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EP Joslin Research Laboratories (L.S., C.J.C., S.B.-W.), Joslin Diabetes Center and the Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02215; and Departments of Medicine and Physiology (D.T.F.), University of Alberta, Edmonton, Canada T6G 2H7
Address all correspondence and requests for reprints to: Dr. Susan Bonner-Weir, Joslin Diabetes Center, 1 Joslin Place, Boston, Massachusetts 02215. E-mail: bonners{at}joslab.harvard.edu
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In the pancreas, a surprising discrepancy between the growth in body
weight and pancreas weight shortly after birth has been reported in
both rats and mice (6, 7). Even though the body weight increased, the
pancreatic weight did not increase from 2–20 days. In this same
period, ß cell mass does not increase (8, 9, 10, 11). ß cell mass can
increase by replication, by hypertrophy of the individual cells, or by
new formation (neogenesis) of islets by differentiation and budding
from ducts (12). The lack of increase is surprising because ß cell
replication rate is high (as compared with that of older animals)
during this time (11, 13). In a study of perinatal islet development,
Kaung found a discordance between the calculated and actual islet cell
population growth and suggested that there may be some ß and 
cell
loss during the first 10 days (13). Because no evidence of islet cell
death was seen, she hypothesized that the loss was due to
transdifferentiation. However, we have reported apoptotic ß cells in
the neonatal rat (11). This finding is consistent with our mathematical
model of the dynamics of the growth of the endocrine pancreas; this
model predicts a wave of cell death between 2 and 18 days of age,
followed by increased neogenesis shortly before weaning (11).
Our model strongly suggested that the developing endocrine pancreas undergoes substantial remodeling and that apoptosis, replication, and neogenesis play roles in this process. Therefore, in this study we quantified these parameters, that is ß cell mass, replication, cell size, and cell death, in the same tissue from developing neonatal rat pancreas to determine if remodeling of the endocrine pancreas occurs and by what mechanisms. These findings provide support for the predictions of the model.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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ß cell replication
Rats (three to four per age) were injected with
5-bromo-2'deoxyuridine (BrdU, Sigma, St. Louis, 100 mg/kg BW ip) 6
h before killing. BrdU is a thymidine analog that is incorporated in
newly synthesized DNA and thus labels replicating cells (14). The
G2 + M phases of the ß cell cycle have been estimated to
be 6 h (15); therefore, a 6-h BrdU incorporation time was used to
maximize the number of labeled cells while still avoiding the detection
of labeled daughter cells. After killing, the pancreas was excised,
cleared of fat and lymph nodes, weighed, fixed in Bouin’s solution,
and embedded in paraffin.
Sections (5 µm) were double stained with immunoperoxidase for BrdU and for the endocrine non-B cells of the islets. Immunostaining for BrdU used a Cell Proliferation Kit (Amersham International, Amersham, UK). Sections were incubated 30 min at room temperature with a mouse monoclonal antibody anti-BrdU, washed with PBS (pH 7.4), incubated with peroxidase-linked sheep antimouse Ig and stained with 3,3'-diamino-benzidine tetrahydrochloride (DAB) plus a substrate/intensifier containing hydrogen peroxide and nickel chloride/cobalt chloride. The sections were then washed with 0.01 mM HCl, then rinsed with distilled water, soaked in PBS plus 1% lamb serum (Life Technologies), and stained for the endocrine non-ß cells using a cocktail of antibodies: rabbit antibovine glucagon (final dilution 1:3000, gift of Dr. M. Appel), rabbit antisynthetic somatostatin (final dilution 1:300, made in our own laboratory), and rabbit antibovine pancreatic polypeptide (final dilution 1:3000, gift of Dr. R. Chance, Eli Lilly Co., Indianapolis, IN). The sections were incubated with this cocktail of antibodies overnight at 4 C, washed with Tris buffer, pH 7.4, sequentially incubated with goat antirabbit Ig and rabbit peroxidase antiperoxidase (PAP) (Cappel Laboratories, Cochranville, PA), stained with DAB and counterstained with hematoxylin. On stained sections the islets were identified by a mantle of endocrine non-ß cells with orange-brown cytosol, a core of ß cells with unstained cytosol, and BrdU positive cells with blue-black nuclei.
BrdU positive and negative ß cells were counted using an Olympus BH-2 microscope connected by a video camera to a black and white monitor at a final magnification of 680x. All the ß cells in each section were counted (range 507-1288 ß cells/animal, 844 mean), and the results expressed as percentage of BrdU positive ß cells, giving an estimate of the number of ß cells in replication.
