Revisiting Proinsulin Processing: Evidence That Human β-Cells Process Proinsulin With Prohormone Convertase (PC) 1/3 but Not PC2.
Level 5 - mechanism / opinion, no new human data
Bench research using human and animal islet tissue, histology, and biochemical assays
PubMed 32291281 · doi:10.2337/db19-0276
What was done
Researchers evaluated proinsulin processing mechanisms in human and rat pancreatic tissue. Immunofluorescence and in situ hybridization were used to evaluate prohormone convertase 2 (PC2) protein and PCSK2 mRNA in healthy human and rat beta-cells, as well as beta-cells from donors with type 2 diabetes, using neighboring alpha-cells as positive controls. In human islets, pulse-chase biochemical experiments with pharmacological inhibitors (brefeldin A, chloroquine, temperature blockade, and specific convertase inhibitors) were performed to assess insulin and glucagon maturation during selective inhibition of PC2 or PC1/3.
What was found
Healthy human beta-cells showed no detectable PC2 immunoreactivity and minimal PCSK2 mRNA, and rat beta-cells similarly lacked PC2 immunoreactivity. In contrast, beta-cells from donors with type 2 diabetes exhibited elevated PC2 immunoreactivity. In biochemical assays, inhibiting PC2 blocked proglucagon processing into mature glucagon but left proinsulin processing into mature insulin intact. Conversely, suppression of PC1/3 blocked mature insulin production without altering proglucagon processing. The abstract reports no quantitative values or statistical effect sizes.
Why it matters
This study challenges the long-standing model derived from mice that proinsulin processing requires both PC1/3 and PC2, demonstrating that normal human beta-cells rely on PC1/3 alone. It also identifies abnormal beta-cell PC2 expression as a potential contributor to impaired proinsulin processing in type 2 diabetes.
Limits
The abstract does not disclose the number of human donors (n) or islet preparations evaluated. Findings are limited to ex vivo and in vitro laboratory models, and no quantitative percentages, concentrations, or statistical significance metrics are provided in the abstract.
Cited by
- supports Prohormone convertase 1 is the enzyme responsible for cleaving C-peptide from the proinsulin molecule to form mature insulin.