321-OR: Deletion of 14-3-3ζ in Pancreatic ß-Cells Increase Mitochondrial Activity and Insulin Secretion
Bibliographic record
Abstract
Pancreatic β-cells continuously sense blood glucose levels and secrete insulin to maintain normoglycemia. In β-cells, ATP generated by glycolysis promotes the closure of ATP-sensitive K+ channels, thereby increasing intracellular calcium and ultimately insulin secretion. 14-3-3 proteins, and in particular 14-3-3ζ, have been found to regulate ATP synthase and mitochondrial respiration, suggesting that members of this family of scaffold proteins in β-cells may influence glucose-stimulated insulin secretion (GSIS) and glucose homeostasis. To date, we have identified critical contributions of 14-3-3 proteins to GSIS. In mouse and human islets, pan-inhibition of 14-3-3 proteins with cell-permeable inhibitors potentiated ex-vivo GSIS. This was associated with increased mitochondrial function, as oxygen consumption and ATP synthesis rates were significantly enhanced. Moreover, increased ATP production was confirmed with luciferase-based assays. Of the seven isoforms, we previously reported critical metabolic roles of 14-3-3ζ in glucose homeostasis, and to understand its role in β-cells, β-cell-specific knockout mice (Ins1CreThor:14-3-3ζfl/fl, β-KO) were generated. When compared to control mice, no differences in body weights or glucose and insulin tolerance were observed, but β-KO mice displayed significantly enhanced insulin secretion following i.p. glucose (2 g/kg), and ex vivo islet perifusion studies revealed enhanced 2nd-phase secretion of GSIS from β-KO islets. Similar to pan-14-3-3 inhibition, increased mitochondrial activity and ATP synthesis were detected in islets of β-KO mice. In summary, these results demonstrate critical functions of 14-3-3ζ and its related proteins in mitochondrial activity in β-cells and the regulation of GSIS. These data also suggest that 14-3-3ζ inhibition may represent a promising target to enhance pancreatic β-cell function in the context of diabetes. Disclosure Y. Mugabo: None. M. Galipeau: None. J. Tan: None. E. Fadzeyeva: None. R. Grygorczyk: None. G.E. Lim: None. Funding Canadian Institutes of Health Research; Canada Research Chairs Program (PJT-153144)
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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) | 0.000 | 0.000 |
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 teacher head, 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".