https://doi.org/10.14712/fb2013059030116

The Effects of DPP-IV Inhibition in NOD Mice with Overt Diabetes

Lenka Vargová1, K. Zacharovová1, E. Dovolilová1, L. Vojtová1, Z. Cimburek2, F. Saudek1

1Institute for Clinical and Experimental Medicine, Prague, Czech Republic
2Institute of Molecular Genetics of the ASCR, v. v. i., Prague, Czech Republic

Received December 2012
Accepted January 2013

Sitagliptin is a dipeptidyl peptidase IV (DPP-IV) inhibitor that exerts an anti-hyperglycaemic effect by preventing degradation of glucagonlike 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.

Funding

This study was supported by Grant No. P304/10/0762 from the Czech Science Foundation, Czech Republic, and partially by Grant SVV-2012-264514 from Charles University in Prague, Czech Republic.

References

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