A Switch From Prohormone Convertase (PC)-2 to PC1/3 Expression in Transplanted α-Cells Is Accompanied by Differential Processing of Proglucagon and Improved Glucose Homeostasis in Mice
Bibliographic record
Abstract
OBJECTIVE: Glucagon, which raises blood glucose levels by stimulating hepatic glucose production, is produced in alpha-cells via cleavage of proglucagon by prohormone convertase (PC)-2. In the enteroendocrine L-cell, proglucagon is differentially processed by the alternate enzyme PC1/3 to yield glucagon-like peptide (GLP)-1, GLP-2, and oxyntomodulin, which have blood glucose-lowering effects. We hypothesized that alteration of PC expression in alpha-cells might convert the alpha-cell from a hyperglycemia-promoting cell to one that would improve glucose homeostasis. RESEARCH DESIGN AND METHODS: We compared the effect of transplanting encapsulated PC2-expressing alpha TC-1 cells with PC1/3-expressing alpha TCDeltaPC2 cells in normal mice and low-dose streptozotocin (STZ)-treated mice. RESULTS: Transplantation of PC2-expressing alpha-cells increased plasma glucagon levels and caused mild fasting hyperglycemia, impaired glucose tolerance, and alpha-cell hypoplasia. In contrast, PC1/3-expressing alpha-cells increased plasma GLP-1/GLP-2 levels, improved glucose tolerance, and promoted beta-cell proliferation. In GLP-1R(-/-) mice, the ability of PC1/3-expressing alpha-cells to improve glucose tolerance was attenuated. Transplantation of PC1/3-expressing alpha-cells prevented STZ-induced hyperglycemia by preserving beta-cell area and islet morphology, possibly via stimulating beta-cell replication. However, PC2-expressing alpha-cells neither prevented STZ-induced hyperglycemia nor increased beta-cell proliferation. Transplantation of alpha TCDeltaPC2, but not alpha TC-1 cells, also increased intestinal epithelial proliferation. CONCLUSIONS: Expression of PC1/3 rather than PC2 in alpha-cells induces GLP-1 and GLP-2 production and converts the alpha-cell from a hyperglycemia-promoting cell to one that lowers blood glucose levels and promotes islet survival. This suggests that alteration of proglucagon processing in the alpha-cell may be therapeutically useful in the context of diabetes.
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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) | 0.001 | 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".