Sitagliptin (MK0431) Inhibition of Dipeptidyl Peptidase IV Decreases Nonobese Diabetic Mouse CD4+ T-Cell Migration Through Incretin-Dependent and -Independent Pathways

  1. Christopher H.S. McIntosh
  1. From the Department of Cellular and Physiological Sciences and the Diabetes Research Group, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada.
  1. Corresponding author: C.H.S. McIntosh, mcintoch{at}interchange.ubc.ca.

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-κB (NF-κB) 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-κB 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.

Footnotes

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  • Received November 4, 2009.
  • Accepted March 21, 2010.

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  1. Diabetes vol. 59 no. 7 1739-1750
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