Characterization of a transgenic mouse tissue-specifically overexpressing pancreatic derived factor (PANDER), a novel, pancreas specific cytokine -like molecule

Pro-inflammatory cytokines have profound effects on islet cells. They inhibit insulin secretion and destroy β-cells resulting in diabetes (Rabinovitch, 1996). Recently, we have identified a novel family of cytokines, FAM3, with the characteristic four-alpha helix bundle. One of its members, FAM3B, or PANDER (PANcreatic DERived factor), is expressed primarily in the α and β-cells of the pancreas (Cao et al., 2003). PANDER is a 26.1kD protein which is structurally homologous to cytokines such as EPO, GM-CSF, growth hormone, IL-2,-3,-4,-5,-6,-7,-9,-10 and -13. PANDER contains a signal peptide and co-localizes to insulin-containing secretory granules of β-cells (Xu et al., 2005). In vitro experiments show that recombinant PANDER or adenoviral expression of PANDER induces apoptosis in rodent and human islets and insulin-secreting β-cell lines (Cao et al., 2003). In an effort to elucidate the function of PANDER in islets I have developed a mouse model, on a B6SJLF1/J background, which overexpresses PANDER exclusively in pancreatic islets using a 1kB fragment of the PDX-1 promoter. Seven lines were obtained which demonstrated overexpression of PANDER in islets. Two lines were further studied, and showed an 8-10% increase in expression of PANDER protein in islets when compared to control. These transgenic mice demonstrate a phenotype similar to a type 2 diabetic model with impaired glucose tolerance appearing after at least 5 weeks on a high fat diet. Islet function, including insulin secretion in response to glucose, is intact in the transgenic model. In addition insulin tolerance does not appear to be affected by PANDER overexpression. Although there is no loss of β-cell mass or increased apoptosis in the PANDER transgenic mouse, the appearance of a glucose intolerant phenotype and a lack of islet dysfunction suggests that PANDER may be a novel pancreatic-derived factor that plays a role in the pathogenesis of type 2 diabetes, perhaps via its action on a tissue other than the pancreas