Pancreas-derived DPP4 is not essential for glucose homeostasis under metabolic stress
Evgenia Fadzeyeva,
Cassandra A.A. Locatelli,
Natasha A. Trzaskalski,
My-Anh Nguyen,
Megan E. Capozzi,
Branka Vulesevic,
Nadya M. Morrow,
Peyman Ghorbani,
Antonio A. Hanson,
Ilka Lorenzen-Schmidt,
Mary-Anne Doyle,
Richard Seymour,
Elodie M. Varin,
Morgan D. Fullerton,
Jonathan E. Campbell,
Erin E. Mulvihill
Affiliations
Evgenia Fadzeyeva
The University of Ottawa, Faculty of Medicine, Department of Biochemistry, Microbiology and Immunology, Ottawa, ON K1H 8M5, Canada; The University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON K1Y4W7, Canada
Cassandra A.A. Locatelli
The University of Ottawa, Faculty of Medicine, Department of Biochemistry, Microbiology and Immunology, Ottawa, ON K1H 8M5, Canada; The University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON K1Y4W7, Canada
Natasha A. Trzaskalski
The University of Ottawa, Faculty of Medicine, Department of Biochemistry, Microbiology and Immunology, Ottawa, ON K1H 8M5, Canada; The University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON K1Y4W7, Canada
My-Anh Nguyen
The University of Ottawa, Faculty of Medicine, Department of Biochemistry, Microbiology and Immunology, Ottawa, ON K1H 8M5, Canada; The University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON K1Y4W7, Canada
Megan E. Capozzi
Duke Molecular Physiology Institute, 300 North Duke Street, Durham, NC 27701, USA
Branka Vulesevic
The University of Ottawa, Faculty of Medicine, Department of Biochemistry, Microbiology and Immunology, Ottawa, ON K1H 8M5, Canada; The University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON K1Y4W7, Canada
Nadya M. Morrow
The University of Ottawa, Faculty of Medicine, Department of Biochemistry, Microbiology and Immunology, Ottawa, ON K1H 8M5, Canada; The University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON K1Y4W7, Canada
Peyman Ghorbani
The University of Ottawa, Faculty of Medicine, Department of Biochemistry, Microbiology and Immunology, Ottawa, ON K1H 8M5, Canada
Antonio A. Hanson
The University of Ottawa, Faculty of Medicine, Department of Biochemistry, Microbiology and Immunology, Ottawa, ON K1H 8M5, Canada; The University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON K1Y4W7, Canada
Ilka Lorenzen-Schmidt
The University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON K1Y4W7, Canada
Mary-Anne Doyle
Division of Endocrinology & Metabolism, Department of Medicine, University of Ottawa, Ottawa, ON K1H 8L6, Canada
Richard Seymour
The University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON K1Y4W7, Canada
Elodie M. Varin
Lunenfeld Tanenbaum Research Institute, Toronto, ON M5G 1X5, Canada
Morgan D. Fullerton
The University of Ottawa, Faculty of Medicine, Department of Biochemistry, Microbiology and Immunology, Ottawa, ON K1H 8M5, Canada; Centre for Infection, Immunity and Inflammation, Ottawa, ON K1H 8M5, Canada
Jonathan E. Campbell
Duke Molecular Physiology Institute, 300 North Duke Street, Durham, NC 27701, USA
Erin E. Mulvihill
The University of Ottawa, Faculty of Medicine, Department of Biochemistry, Microbiology and Immunology, Ottawa, ON K1H 8M5, Canada; The University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON K1Y4W7, Canada; Centre for Infection, Immunity and Inflammation, Ottawa, ON K1H 8M5, Canada; Montreal Diabetes Research Group, Montreal, QC H2X 0A9, Canada; Corresponding author
Summary: Mice systemically lacking dipeptidyl peptidase-4 (DPP4) have improved islet health, glucoregulation, and reduced obesity with high-fat diet (HFD) feeding compared to wild-type mice. Some, but not all, of this improvement can be linked to the loss of DPP4 in endothelial cells (ECs), pointing to the contribution of non-EC types. The importance of intra-islet signaling mediated by α to β cell communication is becoming increasingly clear; thus, our objective was to determine if β cell DPP4 regulates insulin secretion and glucose tolerance in HFD-fed mice by regulating the local concentrations of insulinotropic peptides. Using β cell double incretin receptor knockout mice, β cell- and pancreas-specific Dpp4−/− mice, we reveal that β cell incretin receptors are necessary for DPP4 inhibitor effects. However, although β cell DPP4 modestly contributes to high glucose (16.7 mM)-stimulated insulin secretion in isolated islets, it does not regulate whole-body glucose homeostasis.
