Differential expression of cell-cycle regulators in human beta-cells derived from insulinoma tissue

Introduction. The low frequency of beta-cell replication in the adult human pancreas limits beta-cell regeneration. A better understanding of the regulation of human beta-cell proliferation is crucial to develop therapeutic strategies aiming to enhance beta-cell mass. Methods. To identify factors that control beta-cell proliferation, cell-cycle regulation was examined in human insulinomas as a model of increased beta-cell proliferation (n = 11) and healthy pancreatic tissue from patients with benign pancreatic tumors (n = 9). Tissue sections were co-stained for insulin and cell-cycle proteins. Transcript levels of selected cell-cycle factors in beta-cells were determined by qRT-PCR after performing laser-capture microdissection. Results. The frequency of beta-cell replication was 3.74 +/- 0.92% in the insulinomas and 0.11 +/- 0.04% in controls (p = 0.0016). p21 expression was higher in insulinomas (p = 0.0058), and Rb expression was higher by trend (p = 0.085), whereas p16 (p < 0.0001), Cyclin C (p < 0.0001), and p57 (p = 0.018) expression levels were lower. The abundance of Cyclin D3 (p = 0.62) and p27 (p = 0.68) was not different between the groups. The reduced expression of p16 (p < 0.0001) and p57 (p = 0.012) in insulinomas and the unchanged expression of Cyclin D3 (p = 0.77) and p27 (p ='0.55) were confirmed using qRT-PCR. Conclusions. The expression of certain cell-cycle factors in beta-cells derived from insulinomas and healthy adults differs markedly. Targeting such differentially regulated cell-cycle proteins may evolve as a future strategy to enhance beta-cell regeneration. (C) 2016 Elsevier Inc. All rights reserved.