Journal Article

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

Baggio, Laurie L., Cao, Xiemin, Holman, Rury R., Drucker, Daniel J., Koehler, Jacqueline A., Lokhnygina, Yuliya, Stevens, Susanna R., Varin, Elodie M.

2020

Overview

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. DPP4 inhibitors are used for the treatment of diabetes, but the impact of DPP4 activity and soluble DPP4 on development of diabetes-associated inflammation remains uncertain. Here the authors study whether DPP4 inhibition controls sDPP4 and inflammatory biomarkers, and demonstrate that DPP4 inhibition is dissociated from changes in inflammation in mice and humans.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 38/77 / 631/443 / 64 / 64/60 / 692/163 / 82/80 / Aged / Animals / Antidiabetics / Biomarkers / Biomarkers - analysis / Biomarkers - metabolism / Bone marrow / Bone marrow transplantation / Cardiovascular diseases / Cardiovascular Diseases - blood / Cardiovascular Diseases - immunology / Cardiovascular Diseases - prevention & control / Diabetes / Diabetes mellitus (non-insulin dependent) / Diabetes Mellitus, Type 2 - blood / Diabetes Mellitus, Type 2 - complications / Diabetes Mellitus, Type 2 - drug therapy / Diabetes Mellitus, Type 2 - immunology / Diet, Atherogenic - adverse effects / Diet, High-Fat - adverse effects / Dipeptidyl Peptidase 4 - blood / Dipeptidyl Peptidase 4 - immunology / Dipeptidyl Peptidase 4 - metabolism / Dipeptidyl-peptidase IV / Dipeptidyl-Peptidase IV Inhibitors - administration & dosage / Dipeptidyl-Peptidase IV Inhibitors - adverse effects / Disease Models, Animal / Enzymatic activity / Enzyme activity / Female / Glucagon-Like Peptide-1 Receptor - genetics / Humanities and Social Sciences / Humans / Immune system / Immunoregulation / Inflammation / Inflammation - blood / Inflammation - diagnosis / Inflammation - drug therapy / Inflammation - immunology / Inflammation Mediators - analysis / Inflammation Mediators - metabolism / Lymphocytes / Male / Metformin / Metformin - administration & dosage / Mice / Mice, Knockout / Middle Aged / multidisciplinary / Organs / Peptidase / Peptides / Plasma / Plasma levels / Protein Isoforms - antagonists & inhibitors / Protein Isoforms - blood / Protein Isoforms - metabolism / Science / Science (multidisciplinary) / Sitagliptin Phosphate - administration & dosage / Sitagliptin Phosphate - adverse effects / Transplantation