{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T17:07:46Z","timestamp":1771002466943,"version":"3.50.1"},"reference-count":34,"publisher":"Rockefeller University Press","issue":"1","license":[{"start":{"date-parts":[[2019,9,19]],"date-time":"2019-09-19T00:00:00Z","timestamp":1568851200000},"content-version":"vor","delay-in-days":1011,"URL":"http:\/\/www.rupress.org\/terms\/"},{"start":{"date-parts":[[2017,7,3]],"date-time":"2017-07-03T00:00:00Z","timestamp":1499040000000},"content-version":"vor","delay-in-days":203,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-sa\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["DK098584"],"award-info":[{"award-number":["DK098584"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["DK109407"],"award-info":[{"award-number":["DK109407"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2017,1,1]]},"abstract":"<jats:p>Gain-of-function (GOF) mutations in the pore-forming (Kir6.2) and regulatory (SUR1) subunits of KATP channels have been identified as the most common cause of human neonatal diabetes mellitus. The critical effect of these mutations is confirmed in mice expressing Kir6.2-GOF mutations in pancreatic \u03b2 cells. A second KATP channel pore-forming subunit, Kir6.1, was originally cloned from the pancreas. Although the prominence of this subunit in the vascular system is well documented, a potential role in pancreatic \u03b2 cells has not been considered. Here, we show that mice expressing Kir6.1-GOF mutations (Kir6.1[G343D] or Kir6.1[G343D,Q53R]) in pancreatic \u03b2 cells (under rat-insulin-promoter [Rip] control) develop glucose intolerance and diabetes caused by reduced insulin secretion. We also generated transgenic mice in which a bacterial artificial chromosome (BAC) containing Kir6.1[G343D] is incorporated such that the transgene is only expressed in tissues where Kir6.1 is normally present. Strikingly, BAC-Kir6.1[G343D] mice also show impaired glucose tolerance, as well as reduced glucose- and sulfonylurea-dependent insulin secretion. However, the response to K+ depolarization is intact in Kir6.1-GOF mice compared with control islets. The presence of native Kir6.1 transcripts was demonstrated in both human and wild-type mouse islets using quantitative real-time PCR. Together, these results implicate the incorporation of native Kir6.1 subunits into pancreatic KATP channels and a contributory role for these subunits in the control of insulin secretion.<\/jats:p>","DOI":"10.1085\/jgp.201611653","type":"journal-article","created":{"date-parts":[[2016,12,12]],"date-time":"2016-12-12T15:05:22Z","timestamp":1481555122000},"page":"75-84","update-policy":"https:\/\/doi.org\/10.1085\/jgp.crossmarkpolicy","source":"Crossref","is-referenced-by-count":14,"title":["Diabetes induced by gain-of-function mutations in the Kir6.1 subunit of the KATP channel"],"prefix":"10.1085","volume":"149","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2048-472X","authenticated-orcid":true,"given":"Maria S.","family":"Remedi","sequence":"first","affiliation":[{"name":"Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110 1"},{"name":"Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110 2"},{"name":"Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, St. Louis, MO 63110 3"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan B.","family":"Friedman","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110 2"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Colin G.","family":"Nichols","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110 2"},{"name":"Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, St. Louis, MO 63110 3"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"291","published-online":{"date-parts":[[2016,12,12]]},"reference":[{"key":"2023072704551052900_bib1","doi-asserted-by":"publisher","first-page":"903","DOI":"10.1007\/s001250051247","article-title":"ATP-sensitive K+ channels and insulin secretion: their role in health and disease","volume":"42","author":"Ashcroft","year":"1999","journal-title":"Diabetologia."},{"key":"2023072704551052900_bib2","doi-asserted-by":"publisher","first-page":"1087","DOI":"10.1007\/s00125-010-2039-7","article-title":"Defects in beta cell Ca2+ signalling, glucose metabolism and insulin secretion in a murine model of KATP channel-induced neonatal diabetes mellitus","volume":"54","author":"Benninger","year":"2011","journal-title":"Diabetologia."},{"key":"2023072704551052900_bib3","doi-asserted-by":"publisher","first-page":"799","DOI":"10.1152\/physrev.00027.2009","article-title":"Muscle KATP channels: recent insights to energy sensing and myoprotection","volume":"90","author":"Flagg","year":"2010","journal-title":"Physiol. 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