Plasma levels of DPP4 activity and sDPP4 are dissociated from inflammation in mice and humans.

Abstract

Dipeptidyl peptidase-4 (DPP4) modulates inflammation by enzymatic cleavage of immunoregulatory peptides and through its soluble form (sDPP4) that directly engages immune cells. Here we examine whether reduction of DPP4 activity alters inflammation. Prolonged DPP4 inhibition increases plasma levels of sDPP4, and induces sDPP4 expression in lymphocyte-enriched organs in mice. Bone marrow transplantation experiments identify hematopoietic cells as the predominant source of plasma sDPP4 following catalytic DPP4 inhibition. Surprisingly, systemic DPP4 inhibition increases plasma levels of inflammatory markers in regular chow-fed but not in high fat-fed mice. Plasma levels of sDPP4 and biomarkers of inflammation are lower in metformin-treated subjects with type 2 diabetes (T2D) and cardiovascular disease, yet exhibit considerable inter-individual variation. Sitagliptin therapy for 12 months reduces DPP4 activity yet does not increase markers of inflammation or levels of sDPP4. Collectively our findings dissociate levels of DPP4 enzyme activity, sDPP4 and biomarkers of inflammation in mice and humans.

• Authors: Laurie L Baggio, Elodie M Varin, Jacqueline A Koehler, Xiemin Cao, Yuliya Lokhnygina, Susanna R Stevens, Rury R Holman, Daniel J Drucker
• Journal: Nature communications (Nat Commun) Vol. 11 Issue 1 Pg. 3766 (07 28 2020) ISSN: 2041-1723 [Electronic] England
• PMID: 32724076 (Publication Type: Clinical Trial, Phase III, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers
• Dipeptidyl-Peptidase IV Inhibitors
• Glp1r protein, mouse
• Glucagon-Like Peptide-1 Receptor
• Inflammation Mediators
• Protein Isoforms
• Metformin
• DPP4 protein, human
• Dipeptidyl Peptidase 4
• Dpp4 protein, mouse
• Sitagliptin Phosphate

Topics

• Aged
• Animals
• Biomarkers (analysis, metabolism)
• Cardiovascular Diseases (blood, immunology, prevention & control)
• Diabetes Mellitus, Type 2 (blood, complications, drug therapy, immunology)
• Diet, Atherogenic (adverse effects)
• Diet, High-Fat (adverse effects)
• Dipeptidyl Peptidase 4 (blood, immunology, metabolism)
• Dipeptidyl-Peptidase IV Inhibitors (administration & dosage, adverse effects)
• Disease Models, Animal
• Female
• Glucagon-Like Peptide-1 Receptor (genetics)
• Humans
• Inflammation (blood, diagnosis, drug therapy, immunology)
• Inflammation Mediators (analysis, metabolism)
• Male
• Metformin (administration & dosage)
• Mice
• Mice, Knockout
• Middle Aged
• Protein Isoforms (antagonists & inhibitors, blood, metabolism)
• Sitagliptin Phosphate (administration & dosage, adverse effects)