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Perspective: Postnatal Pancreatic ß Cell Growth

Joslin Diabetes Center Boston, Massachusetts 02215

Address all correspondence and requests for reprints to: Susan Bonner-Weir, Joslin Diabetes Center, 1 Joslin Place, Boston, Massachusetts 02215. E-mail: susan.bonner-weir{at}joslin.harvard.edu

	Introduction

Top Introduction Changes in mass in... Evidence of {beta} cell... Evidence of normal loss... Sources of cells for... Regulation of {beta} cell... Genes that could affect... References

 
Even 15 years ago, the accepted concept was that one was born with all the pancreatic ß cells one ever had. Many thought that insulin resistance would lead to diabetes without change in the ß cells. However, now the concept that diabetes only results when there is an inadequate functional mass of ß cells has gained general acceptance. The more obvious lack of ß cells is seen in type 1 diabetes as the result of autoimmune destruction of ß cells. The lack in type 2 diabetes with its hallmark of peripheral insulin resistance has been less obvious to many, yet the inability of the ß cells to match the increased demand for insulin can be seen as a lack of adequate functional mass. The evidence over the past decade has been compelling that in most cases the ß cells can, and do, compensate for added demand, resulting from pregnancy, obesity, or insulin resistance. It is important to remember that only 15–20% of people with obesity or severe insulin resistance become diabetic; the others maintain normoglycemia due to ß cell compensation.

The new concept is that the ß cell mass is dynamic and increases and decreases both in function and mass to maintain the glycemic level within a very narrow physiological range. The changes in mass can be in both number (hyperplasia) and individual volume of ß cells (hypertrophy). When the mass cannot increase adequately, diabetes ensues. The question remains if such a compensation occurs during the several year long prediabetic phase of type 1 diabetes when ß cell autoantibodies are seen. The general acceptance of the concept of dynamic rather than static ß cell mass is based on clear evidence of changes in ß cell mass in both normal rodents and in "designer" mice (whether transgenic with overexpression or dominate-negative function or ablation of a gene), of varying replication rates of ß cells in vivo and in vitro, the presence of neogenesis or neoformation of islets postnatally and even in the adult, and physiological loss of ß cells indicating turnover. Further discussion of each of these areas follows.

	Changes in mass in normal rodents

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Increase in islet size and ß cell mass throughout the life of an mammal has been reported in the rodent from the pioneering work of Hellerstrom and Hellman in the 60s and 70s, in the calf and even human in the 80s. In a compilation of data from many investigators we found a linear increase in ß cell mass for Sprague Dawley rats from weaning until 3–4 months of age; after that age there were few data points, and before weaning, an intriguing remodeling of the endocrine pancreas to be discussed below (1). Morphometric data on male C57/B6/129 mice from 4 weeks to 6 months show that while ß cell mass data for age-matched mice were scattered, ß cell mass increased at least 10-fold and was linearly correlated with body weight (ß cell mass = -0.27 + 0.054 g body weight; regression coefficient r = 0.831) (2).

Further increase of ß cell mass has been shown in physiological and experimental situations. In a thorough longitudinal study (3), the addition of new cells slowly increased the ß cell mass through most of the life of the male Lewis rat, but from 15 months onwards hypertrophy of the ß cell was the main mechanism of ß cell mass growth. Another physiological situation of ß cell mass expansion is pregnancy. In the rat, ß cell mass increases 50% during pregnancy due to increased ß cell proliferation induced by placental lactogen and increased cell volume (cell hypertrophy) as a functional adaptation (4, 5, 6). However, over the first 10 days postpartum, this increased ß cell mass involutes by reduction of ß cell volume, reduction of ß cell proliferation, and increase of ß cell apoptosis (6, 7, 8). Perhaps the most compelling example of the effect of insulin resistance driving increased ß cell mass are the experiments in mice of known cause of insulin resistance (9). In these mice heterozygous for null deletions of both the insulin receptor and insulin receptor substrate-1 (IRS-1), diabetes was not seen until 6 months of age and then only in a portion of the mixed background mice. In all the double heterozygous mice, the ß cell mass was 10-fold increased compared with wild-type littermates, but some had up to 30-fold increased ß cell mass. These latter mice were extremely insulin resistant (plasma insulin levels 26-fold increased over WT) and were diabetic. The ß cell mass increase was selective because the mass of the non ß endocrine cells did not differ with that of wild-type littermates.

