2023•iScienceOpen access
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 J. Seymour, Elodie M. Varin, Morgan D. Fullerton, Jonathan E. Campbell, Erin E. Mulvihill
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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.