DIABETES Identification of a SIRT1 Mutation in a Family with Type 1 Diabetes Scientists describe a family carrying a mutation in the SIRT1 gene, in which all five affected members developed an autoimmune disorder: four developed type 1 diabetes, and one developed ulcerative colitis. Direct and exome sequencing identified the presence of a T-to-C exchange in exon 1 of SIRT1, corresponding to a leucine-to-proline mutation at residue 107 (SIRT1-L107P). Expression of SIRT1-L107P in insulin-producing cells resulted in overproduction of nitric oxide, cytokines, and chemokines. [Cell Metab] Abstract | Press Release Munc18b Is a Major Mediator of Insulin Exocytosis in Rat Pancreatic β-Cells Scientists found that Munc18b depletion in rat islets disabled SNARE complex formation formed by Syntaxin-2 and Syntaxin-3. Two-photon imaging analysis revealed in Munc18b-depleted β-cells a 40% reduction in primary exocytosis and abrogation of almost all sequential secretory granule (SG)-SG fusion, together accounting for a 50% reduction in glucose-stimulated insulin secretion. [Diabetes] Abstract Stromal Cell-Derived Factor 2 Like-1 (SDF2L1) Associates with the Endoplasmic Reticulum-Associated Degradation (ERAD) Machinery and Retards the Degradation of Mutant Proinsulin in Pancreatic β-Cells Researchers showed that SDF2L1 protein levels are increased in response to endoplasmic reticulum stress-inducing compounds, but not other cell stressors they tested in insulinoma cell lines. SDF2L1 protein levels were also induced by expression of misfolded proinsulin in insulinoma cells and in islets from diabetic mice. [J Cell Sci] Abstract The Hydrolase DDAH2 Enhances Pancreatic Insulin Secretion by Transcriptional Regulation of Secretagogin through a Sirt1-Dependent Mechanism in Mice The authors generated dimethylarginine dimethylaminohydrolase 2 (DDAH2) transgenic (Tg) mice that had lower plasma glucose levels and higher insulin levels during intraperitoneal glucose tolerance tests when fed a high-fat diet (HFD) compared with HFD-fed wild-type mice. Glucose-stimulated insulin secretion was increased in Tg islets by 33%. [FASEB J] Abstract PANCREATIC CANCER Hippo Signaling Regulates Differentiation and Maintenance in the Exocrine Pancreas Researchers investigated the role of the core Hippo kinases-Mst1 and Mst2-in pancreatic development and homeostasis. They used a Cre/LoxP system to create mice with pancreas-specific disruptions in Mst1 and Mst2, the mammalian orthologs of Drosophila Hippo. [Gastroenterology] Abstract PARI Overexpression Promotes Genomic Instability and Pancreatic Tumorigenesis The authors showed that an element of the homologous recombination pathway of DNA repair, the PARP-binding protein C12orf48/PARI, is overexpressed specifically in pancreatic cancer cells where it is an appealing candidate for targeted therapy. PARI upregulation in pancreatic cancer cells or avian DT40 cells conferred DNA repair deficiency and genomic instability. [Cancer Res] Abstract Aberrant Expression of Mucin Core Proteins and O-Linked Glycans Associated with Progression of Pancreatic Cancer Scientists investigated the expression of a number of mucin core proteins and associated O-linked glycans expressed in pancreatic adenocarcinoma – sialyl Tn, Tn, T antigen, sialyl Lewis A, sialyl Lewis C, Lewis X and sialyl Lewis X – during the progression of pancreatic cancer from early stages to metastatic disease. [Clin Cancer Res] Abstract Suppression of AKT Phosphorylation Restores Rapamycin-Based Synthetic Lethality in SMAD4-Defective Pancreatic Cancer Cells Researchers report that SMAD4-deficient pancreatic cancer cells are killed by rapamycin in the absence of serum; however, in the presence of serum they did not observe the predicted synthetic lethality with rapamycin. Rapamycin also induced elevated phosphorylation of the survival kinase Akt at Ser473. Suppression of rapamycin-induced Akt phosphorylation restored rapamycin sensitivity in SMAD4 null, but not SMAD4 wild type pancreatic cancer cells. [Mol Cancer Res] Abstract Net Expression Inhibits the Growth of Pancreatic Ductal Adenocarcinoma Cell PL45 In Vitro and In Vivo Using in vitro and in vivo model systems, researchers found that overexpression of Net inhibited cell growth and survival and induced cell apoptosis in human pancreatic ductal adenocarcinoma cell PL45; the mechanisms by which Net inhibited the cell cycle progression were mainly through P21-Cyclin D1/CDK4 Pathway. [PLoS One] Full Article |