Abstract
The Na+ K+ 2Cl(-) cotransporter-2 (Nkcc2. Slc12a1) is abundantly expressed in the kidney and its inhibition with the loop-diuretics bumetanide and furosemide has been linked to transient or permanent hyperglycemia in mice and humans. Notably, Slc12a1 is expressed at low levels in hypothalamic neurons and in insulin-secreting beta-cells of the endocrine pancreas. The present study was designed to ...
Abstract
The Na+ K+ 2Cl(-) cotransporter-2 (Nkcc2. Slc12a1) is abundantly expressed in the kidney and its inhibition with the loop-diuretics bumetanide and furosemide has been linked to transient or permanent hyperglycemia in mice and humans. Notably, Slc12a1 is expressed at low levels in hypothalamic neurons and in insulin-secreting beta-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 beta-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(KO)) and assessed their islet secretory responses in vitro. Under basal conditions. Nkcc2a(KO) 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(KO) islets within a context of increased islet size related to hyperplastic/hypertrophic glucagon- and insulin-positive cells (alpha-cells and beta-cells. respectively), normal total islet Cl- content, and reduced beta-cell expression of the Cl- extruder Kcc2.
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