	Evidence of ß cell renewal, both replication and neogenesis

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The two mechanisms of ß cell formation from the embryo, neogenesis, or differentiation from ductal precursor cells, and replication of a differentiated ß cell, are maintained postnatally and even in the adult. After weaning, a low level of replication is maintained, but this can be stimulated. Experimentally, increased proliferation of differentiated ß cells is seen in a number of models (10), including three that we have worked on: 96 h glucose infused rat, GLP-1/exendin 4-treated rat, and partial pancreatectomized rat. The chronic glucose infused rat showed that the ß cell mass could increase 50% in just 96 h with 4- to 5-fold increase in ß cell replication and by ß cell hypertrophy; no neogenesis was seen (11). In the second model, a 10-day treatment of exendin-4, a long acting GLP-1 agonist, stimulated a 40% increase in ß cell mass as measured 15 days later at 4 weeks after start of treatment in normal adult rats. Here hypertrophy was not a factor with the increase in ß cells being from both increased proliferation and neogenesis (12). The third example, the 90% pancreatectomized rat, shows the substantial regenerative capacity of the adult pancreas (13, 14). By 8 weeks after surgery, the remnant that had been an anatomically well defined 10% of the whole pancreas, was 27% of the weight, and had 42% of the ß cell mass of the whole pancreas. In the first week after surgery, ß cell proliferation was increased 3- to 5-fold and more importantly, there was massive formation of new acinar and islet cells from expanded ducts, such that whole new lobes of pancreas were formed. In the first week, the remnant weight increases 2.5 more than that of the anatomically equivalent portion of the pancreas, reflecting both the proliferation and neoformation of islet and exocrine tissue.

	Evidence of normal loss or turnover of ß cells

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Nonimmune loss of ß cell mass had been reported in post partum pancreas (7, 8), in a rat model of transplantable insulinomas (15, 16), as loss of individual cells in db/db mice (17), after cessation of glucose infusion (11, 18), and in clinical reports as atrophy of islet tissue in pancreas neighboring insulinomas. The mechanisms of involution varied with the model used. When insulinomas were transplanted, the decrease in ß cell mass was due to nonimmune-mediated apoptosis; however, after transplantation of glucagonomas, only atrophy of cells was seen (16). The reduction of ß cell size after glucose infusions were stopped resulted in the observed decrease in ß cell mass; in this case, the return from hypertrophy took over 1 week even though the cell function had reverted by 24 h (11, 18). Increased apoptosis as well as decreases both of replication and of cell size contribute to the involution in the postpartum period (6).

The normal turnover of ß cells became evident with mathematical modeling of the ß cell mass (1). With 2–3%/24 h (or 0.5–0.7%/6 h) replication of ß cells found in the adult rodent pancreas, the ß cell mass can double in about 1 month. Between 1–2 and 2–3 months of age, the rat ß cell mass does almost double but this monthly doubling does not continue, suggesting a loss of cells as there is renewal. Indeed, in adult (3-month-old) rats, the frequency of apoptotic ß cell nuclei was 0.5%. Unfortunately, we do not know the rate of apoptosis because there are no data on how long apoptotic ß cell nuclei or bodies are visible in vivo; however, apoptotic nuclei and bodies are thought to be transient and visibly detectable for less than 4 h. Because the rate of ß cell death approaches the replication rate, then complete replacement of the ß cell population could occur in about a month for a rat. Thus, the endocrine pancreas should be considered a slowly renewed tissue.

An interesting increase of apoptosis in the neonatal rat pancreas was found. The initial observation was that the ß cell mass did not increase between 1–3 weeks of age even though ß cell replication was considerably higher than in the adult (19, 20). Apoptotic ß cell nuclei were found at a basal frequency (1.5%) through most of the neonatal period but was significantly increased (3.6 ± 0.5%) at 13 and 17 days. The simultaneous high level of apoptosis and replication of ß cells suggested a remodeling of the endocrine pancreas in the neonatal period, possibly due to the inadequacy of available survival factors such as the IGFs (20). Further studies have extended these findings to NOD mice and BB rats with the suggestion that the highly immunogenic apoptotic bodies from ß cells could prime the autoimmune disease (21).

	Sources of cells for renewal: precursor and stem cells

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Because the seminal paper on the pancreatic agenesis found in the IPF-1/PDX-1 null mouse (22), characterization of markers for the cell lineages of islet cells has developed rapidly (23). With these advances and the acceptance of the concept of postnatal growth of the ß cell mass, interest in the adult "pancreatic stem cell" has increased. From three-dimensional reconstruction of rat islets (24), it was clear that there are no "undifferentiated" cells in an adult rat islet. As discussed above, the postnatal proliferation of differentiated ß cells must not be underestimated; the low proliferation rate of ß cells is enough to allow for a slow turnover. It is clear that the replicating cells are truly ß cells: both incorporated bromodeoxyuridine and tritiated thymidine have been localized to cells immunolabeled for insulin, and numerous images of mitotic figures in cells with insulin granules have been published. However, there still may be differences in function in ß cell that can replicate and those that cannot. Such differences may be a matter of differences in pools (replicative vs. senescent) or alternatively, those ß cells that replicate may "dedifferentiate" and transiently lose function as they replicate. Human islets were reported to lose their insulin expression but maintain IPF-1 expression when expanded in vitro as monolayers (25) or to lose their insulin expression and become duct-like when embedded in three-dimensional collagen gels (26).

