β-Cell Replication Is the Primary Mechanism Subserving the Postnatal Expansion of β-Cell Mass in Humans

Abstract

OBJECTIVE-Little is known about the capacity, mechanisms, or timing of growth in ␤-cell mass in humans. We sought to establish if the predominant expansion of ␤-cell mass in humans occurs in early childhood and if, as in rodents, this coincides with relatively abundant ␤-cell replication. We also sought to establish if there is a secondary growth in ␤-cell mass coincident with the accelerated somatic growth in adolescence.RESEARCH DESIGN AND METHODS-To address these questions, pancreas volume was determined from abdominal computer tomographies in 135 children aged 4 weeks to 20 years, and morphometric analyses were performed in human pancreatic tissue obtained at autopsy from 46 children aged 2 weeks to 21 years.RESULTS-We report that 1) ␤-cell mass expands by severalfold from birth to adulthood, 2) islets grow in size rather than in number during this transition, 3) the relative rate of ␤-cell growth is highest in infancy and gradually declines thereafter to adulthood with no secondary accelerated growth phase during adolescence, 4) ␤-cell mass (and presumably growth) is highly variable between individuals, and 5) a high rate of ␤-cell replication is coincident with the major postnatal expansion of ␤-cell mass.CONCLUSIONS-These data imply that regulation of ␤-cell replication during infancy plays a major role in ␤-cell mass in adult humans. Diabetes 57:1584-1594, 2008

Pancreatic adenocarcinoma patients with localised chronic severe pancreatitis show an increased number of single beta cells, without alterations in fractional insulin area

“…Fractional insulin area provides an assessment of the proportion of pancreatic cells that are insulin-positive cells, as an indicator of beta cell mass [21,[25][26][27]. Using this well-accepted method of analysis, very limited differences in fractional insulin area were noted amongst the five study groups using immunohistochemistry (1.4±0.1% autopsy control, 1.1±0.1% no pancreatitis, 2.0±0.2% mild pancreatitis, 1.8 ± 0.7% severe pancreatitis, 1.5 ± 0.2% gastrinoma).…”

“…4). As age has been reported to influence the beta cell replication rate [21] Pancreas samples from all study groups were examined for levels of three transcription factors (PDX1, NEUROD1 and NEUROG3) associated with the differentiation of pancreatic endocrine precursors into adult beta cells. Surprisingly, transcription factor levels in islets from the autopsy control samples were lower than those in all other groups (Fig.…”

“…As suggested by many investigators, the absence of an increase in periductal islets or intraductal insulin-positive cells implies that beta cell regeneration in humans is predominately accomplished by beta cell replication [21]. Islet ductal complexes and isolated insulin-positive cells in ducts have also been reported in pancreases obtained from autopsy specimens and organ donors [21,37].…”

“…Indeed, carefully sorted human beta cells from islet preparations failed to replicate in vitro, in marked contrast to beta cells isolated from rat islets [35]. However, recent reports suggest that the capacity for lifelong beta cell replication exists in humans [21,28,32,36]. While such data in humans are limited, in autopsy samples it was shown that 0.04% of human beta cells produce Ki-67 [32].…”

“…In these samples, the presence or absence of localised inflammation may give an indication of whether inflammation can stimulate changes in beta cell mass. To also allow for inter-hospital comparisons with existing related studies [20,21], we also included autopsy-based specimens from patients without clinical evidence of pancreatic disease as normal controls. Histopathological assessment of the severity of chronic pancreatitis was performed, as was assessment of morphological markers of beta cell replication and cell lineage.…”