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PFKFB3 inhibition restores β-cell responsiveness to acetylcholine in a 3xTg-AD pancreatic tissue-slice model
Pfabe J, Postic S, Miglinci L, Krnjic A, Ahmed H, Eisenberg T, Tadic J, Raval K et al.. bioRxiv, 2026-10-07
Topic: Gut, metabolism and diet
The glycolytic regulator PFKFB3 supports dysfunctional β-cell states, but its role in pancreatic Ca 2+ signaling remains unclear. We examined responses to PFKFB3 inhibitors (AZ67, AZ26) in pancreatic tissue slices from aged 3xTg-AD mice, a model of Alzheimer’s disease that develops impaired glucose tolerance and diabetes as comorbidity. Compared to wild-type controls, β-cells showed weaker glucose-stimulated and acetylcholine-potentiated Ca 2+ activity, accompanied by increased nuclear PFKFB3 positivity in insulin-defined islet-cell populations, used here as a PFKFB3-associated stress-state marker. During glucose and acetylcholine stimulation, AZ67 increased β-cell Ca 2+ event frequency while maintaining short events. In neighboring acinar cells, PFKFB3 inhibitor exposure was followed by renewed oscillations after acetylcholine-evoked activity had waned. β-cell recruitment was preserved during adrenergic inhibition, and enhanced activity persisted after inhibitor withdrawal, although these recordings were exploratory and residual tissue drug exposure could not be excluded. An effect that survives both drug removal and adrenergic opposition identifies a Ca 2+ signaling phenotype in 3xTg-AD β-cells that is acutely inducible yet not transient, and establishes PFKFB3 as a regulator of muscarinic responsiveness in the stressed β-cell. graphical abstract Graphical abstract: PFKFB3 inhibition enhances muscarinic β-cell Ca 2+ responsiveness in 3xTg-AD pancreatic tissue slices. β-cells in 3xTg-AD pancreatic slices exhibit lower glucose-stimulated and acetylcholine (ACh)-potentiated Ca 2+ activity than wild-type (WT) controls. During combined glucose and ACh stimulation, AZ67 increases β-cell Ca 2+ event frequency while maintaining a short-event phenotype. The bell-shaped curves illustrate a working model in which PFKFB3-associated dysregulation shifts muscarinic/IP 3- linked signaling beyond an optimal range for oscillatory activity, whereas PFKFB3 inhibition favors a return toward this range. The schematic thus distinguishes enhanced Ca 2+ oscillatory activity from a simple increase in Ca 2+ release. Direct regulation of β-cell IP 3 r eceptors by PFKFB3 and the depicted consequences for insulin secretion remain proposed mechanisms and functional implications, respectively, rather than outcomes established in these slice experiments.
Key findings
- Compared to wild-type controls, β-cells showed weaker glucose-stimulated and acetylcholine-potentiated Ca 2+ activity, accompanied by increased nuclear PFKFB3 positivity in insulin-defined islet-cell populations, used here as a PFKFB3-associated stress-state marker.
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Study details
- Evidence strengthLow
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 21 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for study design, sample size, effect reported and randomised / blinded because the record does not state it. We have no data on times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multi-centre collaboration, so those were left out: it earned 13 of the 62 points we could judge it on, which is 21 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (bioRxiv) |
| Journal's citation record | 0 / 4 | Not a journal article, so the journal's record does not count |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 4 / 10 | Preprint — not yet peer-reviewed. Hosted on a preprint server. |
| How recent | 5 / 5 | 2026 — within 1 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Laboratory or animal study (title names “3xtg”) — scores zero |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 13 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 13 of the 62 points we could judge it on is 21 out of 100. |
| Total | 21 / 100 | Capped to 16 because this is not a peer-reviewed article. |
What each of these 20 components measures, and what this score is not →
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APA 7th
Pfabe, J., Postic, S., Miglinci, L., Krnjic, A., Ahmed, H., Eisenberg, T., et al. (2026). PFKFB3 inhibition restores β-cell responsiveness to acetylcholine in a 3xTg-AD pancreatic tissue-slice model. bioRxiv. https://doi.org/10.64898/2026.09.30.755766
Vancouver
Pfabe J, Postic S, Miglinci L, Krnjic A, Ahmed H, Eisenberg T, et al. PFKFB3 inhibition restores β-cell responsiveness to acetylcholine in a 3xTg-AD pancreatic tissue-slice model. bioRxiv. 2026. doi:10.64898/2026.09.30.755766.
BibTeX
@article{pfabe2026-5da1af17,
author = {Pfabe, J. and Postic, S. and Miglinci, L. and Krnjic, A. and Ahmed, H. and Eisenberg, T. and Tadic, J. and Raval, K. and others},
title = {{PFKFB3 inhibition restores β-cell responsiveness to acetylcholine in a 3xTg-AD pancreatic tissue-slice model}},
journal = {bioRxiv},
year = {2026},
doi = {10.64898/2026.09.30.755766},
url = {https://doi.org/10.64898/2026.09.30.755766}
}
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