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J Clin Invest. 2017 Oct 2;127(10):3835-3844. doi: 10.1172/JCI91761. Epub 2017 Sep 18.

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

Author information

1
Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
2
Department of Developmental Biology, Stanford University School of Medicine, Stanford, California, USA.
3
Hudson Alpha Institute for Biotechnology, Huntsville, Alabama, USA.
4
Department of Molecular Medicine, Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
5
The Jackson Laboratory, Bar Harbor, Maine, USA.
6
Institute of Cellular Therapeutics, Allegheny-Singer Research Institute, Allegheny Health Network, Pittsburgh, Pennsylvania, USA.
7
Department of Medicine, Stanford University School of Medicine, Stanford California, USA.
8
Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
9
VA Tennessee Valley Healthcare System, Nashville, Tennessee, USA.

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.

PMID:
28920919
PMCID:
PMC5617654
DOI:
10.1172/JCI91761
[Indexed for MEDLINE]
Free PMC Article

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