Within the islets of Langerhans, gap junction coupling is important for synchronizing oscillatory free-calcium activity (Ca2+) and regulating pulsatile insulin release. In islets from multiple models of diabetes, gap junction coupling is disrupted, and Ca2+ synchronization and pulsatile insulin is lost. Functional subpopulations have been identified within the islet that are linked to driving synchronized Ca2+ and insulin release. These subpopulations can be disrupted under conditions associated with diabetes, such as glucolipotoxicity and inflammatory environments, and their loss may drive islet dysfunction. Here we investigated how loss of gap junction coupling influences functional subpopulations under diabetogenic environments. We treated islets with a cocktail of pro-inflammatory cytokines and protected gap junction coupling via co-treatment with a Cx36 peptide S293 that was previously shown to specifically prevent a decline in gap junction permeability and synchronized Ca2+ dynamics. We performed calcium imaging and ChR2 stimulation and analyzed islet Ca2+ dynamics and the presence of functional subpopulations, including hubs and first-responders. 1- or 24-h cytokine treatment disrupted gap junction coupling, which was fully prevented by S293 peptide co-treatment. Treatment with pro-inflammatory cytokines decreased the recruitment of Ca2+ upon ChR2 stimulation, increased the time between first and last responding cells upon glucose stimulation, and reduced the number and consistency of hub cells. When preserving gap junction coupling by S293 during cytokine treatment, the presence and consistency of these subpopulations were only marginally improved. We therefore concluded that while gap junction coupling is important for functional subpopulations to exert their influence on islet function, the restoration of gap junctions alone is not sufficient to recover functional subpopulations under diabetogenic conditions. Thus, preventing a disruption to intrinsic β-cell properties that define functional subpopulations is likely important for preserving these subpopulations during diabetes.
Levitt et al. (Sat,) studied this question.