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

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.

Automated summary

Mice lacking DPP4 have improved islet health, glucoregulation, and reduced obesity with HFD feeding. The improvement can be partly attributed to the loss of DPP4 in non-EC types. Beta cell incretin receptors are necessary for DPP4 inhibitor effects on insulin secretion and glucose tolerance in HFD-fed mice.