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Publication
Impaired glucose tolerance, glucagon, and insulin responses in mice lacking the
loop diuretic-sensitive Nkcc2a transporter.
Authors Kelly L, Almutairi MM, Kursan S, Pacheco R, Dias-Junior E, Castrop H, Di Fulvio
M
Submitted By Submitted Externally on 3/26/2020
Status Published
Journal American journal of physiology. Cell physiology
Year 2019
Date Published 10/1/2019
Volume : Pages 317 : C843 - C856
PubMed Reference 31365295
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 ß-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 ß-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 (Nkcc2aKO)
and assessed their islet secretory responses in vitro. Under basal conditions,
Nkcc2aKO 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 Nkcc2aKO islets within a context of increased islet size
related to hyperplastic/hypertrophic glucagon- and insulin-positive cells
(a-cells and ß-cells, respectively), normal total islet Cl- content, and reduced
ß-cell expression of the Cl- extruder Kcc2.




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