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Here, the small molecular compound, ethyl 5-(3-ethoxy-4-methoxyphenyl)-2-(4-hydroxy-3-methoxybenzylidene)-7-methyl-3-oxo-2,3-dihydro-5H-[1,3]thiazolo[3,2\u2013a]pyrimidine-6-carboxylate (SP6616) was discovered to be a new Kv2.1 inhibitor. It was effective in both promoting GSIS and protecting <jats:italic>\u03b2<\/jats:italic> cells from apoptosis. Evaluation of SP6616 on either high-fat diet combined with streptozocin-induced type 2 diabetic mice or <jats:italic>db\/db<\/jats:italic> mice further verified its efficacy in the amelioration of <jats:italic>\u03b2<\/jats:italic>-cell dysfunction and glucose homeostasis. SP6616 treatment efficiently increased serum insulin level, restored <jats:italic>\u03b2<\/jats:italic>-cell mass, decreased fasting blood glucose and glycated hemoglobin levels, and improved oral glucose tolerance. Mechanism study indicated that the promotion of SP6616 on <jats:italic>\u03b2<\/jats:italic>-cell survival was tightly linked to its regulation against both protein kinases C (PKC)\/extracellular-regulated protein kinases 1\/2 (Erk1\/2) and calmodulin(CaM)\/phosphatidylinositol 3-kinase(PI3K)\/serine\/threonine-specific protein kinase (Akt) signaling pathways. To our knowledge, this may be the first report on the underlying pathway responsible for the Kv2.1-mediated <jats:italic>\u03b2<\/jats:italic>-cell protection. In addition, our study has also highlighted the potential of SP6616 in the treatment of type 2 diabetes.<\/jats:p>","DOI":"10.1038\/cddis.2016.119","type":"journal-article","created":{"date-parts":[[2016,5,5]],"date-time":"2016-05-05T12:43:48Z","timestamp":1462452228000},"page":"e2216-e2216","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["SP6616 as a new Kv2.1 channel inhibitor efficiently promotes \u03b2-cell survival involving both PKC\/Erk1\/2 and CaM\/PI3K\/Akt signaling pathways"],"prefix":"10.1038","volume":"7","author":[{"given":"T T","family":"Zhou","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"L L","family":"Quan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"L P","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"T","family":"Du","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"K X","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J C","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"L","family":"Yu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7182-6756","authenticated-orcid":false,"given":"Y","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"P","family":"Wan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"L L","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"B H","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"L H","family":"Hu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"X","family":"Shen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2016,5,5]]},"reference":[{"key":"BFcddis2016119_CR1","doi-asserted-by":"publisher","first-page":"1047","DOI":"10.1517\/17460441.2014.941352","volume":"9","author":"X Xu","year":"2014","unstructured":"Xu X, Wang G, Zhou T, Chen L, Chen J, Shen X . 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