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Diabetes. 2010 Jul;59(7):1739-50. doi: 10.2337/db09-1618. Epub 2010 Apr 5.

Sitagliptin (MK0431) inhibition of dipeptidyl peptidase IV decreases nonobese diabetic mouse CD4+ T-cell migration through incretin-dependent and -independent pathways.

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  • 1Department of Cellular and Physiological Sciences and Diabetes Research Group, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada.

Abstract

OBJECTIVE:

Treatment of NOD mice with the dipeptidyl peptidase-IV (DPP-IV) inhibitor sitagliptin preserved islet transplants through a pathway involving modulation of splenic CD4(+) T-cell migration. In the current study, effects of sitagliptin on migration of additional subsets of CD4(+) T-cells were examined and underlying molecular mechanisms were further defined.

RESEARCH DESIGN AND METHODS:

Effects of sitagliptin on migration of NOD mouse splenic, thymic, and lymph node CD4(+) T-cells were determined. Signaling modules involved in DPP-IV-, Sitagliptin- and incretin-mediated modulation of CD4(+) T-cell migration were studied using Western blot and Rac1 and nuclear factor-kappaB (NF-kappaB) activity assays.

RESULTS:

Migration of splenic and lymph node CD4(+) T-cells of diabetic NOD mice was reduced by sitagliptin treatment. In vitro treatment of splenic, but not thymic or lymph node CD4(+) T-cells, from nondiabetic NOD mice with soluble (s) DPP-IV increased migration. Sitagliptin abolished sDPP-IV effects on splenic CD4(+) T-cell migration, whereas incretins decreased migration of lymph node, but not splenic, CD4(+) T-cells. Splenic CD4(+) T-cells demonstrating increased in vitro migration in response to sDPP-IV and lymph node CD4(+) T-cells that were nonresponsive to incretins selectively infiltrated islets of NOD mice, after injection. Sitagliptin decreases migration of splenic CD4(+) T-cells through a pathway involving Rac1/vasodilator-stimulated phosphoprotein, whereas its inhibitory effects on the migration of lymph node CD4(+) T-cells involve incretin-activation of the NF-kappaB pathway.

CONCLUSIONS:

Benefits of sitagliptin treatment in diabetic NOD mice may be mediated through selective effects on subpopulations of T-cells that are related to autoimmunity.

PMID:
20368408
[PubMed - indexed for MEDLINE]
PMCID:
PMC2889774
Free PMC Article
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