{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T07:01:10Z","timestamp":1761894070603},"reference-count":32,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2009,2,2]],"date-time":"2009-02-02T00:00:00Z","timestamp":1233532800000},"content-version":"vor","delay-in-days":3260,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2000,3]]},"abstract":"<jats:p>\n<jats:list list-type=\"explicit-label\">\n<jats:list-item>\n<jats:p>We examined the effects of the novel hypoglycaemic agent JTT\u2010608 [trans\u20104\u2010(4\u2010methylcyclohexyl)\u20104\u2010oxobutyric acid] on insulin secretion using rat pancreatic islets, and analysed the mechanism of its effect.<\/jats:p>\n<\/jats:list-item>\n<jats:list-item>\n<jats:p>JTT\u2010608 augmented 8.3\u2003m<jats:sc>M<\/jats:sc> glucose\u2010induced insulin secretion dose\u2010dependently, and there was a stimulatory effect of 100\u2003\u03bc<jats:sc>M<\/jats:sc> JTT\u2010608 at both moderate and high concentrations (8.3, 11.1 and 16.7\u2003m<jats:sc>M<\/jats:sc>) of glucose, but not at low concentrations (3.3 and 5.5\u2003m<jats:sc>M<\/jats:sc>). In perifusion experiments, both phases of insulin release were enhanced, and the effect was eliminated 10\u2003min after withdrawal of the agent.<\/jats:p>\n<\/jats:list-item>\n<jats:list-item>\n<jats:p>In the presence of 200\u2003\u03bc<jats:sc>M<\/jats:sc> diazoxide and a depolarizing concentration (30\u2003m<jats:sc>M<\/jats:sc>) of K<jats:sup>+<\/jats:sup>, there was an augmentation of insulin secretion by 100\u2003\u03bc<jats:sc>M<\/jats:sc> JTT\u2010608, not only under high levels of glucose but also under low levels, and the effects were abolished by 10\u2003\u03bc<jats:sc>M<\/jats:sc> nitrendipine.<\/jats:p>\n<\/jats:list-item>\n<jats:list-item>\n<jats:p>JTT\u2010608 augmented insulin secretion from electrically permeabilized islets in the presence of stimulatory concentrations (0.3 and 1.0\u2003\u03bc<jats:sc>M<\/jats:sc>) of Ca<jats:sup>2+<\/jats:sup>, and the intracellular Ca<jats:sup>2+<\/jats:sup> concentration ([Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>) response under 16.7\u2003m<jats:sc>M<\/jats:sc> glucose, 200\u2003\u03bc<jats:sc>M<\/jats:sc> diazoxide, and 30\u2003m<jats:sc>M<\/jats:sc> K<jats:sup>+<\/jats:sup> was also increased.<\/jats:p>\n<\/jats:list-item>\n<jats:list-item>\n<jats:p>The cyclic AMP content in the islets was increased by 100\u2003\u03bc<jats:sc>M<\/jats:sc> JTT\u2010608, and an additive effect to 1\u2003\u03bc<jats:sc>M<\/jats:sc> forskolin was observed, but not to 50\u2003\u03bc<jats:sc>M<\/jats:sc> 3\u2010isobutyl\u20101\u2010methylxanthine (IBMX). JTT\u2010608 inhibited phosphodiesterase (PDE) activity dose\u2010dependently.<\/jats:p>\n<\/jats:list-item>\n<jats:list-item>\n<jats:p>We conclude that JTT\u2010608 augments insulin secretion by enhancing Ca<jats:sup>2+<\/jats:sup> efficacy and by increasing Ca<jats:sup>2+<\/jats:sup> influx. This appears to be a result of the increased intracellular cyclic AMP concentration due to PDE inhibition.<\/jats:p>\n<\/jats:list-item>\n<\/jats:list>\n<\/jats:p><jats:p><jats:italic>British Journal of Pharmacology<\/jats:italic> (2000) <jats:bold>129<\/jats:bold>, 901\u2013908; doi:<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"doi\" xlink:href=\"10.1038\/sj.bjp.0703133\">10.1038\/sj.bjp.0703133<\/jats:ext-link><\/jats:p>","DOI":"10.1038\/sj.bjp.0703133","type":"journal-article","created":{"date-parts":[[2005,1,28]],"date-time":"2005-01-28T20:46:58Z","timestamp":1106945218000},"page":"901-908","update-policy":"http:\/\/dx.doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["The insulinotropic mechanism of the novel hypoglycaemic agent JTT\u2010608: direct enhancement of Ca<sup>2+<\/sup> efficacy and increase of Ca<sup>2+<\/sup> influx by phosphodiesterase inhibition"],"prefix":"10.1111","volume":"129","author":[{"given":"Eri","family":"Mukai","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hitoshi","family":"Ishida","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shimpei","family":"Fujimoto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mariko","family":"Kajikawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshimasa","family":"Okamoto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun","family":"Fujita","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshiyuki","family":"Hamamoto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshiyuki","family":"Tsuura","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuichiro","family":"Yamada","