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J Endocrinol. 2015 Dec;227(3):153-65. doi: 10.1530/JOE-15-0327. Epub 2015 Sep 23.

Increased Slc12a1 expression in β-cells and improved glucose disposal in Slc12a2 heterozygous mice.

Author information

1
Department of Pharmacology and ToxicologyBoonshoft School of Medicine, Wright State University, 3640 Colonel Glenn Highway, 216 HSB, Dayton, Ohio 45435, USAPacific Northwest Diabetes Research InstituteSeattle, Washington 98122, USA.
2
Department of Pharmacology and ToxicologyBoonshoft School of Medicine, Wright State University, 3640 Colonel Glenn Highway, 216 HSB, Dayton, Ohio 45435, USAPacific Northwest Diabetes Research InstituteSeattle, Washington 98122, USA Mauricio.DiFulvio@wright.edu.

Abstract

The products of the Slc12a1 and Slc12a2 genes, commonly known as Na(+)-dependent K(+)2Cl(-) co-transporters NKCC2 and NKCC1, respectively, are the targets for the diuretic bumetanide. NKCCs are implicated in the regulation of intracellular chloride concentration ([Cl(-)]i) in pancreatic β-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(-) transporters expressed in β-cells. In this report we provide evidence for such a mechanism. Mice lacking a single allele of Slc12a2 exhibit lower fasting glycemia, increased acute insulin response (AIR) and lower blood glucose levels 15-30 min after a glucose load when compared to mice harboring both alleles of the gene. Furthermore, heterozygous expression or complete absence of Slc12a2 associates with increased NKCC2 protein expression in rodent pancreatic β-cells. This has been confirmed by using chronic pharmacological down-regulation of NKCC1 with bumetanide in the mouse MIN6 β-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(-) uptake while preserving glucose-stimulated insulin secretion. Together, our results suggest that NKCCs are involved in insulin secretion and that a single Slc12a2 allele may protect β-cells from failure due to increased homeostatic expression of Slc12a1.

KEYWORDS:

NKCC1; NKCC2; glucose homeostasis; insulin secretion; β-cell

PMID:
26400961
PMCID:
PMC4623298
DOI:
10.1530/JOE-15-0327
[Indexed for MEDLINE]
Free PMC Article

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