Peptide YY (PYY) is a hormone produced by the enteroendocrine L cells in the gut. It is also expressed in the pancreatic islets and brainstem. PYY is secreted from the L cells in proportion to caloric intake and is involved in the regulation of satiety and energy homeostasis. The physiological role of PYY in the pancreatic islets and brainstem is not clear. In order to investigate the physiological role of PYY-expressing cells, I used a transgenic mouse model in which diphtheria toxin receptor (DTR) is expressed downstream of the PYY promoter. This enabled ablation of the PYY-expressing cells following administration of diphtheria toxin (DT) in adult mice. Intraperitoneal administration of DT at a dose of 40ng/g resulted in a significant loss of colonic, pancreatic and brainstem PYY (> 95%). Interestingly, ablation of PYY-expressing cells resulted in a significant loss of pancreatic insulin and hence severe hyperglycaemia in adult mice. In vitro administration of DT in cultured islets resulted in a significant dose-dependent loss of insulin, PYY and glucagon content. Immunohistochemical distribution of DTR was shown to be limited to the periphery of the islet, where PYY is also expressed. These experiments suggest that a product of the PYY-expressing cells may provide a paracrine factor essential for beta cell viability. Replacement of PYY using twice-daily subcutaneous injection of a long-acting PYY analogue (X-PYY) prevented the development of diabetes and reduced the loss of pancreatic insulin content. Administration of the analogue also reduced insulin loss in streptozotocin-treated mice. These studies suggest that PYY may be an important signal for beta cell maintenance. These findings have important implications for identifying novel therapies for prevention of beta cell loss in diabetes mellitus.