The likely source of precursor cells would be the pancreatic ducts because the adult duct epithelium retains the ability to give rise to all the differentiated cell types of the pancreas. The existence of bone marrow-derived stem cells that can differentiate into islet cells as recently reported for hepatic cells (27) may be possible, but these are not important in the Px regeneration. While the precursor cells may be the equivalent to the "oval cells" as have been defined in the liver (28, 29), our data suggest that oval or true stem cells are very few, if any, in the normal rat pancreas and are not involved in normal pancreatic growth nor in the massive regeneration after partial pancreatectomy (10). A recent paper claims to have grown true stem cells from pancreatic ducts from NOD mice and to be able to produce islets from these cells in culture (30). While this may be true, the paper has numerous troublesome flaws, so it is unclear whether any significant portion of the expanded tissue expresses islet hormones.

From studies on pancreatic regeneration in rats (13, 30) we were impressed with the capacity of adult pancreatic duct cells to both expand and differentiate. After rapid replication of the duct cells, the transcription factor PDX-1/IDX-1 was transiently expressed (31). This protein is expressed in the embryonic pancreatic ducts but is repressed in the ducts shortly before birth. We hypothesize that adult duct cells have the potential to lose their specific duct phenotype with rapid proliferation, reverting to the pluripotent cells that can then differentiate into islet cells with the appropriate external stimuli. Our data on the expansion, dedifferentiation and subsequent redifferentiation of duct cells are similar to a recent report of the hepatocyte as a "facultative stem cell" (32). We hypothesize that these PDX-1/IDX-1 + duct cells that transiently regain their pluripotency are the true precursor cells in the adult pancreas (31).

	Regulation of ß cell mass

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It is unclear if the stimulus for ß cell expansion is something other than mild transient hyperglycemia. While many factors have been suggested, glucose is one of the best stimuli for ß cell replication in vitro and in vivo (11, 33). One can envision glucose as the driving force for most ß cell compensation. As glucose uptake by peripheral tissues is diminished by inadequate plasma insulin to meet increased demand or increased insulin resistance, transient postprandial hyperglycemic excursions could occur. The mild hyperglycemia could signal the ß cells that more insulin is needed, so compensation could occur, including functional as well as enhanced ß cell replication and cell size. The increased ß cell mass would secrete more insulin that would overcome the insulin resistance and drive glucose uptake peripherally. While transient or mild hyperglycemia may be beneficial, it is clear that chronic or severe hyperglycemia is detrimental. There are a number of secondary effects of a glycemic environment including the loss of glucose-induced insulin secretion (34) and even loss of specific ß cell differentiation (35).

It must be remembered that a factor does not have to act directly on the ß cell to effect the ß cell mass, an indirect effect that resulted in transient mild hyperglycemia could have an effect on the ß cell mass. This should be kept in mind when interpreting the results of transgenic and knockout mice. For example, mice null for both insulin I and II died by 48 h of hyperglycemia; enlarged islets were found, suggesting to the authors that insulin might function as a negative regulator of ß cell growth (36). Yet 4-month-old mice with ß cell specific knockout of the insulin receptor were normoglycemic but hyperinsulinemic, with mildly impaired glucose tolerance, and a small reduction in insulin content (37). These latter mice show that insulin does not have a profound direct effect on the ß cell. Therefore one must consider if glucose or some other circulating factor stimulated an in utero or postnatal expansion of the ß cells of the insulin-deficient mice.

	Genes that could affect the ß cell mass

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The complexity of compensation of ß cell mass underscores the difficulty in finding the causative genes for type 2 diabetes. The genes (the metabolic enzyme glucokinase, and the transcription factors, hnf-1, hnf-3, ipf-1, neuroD/BETA2) that have been identified as causes of the various monogeneic MODYs all affect the function of the ß cells. There may well be other genes that will be found that affect the ability of the ß cell to increase its biosynthetic or secretory capacity. In addition, any gene that could affect renewal or turnover could contribute to an organism’s ability to compensate. Genes that could affect renewal would include receptors or ligands that determine the response to stimuli, the number of potential replications before senescence, and number of precursor cells. Genes that affect turnover would include sensitivity to survival factors, availability to survival factors, and length of lifespan of cell. Even though the gene may be expressed throughout the body, a mutation or disruption of the gene may be manifested as diabetes because of the delicate balance of adequate functional ß cell mass.

Received April 4, 2000.

	References

Top Introduction Changes in mass in... Evidence of {beta} cell... Evidence of normal loss... Sources of cells for... Regulation of {beta} cell... Genes that could affect... References

 

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