Restoring connexin-36 function in diabetogenic environments precludes mouse and human islet dysfunction

• Published in: The Journal of physiology Vol. 601; no. 18; pp. 4053 - 4072
• Main Authors: St Clair, Joshua R, Westacott, Matthew J, Miranda, Jose, Farnsworth, Nikki L, Kravets, Vira, Schleicher, Wolfgang E, Dwulet, JaeAnn M, Levitt, Claire H, Heintz, Audrey, Ludin, Nurin W F, Benninger, Richard K P
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01-09-2023
• Subjects: Animal models; Animals; Apoptosis; Calcium permeability; Calcium signalling; Connexin 36; Connexins - metabolism; Cytokines; Cytokines - metabolism; Diabetes; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - metabolism; Fatty acids; Fatty Acids, Nonesterified - metabolism; Gap Junctions - physiology; Humans; Inflammation; Insulin; Insulin - metabolism; Insulin secretion; Insulin-Secreting Cells - metabolism; Islets of Langerhans; Islets of Langerhans - metabolism; Mice; Modafinil; Modafinil - metabolism; Palmitic acid; Peptides; Permeability; Phosphorylation; islet of Langerhans; gap junctions; peptide mimetic; Ca2; diabetes
• ISSN: 0022-3751; 1469-7793; 1469-7793
• DOI: 10.1113/JP282114

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 [Ca
] 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 [Ca
] 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 [Ca
] 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 [Ca
] dynamics. Cx36 over-expression and S293 peptide also reduced apoptosis induced by pro-inflammatory cytokines. Critically, S293 peptide rescued gap junction coupling and [Ca
] 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 [Ca
] 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 [Ca
] 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 [Ca
] dynamics and glucose-stimulated insulin secretion in human T2D and mouse models of T2D.