118.3: Intraportal transplantation of neonatal porcine islets cures diabetes mellitus of INSC94Y transgenic pigs
Bibliographic record
Abstract
Introduction: Islet transplantation (Tx) is a promising strategy to cure type 1 diabetes. However, a broad clinical application is currently limited by a shortage of islet donors. A promising alternative islet source are pig islets. Development and validation of novel beta-cell replacement therapies are mainly examined in small animal models or in non-human primates (NHP), both associated with several limitations in translating findings to human patients. Therefore, a non-NHP large animal model for islet transplantation using diabetic INSC94Y transgenic pigs was established and used to evaluate the efficacy of intraportal neonatal porcine islet (NPI) transplantation. Methods: Minimal invasive percutaneous intraportal islet transplantation (PIPIT) was performed to transplant wild-type NPIs (3,300 – 9,700 IEQ/kg body weight) in diabetic INSC94Y transgenic pigs (n = 4) (1). Immunosuppressive regime was adapted from the Edmonton protocol. It consisted of tacrolimus (0.25 mg/kg BW) and mycophenolate mofetil (500 mg) every 12 hours orally, starting one day before transplantation. In addition, the pigs obtained a daily dose of acetylsalicylic acid (100 mg) as anti-platelet treatment. In the observation period, post transplantation fasting blood glucose values were examined on a regular basis. For animal welfare reasons exogenous insulin replacement therapy was performed according to the measured blood glucose values. After a post-transplantation monitoring period between 71 to 103 days, the liver was systematically processed for detailed histological analysis of graft clusters. Results: Three of four pigs which had received NPI grafts reached normoglycemia (<130 mg/dl glucose) after 2 months, thereof two without need of exogenous insulin therapy. These animals accepted oral immunosuppressive drug intake constantly and had a continuous decrease of blood glucose concentration, paralleled with reduced need of exogenous insulin therapy (Fig. 1). The fourth animal lowered blood glucose level constantly below 200 mg/dl after NPI transplantation. Histological analysis of graft-bearing livers revealed graft clusters of heterogenous size (19 µm x 44 µm – 250 µm x 453µm) mainly consisting of beta cells (Fig. 2), with a broad distribution over the transplanted liver lobe. In total, 72 paraffin-embedded liver slices per animal were analyzed with immunohistochemistry. On average, 41% of the examined slices contained islet cell clusters, of which Ø 69% were insulin positive. Conclusion: NPI grafts were able to restore normoglycemia in diabetic recipient pigs. Furthermore, islet Tx lowered or eliminated the need of exogenous insulin treatment. Therefore, this animal model is a novel tool in regenerative medicine to investigate islet cell transplantation settings with a high comparability to human islet cell transplantation.The study was supported by the Deutsche Forschungsgemeinschaft (TRR127) and the European Union’s Horizon 2020 research and innovation program under grant agreement No. 760986 (iNanoBIT). References: 1. (1) Renner, S., et al. (2013). “Permanent Neonatal Diabetes in INSC94Y Transgenic Pigs.” Diabetes 62(5): 1505-1511.
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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 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.006 | 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".