Exendin-4 overcomes cytokine-induced decreases in gap junction coupling via protein kinase A and Epac2 in mouse and human islets

J Physiol. 2019 Jan;597(2):431-447. doi: 10.1113/JP276106. Epub 2018 Nov 29.

Abstract

Key points: The pancreatic islets of Langerhans maintain glucose homeostasis through insulin secretion, where insulin secretion dynamics are regulated by intracellular Ca2+ signalling 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 signalling by increasing connexin36 gap junction levels on the plasma membrane. Our data indicate that protein kinase A 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 signalling 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 signalling. Exendin-4 also protected against protein kinase Cδ-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 protein kinase A (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 indicate 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.

Keywords: Connexin36 Gap Junctions; Exendin-4; Islet of Langerhans.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium Signaling / drug effects
  • Connexins / metabolism*
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Cytokines
  • Exenatide / pharmacology*
  • Gap Junctions / drug effects*
  • Gap Junctions / metabolism
  • Guanine Nucleotide Exchange Factors / metabolism*
  • Humans
  • Hypoglycemic Agents / pharmacology*
  • Insulin / metabolism
  • Islets of Langerhans / drug effects*
  • Islets of Langerhans / metabolism
  • Mice, Inbred C57BL

Substances

  • Connexins
  • Cytokines
  • Guanine Nucleotide Exchange Factors
  • Hypoglycemic Agents
  • Insulin
  • RAPGEF4 protein, human
  • connexin 36
  • Exenatide
  • Cyclic AMP-Dependent Protein Kinases