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- Title
Age-dependent human β cell proliferation induced by glucagon-like peptide 1 and calcineurin signaling.
- Authors
Dai, Chunhua; Yan Hang; Shostak, Alena; Poffenberger, Greg; Hart, Nathaniel; Prasad, Nripesh; Phillips, Neil; Levy, Shawn E.; Greiner, Dale L.; Shultz, Leonard D.; Bottino, Rita; Kim, Seung K.; Powers, Alvin C.; Hang, Yan
- Abstract
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.
- Subjects
CELL physiology; TYPE 2 diabetes; ISLANDS of Langerhans; T cells; GLUCAGON-like peptide 1; PROTEIN metabolism; AGING; ANIMAL experimentation; ANIMALS; CELLULAR signal transduction; HYDROLASES; INSULIN; MICE; PEPTIDES; RESEARCH funding; VENOM
- Publication
Journal of Clinical Investigation, 2017, Vol 127, Issue 10, p3835
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI91761