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

@misc{balasenthilkumaran2026role,
  title = {{Role of GLP1-receptor signaling and α-β communication in functional β-cell heterogeneity}},
  author = {Nirmala V. Balasenthilkumaran and Lidija Križančić Bombek and Shane Browne and David Ramirez and Maja Duh and Maša Skelin Klemen and Eva Paradiž Leitgeb and Jasmina Kerčmar and Jan Kopecky and Yaowen Zhang and Maria Skjott Hansen and Yidi Shao and Annanya Sethiya and Adam Takaoglu and Divya Prabhu and Aining Fan and Shravani Vitalapuram and Christian M. Cohrs and Stephan Speier and Jurij Dolenšek and Rahaf Shishani and Anna Jackson and Bethany P. Cummings and Marko Gosak and Andraž Stožer and Vira Kravets},
  howpublished = {bioRxiv},
  year = {2026},
  month = oct,
  doi = {10.1101/2025.04.25.650736},
  url = {https://europepmc.org/article/PMC/PMC13742627},
  note = {CC BY-NC-ND},
}

TY  - UNPB
TI  - Role of GLP1-receptor signaling and α-β communication in functional β-cell heterogeneity
AU  - Nirmala V. Balasenthilkumaran
AU  - Lidija Križančić Bombek
AU  - Shane Browne
AU  - David Ramirez
AU  - Maja Duh
AU  - Maša Skelin Klemen
AU  - Eva Paradiž Leitgeb
AU  - Jasmina Kerčmar
AU  - Jan Kopecky
AU  - Yaowen Zhang
AU  - Maria Skjott Hansen
AU  - Yidi Shao
AU  - Annanya Sethiya
AU  - Adam Takaoglu
AU  - Divya Prabhu
AU  - Aining Fan
AU  - Shravani Vitalapuram
AU  - Christian M. Cohrs
AU  - Stephan Speier
AU  - Jurij Dolenšek
AU  - Rahaf Shishani
AU  - Anna Jackson
AU  - Bethany P. Cummings
AU  - Marko Gosak
AU  - Andraž Stožer
AU  - Vira Kravets
PY  - 2026
DA  - 2026/10/16
PB  - bioRxiv
DO  - 10.1101/2025.04.25.650736
UR  - https://europepmc.org/article/PMC/PMC13742627
AB  - 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) signaling shapes functional β-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 β-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 β-cells was significantly enhanced in the 2 nd 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 1 st responder β-cells, relative to the 1 st stimulation. Opposite effects were observed with the GLP-1R agonist. The changes in Ca 2+ frequency were more pronounced in α-neighboring β-cells, suggesting local GLP-1R mediated α-β-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 α- and β-cell communication in heterogeneous β-cell function.  Article Highlights: Role of GLP-1R mediated α-β cell communication in functional β-cell heterogeneity was unclear.  Time of response to glucose, 1 st phase amplitude, speed of signal propagation, active time, functional connectivity, and consistency of 1 st responder and hub cell subpopulations are enhanced by GLP-1R signaling.  GLP-1R signaling creates local α-cell-associated functional neighborhoods of β-cells and maintains network organization.  Islet-local GLP-1R communication in absence of exogenous GLP-1 is sufficient for significant control of β -cell function.
SN  - 2692-8205
ER  -