Restoring connexin‐36 function in diabetogenic environments precludes mouse and human islet dysfunction
Joshua R. St. Clair, Matthew J. Westacott, Jose Miranda, Nikki L. Farnsworth, Vira Kravets, Wolfgang E. Schleicher, JaeAnn M. Dwulet, Claire H. Levitt, Audrey Heintz, Nurin W.F. Ludin, Richard K.P. Benninger- Physiology
Abstract
The secretion of insulin from β‐cells in the islet of Langerhans is governed by a series of metabolic and electrical events, which can fail during the progression of type 2 diabetes (T2D). β‐cells are electrically coupled via connexin‐36 (Cx36) gap junction channels, which coordinates the pulsatile dynamics of [Ca2+] and insulin release across the islet. Factors such as pro‐inflammatory cytokines and free fatty acids disrupt gap junction coupling under in vitro conditions. Here we test whether gap junction coupling and coordinated [Ca2+] dynamics are disrupted in T2D, and whether recovery of gap junction coupling can recover islet function. We examine islets from donors with T2D, from db/db mice, and islets treated with pro‐inflammatory cytokines (TNF‐α, IL‐1β, IFN‐ɣ) or free fatty acids (palmitate). We modulate gap junction coupling using Cx36 over‐expression or pharmacological activation via modafinil. We also develop a peptide mimetic (S293) of the c‐terminal regulatory site of Cx36 designed to compete against its phosphorylation. Cx36 gap junction permeability and [Ca2+] dynamics were disrupted in islets from both human donors with T2D and db/db mice, and in islets treated with pro‐inflammatory cytokines or palmitate. Cx36 over‐expression, modafinil treatment and S293 peptide all enhanced Cx36 gap junction coupling and protected against declines in coordinated [Ca2+] dynamics. Cx36 over‐expression and S293 peptide also reduced apoptosis induced by pro‐inflammatory cytokines. Critically, S293 peptide rescued gap junction coupling and [Ca2+] dynamics in islets from both db/db mice and a sub‐set of T2D donors. Thus, recovering or enhancing Cx36 gap junction coupling can improve islet function in diabetes.
Key points
Connexin‐36 (Cx36) gap junction permeability and associated coordination of [Ca2+] dynamics is diminished in human type 2 diabetes (T2D) and mouse models of T2D. Enhancing Cx36 gap junction permeability protects against disruptions to the coordination of [Ca2+] dynamics. A novel peptide mimetic of the Cx36 c‐terminal regulatory region protects against declines in Cx36 gap junction permeability. Pharmacological elevation in Cx36 or Cx36 peptide mimetic recovers [Ca2+] dynamics and glucose‐stimulated insulin secretion in human T2D and mouse models of T2D.