Age-dependent human β cell proliferation induced by glucagon-like peptide 1 and calcineurin signaling
Chunhua Dai, … , Seung K. Kim, Alvin C. Powers
Chunhua Dai, … , Seung K. Kim, Alvin C. Powers
Published September 18, 2017
Citation Information: J Clin Invest. 2017;127(10):3835-3844. https://doi.org/10.1172/JCI91761.
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Age-dependent human β cell proliferation induced by glucagon-like peptide 1 and calcineurin signaling

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.

Authors

Chunhua Dai, Yan Hang, Alena Shostak, Greg Poffenberger, Nathaniel Hart, Nripesh Prasad, Neil Phillips, Shawn E. Levy, Dale L. Greiner, Leonard D. Shultz, Rita Bottino, Seung K. Kim, Alvin C. Powers

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Figure 2

Ex-4 promotes β cell proliferation only in juvenile islets.

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Ex-4 promotes β cell proliferation only in juvenile islets. (A) Both juv...
(A) Both juvenile and adult islets express a similar level of GLP1R mRNA measured by qPCR (juvenile: n = 6, 0.5–9 years old; adult: n = 6, 20–60 years old). (B) Experimental design. After a 2-week islet engraftment period, PBS or Ex-4 was delivered by osmotic pump. The grafts were removed and analyses were performed after 4 weeks of treatment. (C–E) Mouse random glucose (C) and human insulin (D and E) in mice with transplanted juvenile (D, n = 3 donors) or adult (E, n = 3 donors) human islets 48 hours after the implantation of pumps with PBS or Ex-4 (n = 13–14 samples). (F) Representative images of juvenile grafts labeled with insulin (green), Ki67 (red), and DAPI (blue). Insets show proliferating Ki67+ cells. Scale bar: 35 μm. (G and H) Percentage of β cell proliferation in grafts from individual juvenile and adult donors (n = 4–8 grafts per donor). Insets are average percentage in each age group. (I) Statistical analysis of data sets in G and H. Error bars represent SEM. *P < 0.05; **P < 0.01; ***P < 0.001. Unpaired 2-tailed Student’s t test or 1-way ANOVA followed by Newman-Keuls multiple-comparisons test (I) was used for statistical analysis. See also Supplemental Figures 2 and 3.