Selective Ablation of Peptide YY Cells in Adult Mice Reveals Their Role in Beta Cell Survival

Background & Aims In the pancreas, peptide YY (PYY) is expressed by a subpopulation of nonbeta cells in the islets of Langerhans. We investigated the function of these cells in the pancreas of adult mice. Methods We generated mice in which administration of diphtheria toxin (DT) led to specific ablation of PYY-expressing cells. We investigated the effects of loss of PYY cells on glucose homeostasis. Results Loss of PYY cells in adult mice resulted in severe hyperglycemia, which was associated with significant loss of pancreatic insulin and disruption of islet morphology. In vitro administration of DT to isolated islets significantly reduced numbers of PYY-expressing cells and levels of insulin. Administration of either pancreatic polypeptide (a strong agonist of the receptor Y 4 ) or PYY 3–36 (a selective agonist of the receptor Y 2 ) did not restore loss of pancreatic insulin following administration of DT. However, a long-acting PYY analogue reduced the loss of insulin, and administration of this analogue reduced the hyperglycemia and insulin loss induced by streptozotocin in mice. Conclusions PYY appears to regulate beta cell function and survival via the receptor Y 1/2 . These findings might be developed to treat and prevent loss of beta cells in patients with diabetes mellitus.