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Notably, Slc12a1 is expressed at low levels in hypothalamic neurons and in insulin-secreting \u03b2-cells of the endocrine pancreas. The present study was designed to determine if global elimination of one of the Slc12a1 products, i.e., Nkcc2 variant a ( Nkcc2a), the main splice version of Nkcc2 found in insulin-secreting \u03b2-cells, has an impact on the insulin and glucagon secretory responses and fuel homeostasis in vivo. We have used dynamic tests of glucose homeostasis in wild-type mice and mice lacking both alleles of Nkcc2a ( Nkcc2a<jats:sup>KO<\/jats:sup>) and assessed their islet secretory responses in vitro. Under basal conditions, Nkcc2a<jats:sup>KO<\/jats:sup> mice have impaired glucose homeostasis characterized by increased blood glucose, intolerance to the sugar, delayed\/blunted in vivo insulin and glucagon responses to glucose, and increased glycemic responses to the gluconeogenic substrate alanine. Further, we provide evidence of conserved quantitative secretory responses of Nkcc2a<jats:sup>KO<\/jats:sup> islets within a context of increased islet size related to hyperplastic\/hypertrophic glucagon- and insulin-positive cells (\u03b1-cells and \u03b2-cells, respectively), normal total islet Cl<jats:sup>\u2212<\/jats:sup> content, and reduced \u03b2-cell expression of the Cl<jats:sup>\u2212<\/jats:sup> extruder Kcc2. <\/jats:p>","DOI":"10.1152\/ajpcell.00144.2019","type":"journal-article","created":{"date-parts":[[2019,7,31]],"date-time":"2019-07-31T18:55:14Z","timestamp":1564599314000},"page":"C843-C856","source":"Crossref","is-referenced-by-count":11,"title":["Impaired glucose tolerance, glucagon, and insulin responses in mice lacking the loop diuretic-sensitive <i>Nkcc2a<\/i> transporter"],"prefix":"10.1152","volume":"317","author":[{"given":"Lisa","family":"Kelly","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, Wright State University, 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