Very Slow Turnover of β-Cells in Aged Adult Mice

Abstract

Although many signaling pathways have been shown to promote ␤-cell growth, surprisingly little is known about the normal life cycle of preexisting ␤-cells or the signaling pathways required for ␤-cell survival. Adult ␤-cells have been speculated to have a finite life span, with ongoing adult ␤-cell replication throughout life to replace lost cells. However, little solid evidence supports this idea. To more accurately measure adult ␤-cell turnover, we performed continuous long-term labeling of proliferating cells with the DNA precursor analog 5-bromo-2-deoxyuridine (BrdU) in 1-year-old mice. We show that ␤-cells of aged adult mice have extremely low rates of replication, with minimal evidence of turnover. Although some pancreatic components acquired BrdU label in a linear fashion, only 1 in ϳ1,400 adult ␤-cells were found to undergo replication per day. We conclude that adult ␤-cells are very long lived. Diabetes 54: 2557-2567, 2005 I nadequate islet mass is a central finding in both type 1 and type 2 diabetes, resulting in an absolute or relative insulin deficiency and subsequent metabolic complications (1-3). Over the past decade, much has been learned about the specific signaling pathways that direct embryonic islet development (4) and postnatal islet growth (5). To compensate for increased metabolic demands, adult islet mass increases dramatically over the first year of life in rodents (6) and may represent growth within preexisting islets because islet density does not typically increase as mice age (7,8). It has been known for some time that adult ␤-cell growth is dependent on cyclindependent kinase-4 (9). Recently, we (10) and others (11) showed that cyclins D2 and D1 are the likely partners with cyclin-dependent kinase-4 to promote G 1 cell cycle progression in adult ␤-cells. Remarkably, new evidence suggests that much of adult ␤-cell growth may occur by replication of insulin-positive cells and not by ␤-cell neogenesis (12). However, it is possible that ␤-cell neogenesis may exist under some circumstances (13,14). Surprisingly little is known about the factors that promote adult ␤-cell survival, although some amount of ␤-cell apoptosis occurs in normal islets (15) as well as in pathological states (16). Although the absolute ␤-cell death rate is unknown, ␤-cell death appears to be a rare event. Supporting this notion, ␤-cell area increases severalfold throughout adulthood, despite an apparent decline in daily proliferation rate (6,17).Despite the lack of direct evidence, it has been largely assumed that ␤-cells have a finite life span, with dying cells replenished by new ␤-cells on an ongoing basis (12,14,17). One method of estimating cell life span is to measure the growth of total cell populations and cellular proliferation rate. In this model, the cell turnover rate is reflected by the proportion of cellular proliferation that does not contribute to cell population growth. In the simplest example of a stable population of cells with no net growth, cellular proliferation must be explained by ongoing lo...

Pancreas organogenesis: From bud to plexus to gland

“…Under normal physiological conditions, b-cell turnover is slow and decreases progressively with age (Teta et al, 2005(Teta et al, , 2007. Upon injury, it appears that at least some b-cells can re-enter the cell cycle.…”

Glial Cell Line-Derived Neurotrophic Factor Increases β-Cell Mass and Improves Glucose Tolerance

“…Cell proliferation in cultured cells and pancreatic tissue was assessed by immunofluorescence microscopy 13 using an anti-Ki67 polyclonal antibody 14 .…”

Virgin Beta Cells Persist throughout Life at a Neogenic Niche within Pancreatic Islets

“…The current view is that beta cell mass is determined by the net effect of islet neogenesis, beta cell proliferation and hyperplasia, balanced by dedifferentiation and beta cell death through apoptosis (Bonner-Weir et al, 2010). Mice increase beta cell mass by selfreplication to compensate for increased metabolic demand in the context of obesity or pregnancy (Cox et al, 2016;Parsons et al, 1992), although beta cell proliferation rates decline sharply with age (Brennand et al, 2007;Teta et al, 2005). In humans, increases in beta cell mass in response to similar conditions are modest at best.…”