Cellular Sites and Mechanisms Linking Reduction of Dipeptidyl Peptidase-4 Activity to Control of Incretin Hormone Action and Glucose Homeostasis

• Published in: Cell metabolism 2017-01, Vol.25 (1), p.152-165
• Main Authors: Mulvihill, Erin E., Varin, Elodie M., Gladanac, Bojana, Campbell, Jonathan E., Ussher, John R., Baggio, Laurie L., Yusta, Bernardo, Ayala, Jennifer, Burmeister, Melissa A., Matthews, Dianne, Bang, K.W. Annie, Ayala, Julio E., Drucker, Daniel J.
• Format: Article
• Language: English
• Subjects: Animals; Bone Marrow Transplantation; Diet, High-Fat; Dipeptidyl Peptidase 4 - blood; Dipeptidyl Peptidase 4 - metabolism; dipeptidyl peptidase-4; endothelial cells; Enteral Nutrition; enterocytes; Feeding Behavior - drug effects; Gastric Inhibitory Polypeptide - metabolism; glucagon; Glucagon-Like Peptide 1 - metabolism; glucagon-like peptide-1; Glucose - metabolism; Glucose Tolerance Test; glucose-dependent insulinotropic polypeptide; gut; hematopoietic cells; Homeostasis - drug effects; incretin; Incretins - metabolism; insulin; Insulin Resistance; Intestinal Mucosa - drug effects; Intestinal Mucosa - metabolism; Intestines - drug effects; Intestines - enzymology; Male; Mice; Models, Biological; Sitagliptin Phosphate - pharmacology
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2016.10.007

Pharmacological inhibition of the dipeptidyl peptidase-4 (DPP4) enzyme potentiates incretin action and is widely used to treat type 2 diabetes. Nevertheless, the precise cells and tissues critical for incretin degradation and glucose homeostasis remain unknown. Here, we use mouse genetics and pharmacologic DPP4 inhibition to identify DPP4+ cell types essential for incretin action. Although enterocyte DPP4 accounted for substantial intestinal DPP4 activity, ablation of enterocyte DPP4 in Dpp4Gut−/− mice did not produce alterations in plasma DPP4 activity, incretin hormone levels, and glucose tolerance. In contrast, endothelial cell (EC)-derived DPP4 contributed substantially to levels of soluble plasma DPP4 activity, incretin degradation, and glucose control. Surprisingly, DPP4+ cells of bone marrow origin mediated the selective degradation of fasting GIP, but not GLP-1. Collectively, these findings identify distinct roles for DPP4 in the EC versus the bone marrow compartment for selective incretin degradation and DPP4i-mediated glucoregulation. [Display omitted] •Endothelial-derived DPP4 controls the enteroinsular incretin axis•DPP4 expressed by hematopoietic cells selectively regulates cleavage of GIP•DPP4 in villin+ gut epithelium is dispensable for incretin-mediated glucoregulation Mulvihill et al. show that, although a substantial amount of DPP4 is produced by enterocytes, it is the endothelial cell-derived DPP4 that contributes to plasma DPP4 activity and glucose metabolism. Unexpectedly, bone marrow-derived DPP4 selectively inactivates GIP but not GLP-1.