SPECIES-SPECIFIC SEQUENCE VARIATION OF PORCINE ISLET AMYLOID POLYPEPTIDE REDUCES ITS AMYLOIDOGENICITY AND MAY CONTRIBUTE TO IMPROVED FUNCTION AND SURVIVAL OF PIG ISLET XENOGRAFTS
Bibliographic record
Abstract
Introduction: Long-term success of human islet transplants has been limited. Beta cell mass and function in transplanted islets progressively decline over time, resembling the progressive loss of insulin secretion in type2 diabetes. Transplanted islets, like those in type 2 diabetes, are subject to apoptotic beta cell death and the formation of toxic aggregates of the betacell peptide islet amyloid polypeptide (IAPP). Interestingly, porcine islets consistently maintain long-term normoglycemia when transplanted into immune-deficient, diabetic mice. We hypothesized that transplanted pig islets may not be subject to amyloid formation and amyloid-induced cell death, and that this may contribute to the success of porcine islet grafts. Methods & Results: Sequencing of porcine IAPP (pIAPP) from neonatal pig islet (NPI)-extracted RNA confirmed notabledifferences from human IAPP (hIAPP), including a proline substitution within the known amyloidogenic region and a glutamine-for-lysine at the N-terminalcleavage site of porcine proIAPP. Fibril formation was assessed by electron miscroscopy (EM) and Thioflavin T fluorescence. While synthetic hIAPP fibrillized within minutes, pIAPP required 6 weeks to form fibrils detectableby EM. Small peptide fragments of pIAPP failed to aggregate. By Thioflavin T fluorescence assay, hIAPP (40 µM) had an average lag time of 1 h and a 1,000-fold increase in fluorescence by 2 h while pIAPP showed little increase in fluorescence after 20 h. Small peptide fragments of pIAPP also failed to aggregate. hIAPP was significantly more toxic to INS-1 cells than pIAPP (20-200 µM), asassessed by TUNEL (16 h) and Alamar blue (24 h). We also failed to detect amyloid in any (0/9) NPI transplanted into streptozotocin diabetic murine recipients, while human islets had extensive amyloid deposition by 8 weeks post-transplant, associated with graft failure. Conclusion: Porcine IAPP, unlike human IAPP, is only weakly amyloidogenic and cytotoxic. We speculate that decreased fibrillogenicity of porcine compared to human IAPP may underlie the apparent enhanced survival andfunction of pig islet xenografts. KJP is supported by aChild & Family – Rx & D & CIHR – UBC MD PhD Studentship and a MichaelSmith Foundation for Health Research Junior Trainee Award.
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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) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
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".