CCNA1
Cyclin-A1
Publications[править]
Inadequate pancreatic β cell function underlies type 1 and type 2 diabetes mellitus. Strategies to expand functional cells have focused on discovering and controlling mechanisms that limit the proliferation of human β cells. Here, we developed an engraftment strategy to examine age-associated human islet cell replication competence and reveal mechanisms underlying age-dependent decline of β cell proliferation in human islets. We found that exendin-4 (Ex-4), an agonist of the glucagon-like peptide 1 receptor (GLP-1R), stimulates human β cell proliferation in juvenile but not adult islets. This age-dependent responsiveness does not reflect loss of GLP-1R signaling in adult islets, since Ex-4 treatment stimulated insulin secretion by both juvenile and adult human β cells. We show that the mitogenic effect of Ex-4 requires calcineurin/nuclear factor of activated T cells (NFAT) signaling. In juvenile islets, Ex-4 induced expression of calcineurin/NFAT signaling components as well as target genes for proliferation-promoting factors, including NFATC1, FOXM1, and CCNA1. By contrast, expression of these factors in adult islet β cells was not affected by Ex-4 exposure. These studies reveal age-dependent signaling mechanisms regulating human β cell proliferation, and identify elements that could be adapted for therapeutic expansion of human β cells.
MeSH Terms
- Adult
- Aging
- Animals
- Calcineurin
- Cyclin A1
- Exenatide
- Female
- Forkhead Box Protein M1
- Glucagon-Like Peptide 1
- Glucagon-Like Peptide-1 Receptor
- Humans
- Insulin
- Insulin Secretion
- Insulin-Secreting Cells
- Male
- Mice, Inbred NOD
- Middle Aged
- NFATC Transcription Factors
- Peptides
- Signal Transduction
- Venoms