Aims/hypothesis The unfolded protein response (UPR) in endoplasmic reticulum (ER) and autophagy are known to be related. We investigated the role of autophagy in UPR of pancreatic beta cells and the susceptibility of autophagydeficient beta cells to the ER stress that is implicated in the development of diabetes. Methods Rat insulin promoter (RIP)-Cre + ;autophagy-related 7 (Atg7) F/W mice were bred with ob/w mice to derive RIP-Cre + ;Atg7 F/F -ob/ob mice and to induce ER stress in vivo. GFP-LC3 + -ob/ob mice were generated to examine in vivo autophagic activity. Real-time RT-PCR was performed to study the expression of the genes of the UPR machinery. Proteolysis was assessed by determining release of incorporated radioactive leucine.Results Production of UPR machinery was reduced in autophagy-deficient beta cells, which was associated with diminished production of p85α and p85β regulatory subunits of phosphoinositide 3-kinase. Because of compromised UPR machinery, autophagy-deficient beta cells were susceptible to ER stressors in vitro. When mice with beta cell-specific autophagy deficiency, which have mild hyperglycaemia, were bred with ob/ob mice to induce ER stress in vivo, severe diabetes developed, which was accompanied by an increase in beta cell death and accumulation of reactive oxygen species. The increased demand for UPR present in obesity was unmet in autophagy-deficient beta cells. Autophagy level and autophagic activity were enhanced by lipid, while proteolysis was reduced. Conclusions/interpretation These results suggest that autophagy is important for intact UPR machinery and appropriate UPR in response to lipid injury that increases demand for UPR. Autophagy deficiency in pancreatic beta cells may contribute to the progression from obesity to diabetes.

Aims/hypothesis We have shown that chronic administration of the Toll-like receptor 2 (TLR2) agonist Pam3CSK 4 prevents diabetes in NOD mice by inducing TLR2 tolerance of dendritic cells (DCs). We have also reported that a novel dipeptidyl peptidase 4 (DPP4) inhibitor, DA-1229, could increase beta cell mass. Here we investigated whether a combination of DPP4 inhibition, with beneficial effects on beta cell mass, and TLR2 tolerisation, protecting beta cells from autoimmune destruction, could treat a model of established type 1 diabetes. Methods Diabetic NOD mice were treated with 100 μg Pam3CSK 4 , administered three times a week for 3 weeks, in combination with feeding with chow containing 0.3% DA-1229. Beta cell mass and proliferation were studied by immunohistochemistry. DC tolerance was assessed by studying diabetogenic CD4 + T cell priming after adoptive transfer and expression of costimulatory molecules on DCs by flow cytometry. Results