Background and aims: Peptide YY (PYY) is a gut hormone synthesized by enteroendocrine L-cells in the gut. It is also present in the pancreas where in the adult PYY immunoreactivity is restricted to a major subpopulation of -cells, a subpopulation of the -cells and pancreatic polypeptide (PP) cells. PYY gene deletion has demonstrated it plays a key role in body weight regulation without obvious alterations in glucose homeostasis. However, ablation of peptides using germ line knockout approaches can lead to compensatory adaptive changes. So we developed a transgenic mouse expressing diphtheria toxin receptor (DTR) specifically in PYY cells. This allowed the conditional ablation of PYY-expressing cells throughout the body following administration of a single dose of diphtheria toxin (DT) (40ng/g i.p.) to PYY-DTR mice. Results: Body weight and food intake were similar between wild-type and PYY-DTR mice. DTR was expressed by tissues that express PYY; gastrointestinal tract, islets and brainstem. In the pancreas dual labelling demonstrated DTR staining was not likely to be expressed by more than a minority of beta-cells (less than 5%). Administration of DT lead to a 97% reduction in colonic PYY concentrations and cell number and resulted in severe weight loss, but food intake was unaffected. DT-treated PYY-DTR mice had polyuria, suggesting the development of diabetes. In agreement with this these mice were hyperglycaemic, hypoinsulinaemic and had reduced pancreatic insulin content. DT also resulted in dose dependent and significant reductions in PYY and insulin concentrations in isolated islets. Our data are consistent with PYY-expressing cells providing a trophic signal(s) for beta-cell maintenance. If true, pharmacological replacement with this factor(s) would be expected to rescue insulin loss in vivo. Administration of either PP (Y4 receptor agonist, i.p minipump) or PYY3-36 (Y2 receptor agonist, i.p minipump) did not rescue the loss of pancreatic insulin following DT administration. However, a novel long-acting PYY analogue (given i.p.) with high affinity for both Y1 and Y2 receptors significantly reduced the loss of insulin content and beat-cell number. Administration of this analogue also ameliorated the hyperglycaemia and insulin loss induced by streptozotocin. Conclusion: These studies suggest that PYY may play a role in the regulation of beta-cell maintenance and survival via the Y1/2 receptor. This could have important implications for identifying novel therapies for the prevention and treatment of beta-cell loss in diabetes mellitus.