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

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Abstract While islet β-cells were first viewed as a singular functional entity, since the 1970s findings reveal that individual β-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)-mediated α-β-cell communication shapes functional β-cell heterogeneity. To address this, we utilized confocal imaging of calcium responses in isolated islets from GCaMP6s mice and in islets from pancreatic slices of C57BL/6 mice, both before and after a GLP-1R antagonist (exendin-9) treatment. Inhibiting α-β-cell communication prolonged response time, increased 1 st phase heterogeneity, and decreased the 1 st phase response peak. Additionally, it reduced 2 nd phase oscillation frequency and heterogeneity, thereby enhancing 2 nd phase coordination across β-cells. These changes were more pronounced in α-neighboring β-cells. Moreover, addition of exendin-9 disrupted the temporal consistency and α-cell proximity of hub-cells and (to a lesser degree) 1 st responder β-cells. Together, these findings underscore the importance of engineering islets containing both α- and β-cells for stem cellderived islet replacement therapies for Type-1diabetes. Article Highlights ◦ Role of GLP-1R mediated α−β cell communication in functional β-cell heterogeneity was unclear. ◦ Does GLP-1R inhibition affect all β-cells uniformly, or will α-neighboring cells be affected more? Is existence of 1 st responder and hub cell subpopulations shaped by GLP-1R signaling? ◦ GLP-1R inhibition decreases multiple metrics or β-cell responsiveness - especially in α-neighboring β-cells. It diminishes spatiotemporal consistency of hub β-cells and (to a lesser degree) 1 st responders. ◦ Islet-local GLP-1R communication in absence of exogenous GLP-1 is sufficient for significant control of β-cell function. Incorporating α-cells into the engineered islets can improve islet replacement outcomes.

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