Role of GLP1-receptor signaling and α-β-cell communication in functional β-cell heterogeneity.

Abstract

While islet {beta}-cells were first viewed as a singular functional entity, since the 1970s findings reveal that individual {beta}-cells differ in their insulin secretion. More recently distinct functional subpopulations based on differential calcium dynamics have been demonstrated to drive islet function. Here, we investigate how paracrine signaling, specifically glucagon-like peptide receptor (GLP-1R) signaling shapes functional {beta}-cell heterogeneity. To address this, we utilized confocal imaging of calcium responses of in-vitro islets from MIP-CreER-GCaMP6s mice, C57BL/6 mice, and {beta}-cell-specific humanized GLP-1R Cre-inducible KO mice. Responses in isolated islets vs pancreatic slices both before and after GLP-1R antagonist (exendin-9) or agonist (exendin-4) treatment were compared. We employ consecutive glucose stimulations in the same islet, where first stimulation serves as a control for the second stimulation. Function of the {beta}-cells was significantly enhanced in the 2nd glucose stimulation, reflecting previously reported time-dependent glucose potentiation phenomenon. GLP-1R antagonism delayed response time, decreased peak amplitude, active time and oscillation frequency, and disrupted the temporal consistency of hub-cells and 1st responder {beta}-cells, relative to the 1st stimulation. Opposite effects were observed with the GLP-1R agonist. The changes in calcium frequency were more pronounced in -neighboring {beta}-cells, suggesting local GLP-1R mediated - {beta}-cell communication. GLP-1R KO elicited deleterious effects, which, aside from the network connectivity, mirrored those of the ex-9. Together, these findings underscore the importance of GLP-1R-mediated - and {beta}-cell communication in heterogeneous {beta}-cell function.