Beta‐cell Prohormone Convertase 1/3 Plays a Larger Role in Glucose Homeostasis Than Beta‐cell Prohormone Convertase 2 in Mice
Bibliographic record
Abstract
Insulin is synthesized in pancreatic beta cells from its precursor proinsulin, which is cleaved by the prohormone convertases 1/3 (PCSK1) and 2 (PCSK2) to generate mature insulin. In patients with type 1 or type 2 diabetes, proinsulin processing to mature insulin is impaired and elevated circulating proinsulin:insulin ratios are found in both conditions. It is unknown whether the beta‐cell prohormone processing impairments observed in diabetes contribute to or are secondary consequences of beta‐cell failure. Given the key role of PCSK1 and PCSK2 in insulin synthesis and beta‐cell function, we hypothesized that beta‐cell PCSK1 or PCSK2 deficiency would result in beta‐cell dysfunction and glucose intolerance. Beta‐cell specific knockout mouse models of Pcsk1 (Pcsk1 betaKO ) and Pcsk2 (Pcsk2 betaKO ) were generated using cre‐lox recombination and monitored for changes in glycemia on chow and high‐fat (HF) diets. Neither Pcsk1 betaKO or Pcsk2 betaKO chow‐fed animals displayed hyperglycemia or impaired glucose tolerance in the first 14 weeks of life. By 26 weeks of age Pcsk1 betaKO , but not Pcsk2 betaKO , chow‐fed male mice displayed fasting hyperglycemia and impaired glucose tolerance. After 19 weeks of HF diet, 3 of 5 Pcsk1 betaKO male mice developed diabetes (fasting glycemia > 16mM), while no hyperglycemia was observed in Pcsk2 betaKO mice up to 30 weeks of diet duration. Pcsk1 betaKO mice displayed elevated islet and plasma (pro)insulin levels, decreased islet mature insulin levels, translucent insulin granules, and trended toward increased beta‐cell area in the pancreas. Despite altered insulin biosynthesis and immature granules, Pcsk1 betaKO islets displayed similar insulin secretion kinetics to Pcsk1 wild‐type islets ex vivo. Our data suggest that Pcsk1 plays a larger role in proinsulin processing and beta‐cell function in mice than Pcsk2. However, despite severe impairments in insulin biosynthesis, Pcsk1‐deficient beta cells compensate remarkably well at early ages and hyperglycemia is only observed in states of increased beta‐cell secretory demand (mild insulin resistance associated with aging or HF diet in mice). Thus, impaired Pcsk1‐mediated prohormone processing, but not Pcsk2‐mediated processing, in beta cells increases diabetes susceptibility in mice. Support or Funding Information Funding was provided by the Canadian Institutes of Health Research and Canucks for Kids Fund Childhood Diabetes Laboratories
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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 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.007 | 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".