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The pancreatic islets of Langerhans maintain glucose homeostasis through insulin secretion, where insulin secretion dynamics are regulated by intracellular Ca signaling and electrical coupling of the insulin producing β-cells in the islet We have previously shown that cytokines decrease β-cell coupling and that compounds which increase cAMP can increase coupling In both mouse and human islets Exendin-4, which increases cAMP, protected against cytokine-induced decreases in coupling and in mouse islets preserved glucose-stimulated calcium signaling by increasing connexin36 gap junction levels on the plasma membrane Our data indicates that PKA regulates β-cell coupling through a fast mechanism such as channel gating or membrane organization, while Epac2 regulates slower mechanisms of regulation, such as gap junction turnover Increases in β-cell coupling with Exendin-4 may protect against cytokine mediated β-cell death as well as preserve insulin secretion dynamics during the development of diabetes
The pancreatic islets of Langerhans maintain glucose homeostasis. Insulin secretion from islet β-cells is driven by glucose metabolism, depolarization of the cell membrane and an influx of calcium which initiates the release of insulin. Gap junctions composed of connexin36 (Cx36) electrically couple β-cells, regulating calcium signaling and insulin secretion dynamics. Cx36 coupling is decreased in pre-diabetic mice, suggesting a role for altered coupling in diabetes. Our previous work has shown that pro-inflammatory cytokines decrease Cx36 coupling and that compounds which increase cAMP can increase Cx36 coupling. The goal of this study was to determine if Exendin-4, which increases cAMP, can protect against cytokine-induced decreases in Cx36 coupling and altered islet function. In both mouse and human islets Exendin-4 protected against cytokine-induced decreases in coupling and preserved glucose-stimulated calcium signaling. Exendin-4 also protected against protein kinase C delta-mediated decreases in Cx36 coupling. Exendin-4 preserved coupling in mouse islets by preserving Cx36 levels on the plasma membrane. Exendin-4 regulated Cx36 coupling via both PKA and Epac2 mediated mechanisms in cytokine treated islets. In mouse islets, modulating Epac2 had a greater impact in mediating Cx36 coupling, while in human islets modulating PKA had a greater impact on Cx36 coupling. Our data indicates that PKA regulates Cx36 coupling through a fast mechanism such as channel gating, while Epac2 regulates slower mechanisms of regulation, such as Cx36 turnover in the membrane. Increases in Cx36 coupling with Exendin-4 may protect against cytokine mediated β-cell dysfunction to insulin secretion dynamics during the development of diabetes. This article is protected by copyright. All rights reserved.
This article was published in the following journal.
Name: The Journal of physiology
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