Accessible Requires Authentication Published by De Gruyter March 1, 2009

Phenotyping of congenic dipeptidyl peptidase 4 (DP4) deficient Dark Agouti (DA) rats suggests involvement of DP4 in neuro-, endocrine, and immune functions

Nadine Frerker, Kerstin Raber, Felix Bode, Thomas Skripuletz, Heike Nave, Christian Klemann, Reinhard Pabst, Michael Stephan, Jutta Schade, Georg Brabant, Dirk Wedekind, Roland Jacobs, Anne Jörns, Ulf Forssmann, Rainer H. Straub, Sigrid Johannes, Torsten Hoffmann, Leona Wagner, Hans-Ulrich Demuth and Stephan von Hörsten

Abstract

Background: Treatment of diabetes type 2 using chronic pharmacological inhibition of dipeptidyl peptidase 4 (DP4) still requires an in-depth analysis of models for chronic DP4 deficiency, because adverse reactions induced by some DP4 inhibitors have been described.

Methods: In the present study, a novel congenic rat model of DP4 deficiency on a “DP4-high” DA rat genetic background was generated (DA.F344-Dpp4m/SvH rats) and comprehensively phenotyped.

Results: Similar to chronic pharmacological inhibition of DP4, DP4 deficient rats exhibited a phenotype involving reduced diet-induced body weight gain and improved glucose tolerance associated with increased levels of glucagon-like peptide-1 (GLP-1) and bound leptin as well as decreased aminotransferases and triglycerides. Additionally, DA.F344-Dpp4m/SvH rats showed anxiolytic-like and reduced stress-like responses, a phenomenon presently not targeted by DP4 inhibitors. However, several immune alterations, such as differential leukocyte subset composition at baseline, blunted natural killer cell and T-cell functions, and altered cytokine levels were observed.

Conclusions: While this animal model confirms a critical role of DP4 in GLP-1-dependent glucose regulation, genetically induced chronic DP4 deficiency apparently also affects stress-regulatory and immune-regulatory systems, indicating that the use of chronic DP4 inhibitors might have the potential to interfere with central nervous system and immune functions in vivo.

Clin Chem Lab Med 2009;47:275–87.


Corresponding author: Dr. Stephan von Hörsten, Experimental Therapy, Franz-Penzoldt-Center, Friedrich-Alexander-University Erlangen-Nürnberg, Palmsanlage 5, 91054 Erlangen, Germany Phone: +49-9131-8523504, Fax: +49-9131-8523502,

Received: 2008-11-10
Accepted: 2009-1-22
Published Online: 2009-03-01
Published in Print: 2009-03-01

©2009 by Walter de Gruyter Berlin New York