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

Dai C, Hang Y, Shostak A, Poffenberger G, Hart N, Prasad N, Phillips N, Levy SE, Greiner DL, Shultz LD, Bottino R, Kim SK, Powers AC
J Clin Invest. 2017 127 (10): 3835-3844

PMID: 28920919 · PMCID: PMC5617654 · DOI:10.1172/JCI91761

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 (21)

Adult Aging Animals Calcineurin Cyclin A1 Exenatide Female Forkhead Box Protein M1 Glucagon-Like Peptide-1 Receptor Glucagon-Like Peptide 1 Humans Insulin Insulin-Secreting Cells Insulin Secretion Male Mice, Inbred NOD Middle Aged NFATC Transcription Factors Peptides Signal Transduction Venoms

Connections (1)

This publication is referenced by other Labnodes entities: