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

doi:10.1016/j.isci.2023.106748

Pancreas-derived DPP4 is not essential for glucose homeostasis under metabolic stress

iScience. 2023 Apr 26;26(5):106748. doi: 10.1016/j.isci.2023.106748. eCollection 2023 May 19.

Authors

Evgenia Fadzeyeva^{1

2}, Cassandra A A Locatelli^{1

2}, Natasha A Trzaskalski^{1

2}, My-Anh Nguyen^{1

2}, Megan E Capozzi³, Branka Vulesevic^{1

2}, Nadya M Morrow^{1

2}, Peyman Ghorbani¹, Antonio A Hanson^{1

2}, Ilka Lorenzen-Schmidt², Mary-Anne Doyle⁴, Richard Seymour², Elodie M Varin⁵, Morgan D Fullerton^{1

6}, Jonathan E Campbell³, Erin E Mulvihill^{1

2

6

7}

Affiliations

¹ The University of Ottawa, Faculty of Medicine, Department of Biochemistry, Microbiology and Immunology, Ottawa, ON K1H 8M5, Canada.
² The University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON K1Y4W7, Canada.
³ Duke Molecular Physiology Institute, 300 North Duke Street, Durham, NC 27701, USA.
⁴ Division of Endocrinology & Metabolism, Department of Medicine, University of Ottawa, Ottawa, ON K1H 8L6, Canada.
⁵ Lunenfeld Tanenbaum Research Institute, Toronto, ON M5G 1X5, Canada.
⁶ Centre for Infection, Immunity and Inflammation, Ottawa, ON K1H 8M5, Canada.
⁷ Montreal Diabetes Research Group, Montreal, QC H2X 0A9, Canada.

Abstract

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.

Keywords: Biological sciences; Cell biology; Molecular biology; Physiology.

Abstract

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