TY - JOUR T1 - Genetically engineered pigs manifesting pancreatic agenesis with severe diabetes JF - BMJ Open Diabetes Research & Care JO - BMJ Open Diab Res Care DO - 10.1136/bmjdrc-2020-001792 VL - 8 IS - 2 SP - e001792 AU - Masaki Nagaya AU - Koki Hasegawa AU - Masahito Watanabe AU - Kazuaki Nakano AU - Kazutoshi Okamoto AU - Takeshi Yamada AU - Ayuko Uchikura AU - Kenji Osafune AU - Harumasa Yokota AU - Taiji Nagaoka AU - Hitomi Matsunari AU - Kazuhiro Umeyama AU - Eiji Kobayashi AU - Hiromitsu Nakauchi AU - Hiroshi Nagashima Y1 - 2020/11/01 UR - http://drc.bmj.com/content/8/2/e001792.abstract N2 - Introduction Pancreatic duodenum homeobox 1 (Pdx1) expression is crucial for pancreatic organogenesis and is a key regulator of insulin gene expression. Hairy and enhancer of split 1 (Hes1) controls tissue morphogenesis by maintaining undifferentiated cells. Hes1 encodes a basic helix loop helix (bHLH) transcriptional repressor and functionally antagonizes positive bHLH genes, such as the endocrine determination gene neurogenin-3. Here, we generated a new pig model for diabetes by genetic engineering Pdx1 and Hes1 genes.Research design and methods A transgenic (Tg) chimera pig with germ cells carrying a construct expressing Hes1 under the control of the Pdx1 promoter was used to mate with wild-type gilts to obtain Tg piglets.Results The Tg pigs showed perinatal death; however, this phenotype could be rescued by insulin treatment. The duodenal and splenic lobes of the Tg pigs were slender and did not fully develop, whereas the connective lobe was absent. β cells were not detected, even in the adult pancreas, although other endocrine cells were detected, and exocrine cells functioned normally. The pigs showed no irregularities in any organs, except diabetes-associated pathological alterations, such as retinopathy and renal damage.Conclusion Pdx1-Hes1 Tg pigs were an attractive model for the analysis of pancreatic development and testing of novel treatment strategies for diabetes. ER -