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The high coincidence ratio between HMSN-P and diabetes mellitus suggests TFG to have an important role(s) in glucose homeostasis. To examine this possibility, \u03b2-cell specific TFG knockout mice (\u03b2TFG KO) were generated. Interestingly, \u03b2TFG KO displayed marked glucose intolerance with reduced insulin secretion. Immunohistochemical analysis revealed smaller \u03b2-cell masses in \u03b2TFG KO than in controls, likely attributable to diminished \u03b2-cell proliferation. Consistently, \u03b2-cell expansion in response to a high-fat, high-sucrose (HFHS) diet was significantly impaired in \u03b2TFG KO. Furthermore, glucose-induced insulin secretion was also markedly impaired in islets isolated from \u03b2TFG KO. Electron microscopic observation revealed endoplasmic reticulum (ER) dilatation, suggestive of ER stress, and smaller insulin crystal diameters in \u03b2-cells of \u03b2TFG KO. Microarray gene expression analysis indicated downregulation of NF-E2 related factor 2 (Nrf2) and its downstream genes in TFG depleted islets. Collectively, TFG in pancreatic \u03b2-cells plays a vital role in maintaining both the mass and function of \u03b2-cells, and its dysfunction increases the tendency to develop glucose intolerance.<\/jats:p>","DOI":"10.1038\/s41598-017-13432-x","type":"journal-article","created":{"date-parts":[[2017,10,6]],"date-time":"2017-10-06T09:55:08Z","timestamp":1507283708000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Trk-fused gene (TFG) regulates pancreatic \u03b2 cell mass and insulin secretory activity"],"prefix":"10.1038","volume":"7","author":[{"given":"Takeshi","family":"Yamamotoya","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yusuke","family":"Nakatsu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1385-7487","authenticated-orcid":false,"given":"Akifumi","family":"Kushiyama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuka","family":"Matsunaga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koji","family":"Ueda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Inoue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masa-Ki","family":"Inoue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideyuki","family":"Sakoda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Midori","family":"Fujishiro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiraku","family":"Ono","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Kiyonari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hisamitsu","family":"Ishihara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoichiro","family":"Asano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,10,12]]},"reference":[{"key":"13432_CR1","doi-asserted-by":"publisher","first-page":"6118","DOI":"10.1128\/MCB.15.11.6118","volume":"15","author":"A Greco","year":"1995","unstructured":"Greco, A. et al. The DNA rearrangement that generates the TRK-T3 oncogene involves a novel gene on chromosome 3 whose product has a potential coiled-coil domain. Mol Cell Biol \n                           15, 6118\u20136127 (1995).","journal-title":"Mol Cell Biol"},{"key":"13432_CR2","doi-asserted-by":"crossref","first-page":"3265","DOI":"10.1182\/blood.V94.9.3265","volume":"94","author":"L Hernandez","year":"1999","unstructured":"Hernandez, L. et al. TRK-fused gene (TFG) is a new partner of ALK in anaplastic large cell lymphoma producing two structurally different TFG-ALK translocations. Blood \n                           94, 3265\u20133268 (1999).","journal-title":"Blood"},{"key":"13432_CR3","doi-asserted-by":"publisher","first-page":"550","DOI":"10.1038\/ncb2225","volume":"13","author":"K Witte","year":"2011","unstructured":"Witte, K. et al. TFG-1 function in protein secretion and oncogenesis. 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