Age-dependent human ? cell proliferation induced by glucagon-like peptide 1 and calcineurin signaling.

ABSTRACT: Inadequate pancreatic ? 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 ? cells. Here, we developed an engraftment strategy to examine age-associated human islet cell replication competence and reveal mechanisms underlying age-dependent decline of ? 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 ? 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 ? 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 ? cells was not affected by Ex-4 exposure. These studies reveal age-dependent signaling mechanisms regulating human ? cell proliferation, and identify elements that could be adapted for therapeutic expansion of human ? cells.

SUBMITTER: Dai C 

PROVIDER: S-EPMC5617654 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature