Fadzeyeva_2023_iScience_26_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 alpha to beta cell communication is becoming increasingly clear; thus, our objective was to determine if beta cell DPP4 regulates insulin secretion and glucose tolerance in HFD-fed mice by regulating the local concentrations of insulinotropic peptides. Using beta cell double incretin receptor knockout mice, beta cell- and pancreas-specific Dpp4(-/-) mice, we reveal that beta cell incretin receptors are necessary for DPP4 inhibitor effects. However, although beta cell DPP4 modestly contributes to high glucose (16.7 mM)-stimulated insulin secretion in isolated islets, it does not regulate whole-body glucose homeostasis.