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Noboru","family":"Furukawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takeshi","family":"Ohta","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yutaka","family":"Seino","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2009,2,2]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/363356a0"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/0079-6107(89)90013-8"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.1995.75.4.725"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1995.1149"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.46.4.615"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.139.3.1133"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI115714"},{"key":"e_1_2_7_9_1","doi-asserted-by":"crossref","first-page":"12207","DOI":"10.1016\/S0021-9258(18)98882-4","article-title":"Cyclic AMP as a determinant for glucose induction of fast Ca2+ oscillations in isolated pancreatic \u03b2\u2010cells","volume":"266","author":"GRAPENGIESSER E.","year":"1991","journal-title":"J. Biol. Chem."},{"key":"e_1_2_7_10_1","doi-asserted-by":"crossref","first-page":"57","DOI":"10.2337\/diab.47.1.57","article-title":"Glucagon\u2010like peptide 1(7\u201036) amide stimulates exocytosis in human pancreatic \u03b2\u2010cells by both proximal and distal regulatory steps in stimulus\u2010secretion coupling","volume":"47","author":"GROMADA J.","year":"1998","journal-title":"Diabetes"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/0014-5793(86)80898-5"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI118688"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.44.1.67"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.132.1.94"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1006\/abbi.1995.1429"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0702481"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-2999(98)00952-2"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/s001250050351"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1995.2858"},{"key":"e_1_2_7_20_1","doi-asserted-by":"crossref","first-page":"438","DOI":"10.2337\/diab.41.4.438","article-title":"Dual functional role of membrane depolarization\/Ca2+ influx in rat pancreatic \u03b2\u2010cell","volume":"41","author":"SAITO Y.","year":"1992","journal-title":"Diabetes"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.1995.tb16641.x"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF01223617"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm9804228"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI109665"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1097\/00007890-198612000-00022"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/0014-5793(85)80825-5"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi00778a018"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/0026-0495(88)90064-9"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.2337\/diacare.7.5.491"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.133.4.1685"},{"key":"e_1_2_7_31_1","doi-asserted-by":"crossref","first-page":"295","DOI":"10.2337\/diab.45.3.295","article-title":"CAMP\u2010signaling pathway acts in selective synergism with glucose or tolbutamide to increase cytosolic Ca2+ in rat pancreatic \u03b2\u2010cells","volume":"45","author":"YAEKURA K.","year":"1996","journal-title":"Diabetes"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI3920"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.7.3223"}],"container-title":["British Journal of Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1038%2Fsj.bjp.0703133","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1038%2Fsj.bjp.0703133","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1038\/sj.bjp.0703133","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,28]],"date-time":"2023-09-28T03:50:22Z","timestamp":1695873022000},"score":1,"resource":{"primary":{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/10.1038\/sj.bjp.0703133"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2000,3]]},"references-count":32,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2000,3]]}},"alternative-id":["10.1038\/sj.bjp.0703133"],"URL":"https:\/\/doi.org\/10.1038\/sj.bjp.0703133","archive":["Portico"],"relation":{},"ISSN":["0007-1188","1476-5381"],"issn-type":[{"value":"0007-1188","type":"print"},{"value":"1476-5381","type":"electronic"}],"subject":[],"published":{"date-parts":[[2000,3]]},"assertion":[{"value":"2009-02-02","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}