Cell cycle control of beta-cell replication in the prenatal and postnatal human pancreas

Kohler CU, Olewinski M, Tannapfel A, Schmidt WE, Fritsch H, Meier JJ. Cell cycle control of beta-cell replication in the prenatal and postnatal human pancreas. Am J Physiol Endocrinol Metab 300: E221-E230, 2011. First published October 26, 2010; doi:10.1152/ajpendo.00496.2010.-beta-Cell regeneration declines with aging, but the molecular mechanisms controlling beta-cell replication in humans are not well understood. We compared the expression of selected cell cycle proteins in prenatal and adult tissue and examined the association of these proteins with beta-cell replication. Pancreatic tissue from a total of 20 human fetuses and adults was stained for Ki67, cyclin D3, p16 and p27, and insulin. The beta-cellular expression of these cell cycle proteins was determined. The frequency of beta-cell replication was lower in adult compared with prenatal beta-cells (<0.5 vs. 3.4 +/- 0.5%, respectively; P < 0.0001). p16 was sporadically expressed in prenatal beta-cells (8.0 +/- 1.1%) but highly enriched in adult beta-cells (63.1 +/- 5.2%, P < 0.0001). Likewise, the expression of p27 was much lower in prenatal beta-cells (1.7 +/- 0.4 vs. 44.1 +/- 5.4%, respectively, P < 0.0001), and cyclin D3 expression increased from 24.2 +/- 4.1 to 47.25 +/- 5.0%, respectively (P < 0.001), with aging. The expression of all three proteins was significantly correlated with each other (P < 0.01 and r > 0.75, respectively). The strong expression of cyclin D3 in adult human beta-cells and its correlation to p27 and p16 suggest a positive role in human beta-cell cycle regulation. p16 and p27 appear to restrict beta-cell replication with aging. The age dependency of cell cycle regulation in human beta-cells might explain the reduced beta-cell regeneration in adult humans.