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

• Published in: iScience Vol. 26; no. 5; p. 106748
• Main Authors: Fadzeyeva, Evgenia, Locatelli, Cassandra A.A., Trzaskalski, Natasha A., Nguyen, My-Anh, Capozzi, Megan E., Vulesevic, Branka, Morrow, Nadya M., Ghorbani, Peyman, Hanson, Antonio A., Lorenzen-Schmidt, Ilka, Doyle, Mary-Anne, Seymour, Richard, Varin, Elodie M., Fullerton, Morgan D., Campbell, Jonathan E., Mulvihill, Erin E.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 19-05-2023; Elsevier
• Subjects: Biological sciences; Cell biology; Molecular biology; Physiology; Cell biology; Biological sciences; Physiology; Molecular biology
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2023.106748

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.
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•β cell incretin receptors are required for DPP4i-mediated glucose lowering•Dpp4β-cell−/− increases glucose-stimulated (16.7 mM) insulin secretion in isolated islets•Glucose tolerance is not improved in HFD-fed Dpp4β-cell−/− or Dpp4Pan−/− mice•Insulin secretion is unchanged in HFD-fed Dpp4β-cell−/− or Dpp4Pan−/− mice
Biological sciences; Physiology; Molecular biology; Cell biology