2175-P: Isoform-Specific Roles of Prolyl Hydroxylase Domain Proteins in Regulating Beta-Cell Function
Bibliographic record
Abstract
Pancreatic β-cells secrete insulin in a biphasic manner via KATP-channel dependent and independent pathways. The KATP-channel independent pathway produces a rise in the NADPH/NADP+ ratio and cytosolic α-ketoglutarate (α-KG). Prolyl hydroxylase domain proteins (PHDs) belong to the α-KG-dependent dioxygenase superfamily and regulates stability of hypoxia-inducible factor α (HIF-α). Prolyl hydroxylation of HIF-α for ubiquitin-mediated proteasomal degradation requires sufficient levels of oxygen, iron and α-KG. We have previously shown pharmacological inhibition of PHDs reduces glucose-stimulated insulin secretion (GSIS), glucose utilization, and mitochondrial function in clonal β-cells. Glucose-induced changes in cytosolic α-KG may regulate PHD and thus β-cell function. In mouse pancreatic β-cells, PHD isoforms express unique subcellular localization: PHD1 is expressed exclusively in the cytosol, PHD2 is expressed in the cytosol and nucleus, and PHD3 is mainly expressed in the nucleus. To further explore the isoform-specific roles of PHD, we employed a β-cell specific knockout (β-PHD KO) mouse model for each of the PHD isoforms. β-PHD1 KO, β-PHD2 KO and β-PHD3 KO. β-PHD KO mice show no significant in vivo defects associated with glucose tolerance and insulin resistance; however, β-PHD1 KO and β-PHD2 KO mice have significantly increased plasma insulin compared to wild type (WT) controls (p<0.05). Consistent with our cell culture model of PHD knockdown, PHD1 and PHD3 regulate insulin secretion as both β-PHD1 KO and β-PHD3 KO mice show impaired GSIS. Only β-PHD1 KO mice have reduced beta-cell mass (p<0.01). In conclusion, there are significant and unique effects observed with isoform-specific suppression of PHD. Disclosure M. Hoang: None. S.M. Janssen: None. J.W. Joseph: None. Funding Natural Sciences and Engineering Research Council of Canada; 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) | 0.000 | 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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.005 | 0.003 |
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".