{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T18:06:09Z","timestamp":1793729169634,"version":"4.6.1"},"reference-count":60,"publisher":"Bioscientifica","issue":"3","license":[{"start":{"date-parts":[[2015,9,23]],"date-time":"2015-09-23T00:00:00Z","timestamp":1442966400000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/3.0\/deed.en_GB"}],"content-domain":{"domain":["joe.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2015,12]]},"abstract":"<jats:p>\n                    The products of the\n                    <jats:italic>Slc12a1<\/jats:italic>\n                    and\n                    <jats:italic>Slc12a2<\/jats:italic>\n                    genes, commonly known as Na\n                    <jats:sup>+<\/jats:sup>\n                    -dependent K\n                    <jats:sup>+<\/jats:sup>\n                    2Cl\n                    <jats:sup>\u2212<\/jats:sup>\n                    co-transporters NKCC2 and NKCC1, respectively, are the targets for the diuretic bumetanide. NKCCs are implicated in the regulation of intracellular chloride concentration ([Cl\n                    <jats:sup>\u2212<\/jats:sup>\n                    ]\n                    <jats:sub>i<\/jats:sub>\n                    ) in pancreatic \u03b2-cells, and as such, they may play a role in glucose-stimulated plasma membrane depolarization and insulin secretion. Unexpectedly, permanent elimination of NKCC1 does not preclude insulin secretion, an event potentially linked to the homeostatic regulation of additional Cl\n                    <jats:sup>\u2212<\/jats:sup>\n                    transporters expressed in \u03b2-cells. In this report we provide evidence for such a mechanism. Mice lacking a single allele of\n                    <jats:italic>Slc12a2<\/jats:italic>\n                    exhibit lower fasting glycemia, increased acute insulin response (AIR) and lower blood glucose levels 15\u201330\u200amin after a glucose load when compared to mice harboring both alleles of the gene. Furthermore, heterozygous expression or complete absence of\n                    <jats:italic>Slc12a2<\/jats:italic>\n                    associates with increased NKCC2 protein expression in rodent pancreatic \u03b2-cells. This has been confirmed by using chronic pharmacological down-regulation of NKCC1 with bumetanide in the mouse MIN6 \u03b2-cell line or permanent molecular silencing of NKCC1 in COS7 cells, which results in increased NKCC2 expression. Furthermore, MIN6 cells chronically pretreated with bumetanide exhibit increased initial rates of Cl\n                    <jats:sup>\u2212<\/jats:sup>\n                    uptake while preserving glucose-stimulated insulin secretion. Together, our results suggest that NKCCs are involved in insulin secretion and that a single\n                    <jats:italic>Slc12a2<\/jats:italic>\n                    allele may protect \u03b2-cells from failure due to increased homeostatic expression of\n                    <jats:italic>Slc12a1<\/jats:italic>\n                    .\n                  <\/jats:p>","DOI":"10.1530\/joe-15-0327","type":"journal-article","created":{"date-parts":[[2015,10,27]],"date-time":"2015-10-27T23:13:44Z","timestamp":1445987624000},"page":"153-165","update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-1","source":"Crossref","is-referenced-by-count":17,"title":["Increased Slc12a1 expression in \u03b2-cells and improved glucose disposal in Slc12a2 heterozygous mice"],"prefix":"10.1530","volume":"227","author":[{"given":"Saeed","family":"Alshahrani","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed Mashari","family":"Almutairi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shams","family":"Kursan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduardo","family":"Dias-Junior","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed Mahmoud","family":"Almiahuob","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lydia","family":"Aguilar-Bryan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mauricio","family":"Di Fulvio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"416","reference":[{"key":"2015110216243343000_227.3.153.1","doi-asserted-by":"publisher","DOI":"10.1530\/JOE-12-0244"},{"key":"2015110216243343000_227.3.153.2","doi-asserted-by":"publisher","DOI":"10.1159\/000339050"},{"key":"2015110216243343000_227.3.153.3","doi-asserted-by":"crossref","unstructured":"Alvarez-Leefmans F 2012 Intracellular Chloride Regulation. 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