UMMS Affiliation

Program in Molecular Medicine; Diabetes Center of Excellence

Publication Date

10-2-2017

Document Type

Article

Disciplines

Cell Biology | Cellular and Molecular Physiology | Endocrine System Diseases | Endocrinology, Diabetes, and Metabolism | Immune System Diseases | Nutritional and Metabolic Diseases

Abstract

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

Rights and Permissions

Copyright © 2017, American Society for Clinical Investigation. Publisher PDF posted as allowed by the publisher's terms of use at https://www.jci.org/kiosks/terms.

DOI of Published Version

10.1172/JCI91761

Source

J Clin Invest. 2017 Oct 2;127(10):3835-3844. doi: 10.1172/JCI91761. Epub 2017 Sep 18. Link to article on publisher's site

Journal/Book/Conference Title

The Journal of clinical investigation

Related Resources

Link to Article in PubMed

PubMed ID

28920919

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