Exendin‐4 Overcomes Cytokine‐Induced Decreases in Gap Junction Coupling via PKA and Epac2 in Mouse and Human Islets

Key Points Summary

The pancreatic islets of Langerhans maintain glucose homeostasis through insulin secretion, where insulin secretion dynamics are regulated by intracellular Ca²⁺ 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

Abstract

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.

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