Unfortunately, we cannot measure β cell mass in live humans, determine how that mass might change over time, or trace the source of any newly formed β cells. Therefore, studies of β cell growth and regeneration have turned to animal models, most commonly that of rodents. During fetal development in rodents, β cells differentiate from non–β cell precursors through a process termed neogenesis (Figure ). Studies in rodent embryos have worked out the pathways and genes involved in fetal neogenesis of β cells (10
). A critical step in this process is the decision by pancreatic progenitor cells to adopt an endocrine fate, as opposed to an acinar or duct cell fate. The transcription factor neurogenin 3 (NGN3, also known as Neurog3) controls the endocrine fate decision: its activation in scattered cells within the cords of pancreatic progenitor cells that form the fetal pancreatic ducts is both necessary and sufficient to drive their differentiation into endocrine cells (10
). Because NGN3 expression is transient, it also acts as a useful marker of cells in the process of differentiating into endocrine cells, and the abundance of these NGN3-expressing endocrine progenitor cells is often used as a surrogate for the rate of fetal endocrine cell neogenesis.
A model for β cell generation and regeneration in mice.
Fetal neogenesis of β cells in rodents stops at birth (11
), but the newly differentiated β cells, which are initially quiescent, start to proliferate rapidly, outstripping the overall growth rate and insulin requirement of the organism (15
). This perinatal wave of proliferation also occurs in humans and causes a growth spurt in the β cell population that establishes the size of the β cell pool prior to the onset of puberty and adulthood (1
). Once this wave passes, rates of β cell proliferation drop dramatically and slowly decrease further with age in both humans and mice.
After the perinatal wave of proliferation, how much capacity does the mature pancreas retain to generate new β cells? A long-standing literature has attested to the ability of the pancreas to increase β cell mass in adults of multiple mammalian species in settings of increased insulin demand due to weight gain, glucose infusion, or pregnancy, and to regenerate β cells in response to pancreatic damage or selective β cell loss. In many of these studies, indirect evidence from morphological assessment and mathematical deduction based on differences between rates of proliferation and growth of the β cell population supported the conclusion that neogenesis plays an important role in adult β cell replacement, expansion, and regeneration (reviewed in refs. 16
). In 2004, however, a prominent study changed the debate regarding sources of β cells in the adult pancreas. Using a tamoxifen-inducible Cre recombinase transgene to permanently mark the existing β cells in young adult mice, Dor et al. showed that most, if not all, of the β cells present a year later descended from those initial β cells and thus did not arise via neogenesis or transdifferentiation from a non–β cell source (18
). Further, Dor et al. found no evidence of substantial contributions from neogenesis to the regeneration of β cell mass after partial pancreatectomy, although they could not rule out a small contribution, and they did not test other models of adult β cell expansion or regeneration.
In contrast, in 2008 Xu et al. reported the first explicit evidence of neogenesis in the adult mouse pancreas (19
). They showed that partial duct ligation, a time-honored model of pancreatic damage (17
), induced the formation of NGN3+
cells near the ducts of the damaged lobes of the ligated pancreas and that new functional β cells derived from those NGN3+
cells. Following this report, Inada et al. used a carbonic anhydrase II promoter to mark duct cells prior to duct ligation and showed that duct cells contributed to the generation of new β cells after partial duct ligation (20
). However, 2 subsequent studies using the Hnf1
) and Sox9
) promoters to genetically mark the duct cells and trace their descendents failed to show any contribution from duct cells to β cell regeneration after partial duct ligation. A recent study from Pan et al. provides a potential explanation for these contradictory results by showing that the ductal NGN3+
cells identified in the partial duct ligation model actually originate from acinar cells that rapidly acquire characteristics of fetal pancreatic duct cells after duct ligation (21
Interestingly, studies using a recently described mouse model of extreme β cell loss that involves treatment with diphtheria toxin to selectively destroy β cells expressing a human diphtheria toxin receptor transgene revealed a robust capacity for β cell regeneration, but many of these new β cells originated from glucagon-expressing α cells and not from Sox9+
duct cells (22
). In contrast, another group found that when the same diphtheria toxin receptor model was used to ablate all islet and acinar cells, β cells regenerated from the remaining duct cells (24