365-OR: The NLRP3 Inflammasome Mediates Early Beta-Cell Dysfunction Triggered by Islet Amyloid
Bibliographic record
Abstract
Islet amyloid, formed by islet amyloid polypeptide (IAPP) aggregates, may be a trigger of islet inflammation in T2D. In vitro studies using bone marrow-derived macrophages suggest roles for Toll-like receptor 2 (TLR2), and the NLRP3 inflammasome in mediating IAPP aggregate-induced inflammatory gene expression. To assess the impact of amyloid on islet macrophages in vivo, we performed single cell RNA sequencing on sorted islet immune cells from mice which develop islet amyloid via expression of human IAPP (hIAPP-Tg mice); this uncovered robust changes in islet macrophage populations, including upregulation of TLR2 (∼3.0 fold, p=0.002) and NLRP3 (∼2.8 fold, p=0.006) in proinflammatory macrophages. To test whether these receptors mediate IAPP aggregate-induced inflammation and beta cell dysfunction in vivo, we examined if TLR2 or NLRP3 deletion attenuated islet amyloid-induced beta cell dysfunction by crossing hIAPP-Tg mice to Tlr2-/- or Nlrp3-/- mice. Loss of TLR2 did not impact beta cell dysfunction in hIAPP-Tg Tlr2-/- male or female mice compared to hIAPP-Tg Tlr2+/+ littermates, revealing that TLR2 is not necessary for islet-amyloid driven beta cell pathology. In contrast, NLRP3 knockout improved glucose tolerance in young hIAPP-Tg male mice and delayed diabetes onset on high fat diet (HFD) (10.9 vs. 4.9 weeks; p=0.02) compared to hIAPP-Tg littermates with intact NLRP3. However, hIAPP-Tg Nlrp3-/- males eventually developed diabetes and glucose intolerance on long-term HFD. In female hIAPP-Tg mice, in which islet amyloid forms more slowly, NLRP3 deletion markedly improved glucose tolerance after 18 weeks of HFD relative to hIAPP-Tg Nlrp3+/+ controls (AUC: 886 ± 207 vs. 1854 ± 296, p<0.0001). The glycemic benefit of NLRP3 knockout was not due to altered insulin sensitivity, and was absent in non-hIAPP expressing mice, which do not form amyloid. Thus, NLRP3, but not TLR2, mediates early islet amyloid-induced beta cell dysfunction, and may be a therapeutic target for islet inflammation in T2D. Disclosure H.C. Denroche: Advisory Panel; Self; Integrated Nanotherapeutics. N. Kim: Employee; Self; Integrated Nanotherapeutics. K. Yau: None. D. Nackiewicz: None. P.C. Orban: None. I. Suen: None. C.B. Verchere: Advisory Panel; Self; Sirona Biochem. Board Member; Self; Integrated Nanotherapeutics. Funding JDRF; Canadian Institutes of Health Research
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.005 | 0.002 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".