title: Cellular Sites and Mechanisms Linking Reduction of Dipeptidyl Peptidase-4 Activity to Control of Incretin Hormone Action and Glucose Homeostasis.
abstract: 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.
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, ON M5G 1X5, Canada.
authors.forename: Erin E
authors.initials: EE
authors.lastname: Mulvihill
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, ON M5G 1X5, Canada.
authors.forename: Elodie M
authors.initials: EM
authors.lastname: Varin
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, ON M5G 1X5, Canada.
authors.forename: Bojana
authors.initials: B
authors.lastname: Gladanac
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, ON M5G 1X5, Canada.
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Campbell
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, ON M5G 1X5, Canada.
authors.forename: John R
authors.initials: JR
authors.lastname: Ussher
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, ON M5G 1X5, Canada.
authors.forename: Laurie L
authors.initials: LL
authors.lastname: Baggio
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, ON M5G 1X5, Canada.
authors.forename: Bernardo
authors.initials: B
authors.lastname: Yusta
authors.affiliation: Sanford Burnham Prebys Medical Discovery Institute at Lake Nona, Center for Metabolic Origins of Disease, Orlando, FL 32827, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Ayala
authors.affiliation: Sanford Burnham Prebys Medical Discovery Institute at Lake Nona, Center for Metabolic Origins of Disease, Orlando, FL 32827, USA.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Burmeister
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, ON M5G 1X5, Canada.
authors.forename: Dianne
authors.initials: D
authors.lastname: Matthews
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, ON M5G 1X5, Canada; Division of Reproductive Sciences, University of Toronto, Toronto, ON M5S 2J7, Canada; Institute of Medical Sciences, University of Toronto, Toronto, ON M5S 2J7, Canada.
authors.forename: K W Annie
authors.initials: KWA
authors.lastname: Bang
authors.affiliation: Sanford Burnham Prebys Medical Discovery Institute at Lake Nona, Center for Metabolic Origins of Disease, Orlando, FL 32827, USA.
authors.forename: Julio E
authors.initials: JE
authors.lastname: Ayala
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, ON M5G 1X5, Canada; Department of Medicine, University of Toronto, Toronto, ON M5S 2J7, Canada. Electronic address: drucker@lunenfeld.ca.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Drucker
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D059305:Diet, High-Fat; D018819:Dipeptidyl Peptidase 4 / Q000097:blood / Q000378:metabolism*; D004750:Enteral Nutrition; D005247:Feeding Behavior / Q000187:drug effects; D005749:Gastric Inhibitory Polypeptide / Q000378:metabolism*; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D006706:Homeostasis / Q000187:drug effects; D054795:Incretins / Q000378:metabolism*; D007333:Insulin Resistance; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism; D007422:Intestines / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D008954:Models, Biological; D000068900:Sitagliptin Phosphate / Q000494:pharmacology
chemical_list: D054795:Incretins; D005749:Gastric Inhibitory Polypeptide; D052216:Glucagon-Like Peptide 1; D018819:Dipeptidyl Peptidase 4; D005947:Glucose; D000068900:Sitagliptin Phosphate
keywords: dipeptidyl peptidase-4; endothelial cells; enterocytes; glucagon; glucagon-like peptide-1; glucose metabolism; glucose-dependent insulinotropic polypeptide; gut; hematopoietic cells; incretin; insulin