{
  "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) 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.\n\nArticle Highlights: Role of GLP-1R mediated α-β cell communication in functional β-cell heterogeneity was unclear.\n\nTime 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.\n\nGLP-1R signaling creates local α-cell-associated functional neighborhoods of β-cells and maintains network organization.\n\nIslet-local GLP-1R communication in absence of exogenous GLP-1 is sufficient for significant control of β -cell function.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 26,
  "authors": [
    {
      "name": "Nirmala V. Balasenthilkumaran"
    },
    {
      "name": "Lidija Križančić Bombek"
    },
    {
      "name": "Shane Browne"
    },
    {
      "name": "David Ramirez"
    },
    {
      "name": "Maja Duh"
    },
    {
      "name": "Maša Skelin Klemen"
    },
    {
      "name": "Eva Paradiž Leitgeb"
    },
    {
      "name": "Jasmina Kerčmar"
    },
    {
      "name": "Jan Kopecky"
    },
    {
      "name": "Yaowen Zhang"
    },
    {
      "name": "Maria Skjott Hansen"
    },
    {
      "name": "Yidi Shao"
    },
    {
      "name": "Annanya Sethiya"
    },
    {
      "name": "Adam Takaoglu"
    },
    {
      "name": "Divya Prabhu"
    },
    {
      "name": "Aining Fan"
    },
    {
      "name": "Shravani Vitalapuram"
    },
    {
      "name": "Christian M. Cohrs"
    },
    {
      "name": "Stephan Speier"
    },
    {
      "name": "Jurij Dolenšek"
    },
    {
      "name": "Rahaf Shishani"
    },
    {
      "name": "Anna Jackson"
    },
    {
      "name": "Bethany P. Cummings"
    },
    {
      "name": "Marko Gosak"
    },
    {
      "name": "Andraž Stožer"
    },
    {
      "name": "Vira Kravets"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/c9ngnjc2tx707.bib",
  "cited_by": 2,
  "doi": "10.1101/2025.04.25.650736",
  "fulltext_url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13742627/?tool=EBI",
  "id": "c9ngnjc2tx707",
  "issns": [
    "2692-8205"
  ],
  "landing_url": "https://europepmc.org/article/PMC/PMC13742627",
  "language": "eng",
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Article"
    ],
    [
      "openalex",
      "2712|Pancreatic function and diabetes"
    ]
  ],
  "openalex": "W4409864379",
  "pdf_url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13742627/pdf/?tool=EBI",
  "pmcid": "PMC13742627",
  "pmid": "42999185",
  "published": "2026-10-16",
  "publisher": "Cold Spring Harbor Laboratory Preprints",
  "ris": "https://research.draconitic.com/paper/c9ngnjc2tx707.ris",
  "sources": [
    {
      "first_seen": "2026-11-09T15:20:34Z",
      "native_id": "PMC:PMC13742627",
      "source": "europepmc",
      "url": "https://europepmc.org/article/PMC/PMC13742627"
    },
    {
      "first_seen": "2026-11-10T12:23:26Z",
      "native_id": "PMC13742627",
      "source": "pmc",
      "url": "https://doi.org/10.1101/2025.04.25.650736"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2712|Pancreatic function and diabetes",
      "subfield": "endocrinology-metabolism"
    }
  ],
  "title": "Role of GLP1-receptor signaling and α-β communication in functional β-cell heterogeneity",
  "title_text": "Role of GLP1-receptor signaling and α-β communication in functional β-cell heterogeneity",
  "type": "preprint",
  "updated_at": "2026-11-10T12:23:26Z",
  "url": "https://research.draconitic.com/paper/c9ngnjc2tx707",
  "venue": "bioRxiv",
  "versions": []
}