Role of GLP1-receptor-mediated α-β-cell communication in functional β-cell heterogeneity

While the islet β-cells were traditionally viewed as a singular functional entity, findings of 1970’s and up until recent years, reveal that individual β-cells differ in their calcium dynamics and insulin secretion, forming distinct subpopulations that together maintain glucose homeostasis. However, the underlying mechanisms driving functional β-cell heterogeneity are still not fully understood. Here, we aimed to investigate how paracrine signaling, specifically GLP-1R mediated α-β-cell communication shapes functional β-cell heterogeneity. To address this question, we sought to understand how β-cell function and heterogeneity are altered when the α-to β-cell communication was inhibited via GLP1-R antagonist, exendin-9. To this end, we utilized confocal imaging to record calcium response in isolated islets from GCaMP6s mice and in islets from pancreatic slices from C57Bl6 mice, both before and after the application of exendin-9. We found that inhibiting α-β-cell communication prolonged the response-time, increased 1 ^st phase heterogeneity, and decreased the peak of the 1 ^st phase islet’s response. Additionally, it reduced 2 ^nd phase oscillation frequency and 2 ^nd phase heterogeneity, thereby enhancing 2 ^nd phase coordination across β-cells. These changes in oscillation frequency were also found to be more pronounced in α-neighboring β-cells. Additionally, we also found that inhibiting GLP1-R mediated α-β-cell communication disrupted the temporal consistency and α-cell proximity of 1 ^st responder and hub-cell functional β-cell subpopulations in the islet.