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

Clin Chem Lab Med. 2009;47(3):275-87. doi: 10.1515/CCLM.2009.064.


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-Dpp4(m)/ 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-Dpp4(m)/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 immuneregulatory systems, indicating that the use of chronic DP4 inhibitors might have the potential to interfere with central nervous system and immune functions in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Congenic
  • Body Weight
  • Cytokines / immunology
  • Dipeptidyl Peptidase 4 / deficiency
  • Dipeptidyl Peptidase 4 / genetics
  • Dipeptidyl Peptidase 4 / immunology*
  • Dipeptidyl Peptidase 4 / metabolism*
  • Disease Models, Animal
  • Female
  • Glucagon-Like Peptide 1 / immunology
  • Killer Cells, Natural / immunology
  • Leptin / immunology
  • Phenotype
  • Rats
  • Rats, Inbred F344
  • T-Lymphocytes / immunology
  • Transaminases / metabolism
  • Triglycerides / metabolism


  • Cytokines
  • Leptin
  • Triglycerides
  • Glucagon-Like Peptide 1
  • Transaminases
  • Dipeptidyl Peptidase 4