Cyclin D2 (CCND2) is an essential cell cycle regulator of rodent pancreatic β cells, while its expression in human islets is still controversial in the past studies. It may be because few proliferative β cell is generally present in human adult islets. In contrast, expansion of β cell population mainly depends on a cell proliferation in human perinatal islets. Therefore, CCND2 is expected to be implicated in β cell proliferation in human perinatal islets. The aim of this study is to explore the implication of CCND2 in proliferation of human perinatal β cells. We evaluated pancreata of 39 autopsy cases from prenatal 24 weeks old to postnatal 19 years old. The subjects were divided into fetus (F: prenatal 24-31 weeks), infant (I: 0-1 years), child (C: 2-12 years) and adolescence (A: 13-19 years). Quintuple-immunohistochemistry (IHC) for glucagon, insulin, somatostatin, pp and Ki-67 was performed for the measurement of islet cell volume density (V) and cell replication status. Double-IHC for insulin with CCND2, 5-hydroxy tryptophan (5-HT) and p16 were performed. Double positive cells for each staining were counted. Morphometric analysis revealed that Vα and Vβ were increased with maturation. Ki-67 positivity for α and Δ cells was the highest in F (p<0.01), whereas that of β cells was the highest in I (p<0.01). CCND2 was robustly expressed in the nucleus of β cells in F (>90%) and I (>90%). Thereafter, its expression was dramatically declined in C and A (2.25±1.4%). 5-HT was highly expressed in perinatal subjects but not in C and A. Conversely, p16 expression was minimum before adolescence and its expression was evident in A. Our results clearly suggested that CCND2 could be implicated in the development of human β cell population in perinatal stage. The expression of CCND2 might be independently regulated by 5-HT and p16, while other factors may be implicated in the expression mechanism. To elucidate the regulation mechanism of CCND2 in human islets may lead to develop a novel strategy for diabetes treatments.
S. Osonoi: None. H. Ichinohe: None. K. Kudo: None. S. Yagihashi: None. H. Mizukami: None.