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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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Research Article Endocrinology

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

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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 1

Endocrine cell proliferation is greater in transplanted human juvenile islets than in adult islets.

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Endocrine cell proliferation is greater in transplanted human juvenile i...
(A) Schematic of experimental design. Grafts were removed for analysis 6 weeks after transplantation. (B, C, F, G, J, and K) Images of juvenile (left panels) and adult (right panels) grafts labeled with insulin (INS, B and C), glucagon (GLU, F and G), or somatostatin (SOM, J and K) in green; Ki67 in red; DAPI in blue. Insets show proliferating Ki67+ cells. Scale bar: 50 μm (bar in K applies to all other images in this figure). (D, E, H, I, L, and M) Quantification of percentage Ki67+ β (D and E), α (H and I), and δ (L and M) cells of transplanted grafts from individual juvenile (Juv) and adult donors (n = 2–5 grafts per donor; age shown on x axis). The average number of β, α, and δ cells counted in each donor sample was approximately 6,000, 3,000, and 2,000, respectively. Insets are average percentage proliferating cells in each age group (β cells: data from D and E; α cells: data from H and I; δ cells: data from L and M). Error bars represent SEM. **P < 0.01; ***P < 0.001. An unpaired 2-tailed Student’s t test was used for statistical analysis. See also Supplemental Figure 1.
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