Publication Date
2014
Document Type
Thesis
Committee Members
Norma Adragna (Committee Member), David Cool (Committee Member), Mauricio Di Fulvio (Advisor)
Degree Name
Master of Science (MS)
Abstract
Insulin secretion depends on the electrical properties of the ß-cells in pancreatic islets. The consensus mechanism of insulin secretion involves glucose-stimulated metabolic increase in the ATP/ADP ratio. This increase closes ATP-sensitive K+ (KATP) channels resulting in ß-cell plasma membrane depolarization, which in turn activates voltage-dependent Ca2+ channels further resulting in Ca2+ influx and release of insulin stored in granules. In addition to this well-known consensus mechanism, insulin secretion also depends on electrogenic efflux of Cl- ions. The Na+K 2Cl- cotransporters (NKCCs) maintain the intracellular concentration of Cl- ([Cl-]i) at values higher than those predicted at thermodynamic equilibrium. This distribution of Cl-makes possible the electrogenic exit of the anion from ß-cells upon opening of volume-regulated anion channels (VRAC). Therefore, the prevailing notion states that disruption of the ß-cell Cl- gradient by inhibition of NKCCs with loop diuretics such as furosemide or bumetanide (BTD) impairs insulin secretion. Our results challenge that long-standing concept by demonstrating that long-term BTD does not impair insulin secretion in mouse ß-cells in vitro and that this effect is related to changes in the NKCC expression pattern and Cl-uptake in response to the diuretic.
Page Count
87
Department or Program
Department of Pharmacology and Toxicology
Year Degree Awarded
2014
Copyright
Copyright 2014, some rights reserved. My ETD may be copied and distributed only for non-commercial purposes and may be modified only if the modified version is distributed with these same permissions. All use must give me credit as the original author.
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.
