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.

Despite growing interest in the relationship between autophagy and systemic metabolism, how global changes in autophagy affect metabolism remains unclear. Here we show that mice with global haploinsufficiency of an essential autophagy gene (Atg7 þ / À mice) do not show metabolic abnormalities but develop diabetes when crossed with ob/ob mice. Atg7 þ / À -ob/ob mice show aggravated insulin resistance with increased lipid content and inflammatory changes, suggesting that autophagy haploinsufficiency impairs the adaptive response to metabolic stress. We further demonstrate that intracellular lipid content and insulin resistance after lipid loading are increased as a result of autophagy insufficiency, and provide evidence for increased inflammasome activation in Atg7 þ / À -ob/ob mice. Imatinib or trehalose improves metabolic parameters of Atg7 þ / À -ob/ob mice and enhances autophagic flux. These results suggest that systemic autophagy insufficiency could be a factor in the progression from obesity to diabetes, and autophagy modulators have therapeutic potential against diabetes associated with obesity and inflammation.

Purpose To determine the relationship between tumor heterogeneity assessed by means of magnetic resonance (MR) imaging texture analysis and survival outcomes in patients with primary breast cancer. Materials and Methods Between January and August 2010, texture analysis of the entire primary breast tumor in 203 patients was performed with T2-weighted and contrast material-enhanced T1-weighted subtraction MR imaging for preoperative staging. Histogram-based uniformity and entropy were calculated. To dichotomize texture parameters for survival analysis, the 10-fold cross-validation method was used to determine cutoff points in the receiver operating characteristic curve analysis. The Cox proportional hazards model and Kaplan-Meier analysis were used to determine the association of texture parameters and morphologic or volumetric information obtained at MR imaging or clinical-pathologic variables with recurrence-free survival (RFS). Results There were 26 events, including 22 recurrences (10 local-regional and 12 distant) and four deaths, with a mean follow-up time of 56.2 months. In multivariate analysis, a higher N stage (RFS hazard ratio, 11.15 [N3 stage]; P = .002, Bonferroni-adjusted α = .0167), triple-negative subtype (RFS hazard ratio, 16.91; P < .001, Bonferroni-adjusted α = .0167), high risk of T1 entropy (less than the cutoff values [mean, 5.057; range, 5.022-5.167], RFS hazard ratio, 4.55; P = .018), and T2 entropy (equal to or higher than the cutoff values [mean, 6.013; range, 6.004-6.035], RFS hazard ratio = 9.84; P = .001) were associated with worse outcomes. Conclusion Patients with breast cancers that appeared more heterogeneous on T2-weighted images (higher entropy) and those that appeared less heterogeneous on contrast-enhanced T1-weighted subtraction images (lower entropy) exhibited poorer RFS. RSNA, 2016 Online supplemental material is available for this article.