ß cell mass
ß cell mass was measured by point counting morphometry on the
same stained section as above. Each section was covered systematically
at a magnification of 340 x using a 48-point grid to obtain the
number of intercepts over ß cell, endocrine non-ß cell, exocrine
pancreatic tissue, and nonpancreatic tissue. The ß cell relative
volume was calculated by dividing the intercepts over ß cells by
intercepts over total pancreatic tissue; the ß cell mass was then
estimated by multiplying the ß cell relative volume by the corrected
pancreatic weight. The non-ß cell mass was similarly calculated.
Pancreatic weight was corrected by subtracting from the pancreas weight
a correction factor obtained by multiplying pancreatic weight by the
ratio of intercepts over non pancreatic tissue to intercepts over total
tissue. A nomogram relating number of points counted to volume density
and expected relative standard error in percentage of mean (<10%) had
been used to determine the number of intercepts needed for a
representative sampling (16).
ß cell size
ß cell size (cross-sectional area) was measured on electron
micrographs. To this end, the pancreas from three rats at each age were
removed, minced in 2.5% glutaraldehyde, 0.1 M phosphate
buffer pH 7.4, and routinely processed with osmication and subsequently
embedded in Araldite. Ultrathin sections of islets were stained with
lead citrate and uranyl acetate and photographed on a Phillips 301
electron microscope. For each time point, at least three random islets
were analyzed.
To minimize the variations in cross-sectional area due to different planes of section of the cells, only ß cells that had a visible capillary face and a nuclear cross-section were measured for cross-sectional area using an electronic planimetry program (Sigma Scan, Jandel Scientific). For each age cross-sectional areas of 60–100 cells were measured. The magnification of each set of micrographs was calibrated using a photograph of a calibration grid. In addition, apoptotic cells were photographed from these samples.
ß cell death
For quantification of apoptotic ß cell death, sections were
both immunostained for non-ß endocrine cells and stained with
propidium iodide. Propidium iodide is a fluorescent dye that binds to
nucleic acids and therefore allows the detection of condensed or
fragmented nuclei characteristic of apoptotic cells. Sections (3 µm)
from the same paraffin blocks used for ß cell replication and mass
were deparaffinized with xylene and rehydrated, stained for endocrine
non-ß cells as described above, soaked with PBS pH 7.4 and incubated
for 10 min with propidium iodide 10 µg/ml and RNAse A 100 µg/ml at
37 C. Sections were then washed extensively with PBS, rinsed with
distilled water and mounted with an aqueous media (AFT, Behring
Diagnostics, Somerville, NJ).
On a fluorescent microscope, islet tissue was identified on bright field and then using a rhodamine filter set, normal, and apoptotic nuclei were counted. Sections were covered systematically, and all the ß cells in each section were counted (range 203-1315, mean 737 for neonates; at least 1100 for each of 5 adult animals). The results expressed as percentage of fragmented and condensed nuclei (apoptotic cells) estimate the occurrence of cell death.
Statistical analysis
All data are expressed as mean ± [sem]se.
Comparison between groups was performed by one-way ANOVA with multiple
comparisons by Fisher’s PLSD. Differences between groups were
evaluated using the unpaired two tailed Student’s t test. A
P value 
0.05 was considered significant. For
analysis of the distribution of cell population, a multivariate
analysis was performed and the Chi Square with a P
value 0.05 was considered significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). In contrast to the
literature, the pancreatic weight (Fig. 1B) also significantly
increased between each time point, with the exception at day 31 that
did not differ from day 24. The rate of increase was highest in the
preweaning period (17–24 days), with a doubling of pancreatic weight
between 17 and 20 days. Between 2 and 17 days, linear regressions of
the values of body weight (y = 7.448x + 4.407) and pancreatic
weight (y = 2.263x + 2.557) show marked differences in slopes.
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). However, ß cell growth was not linear. In fact,
ß cell mass remained stable from 2–20 days of age; only at 24 and 31
days had the ß cell mass significantly increased. The non-ß cell
mass also remained stable from 2–20 days (2 day: 0.28 ± 0.08 mg;
20 day: 0.58 ± 0.12 mg) with significant increase only at 24 and
31 days (24 day: 0.82 ± 0.06 mg; 31 day: 0.83 ± 0.07,
P < 0.005 as compared with 2 day).
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). During the period of flat
growth of ß cell mass (between 2 and 20 days), the ß cell
replication rate are substantial compared with our previously reported
0.22 ± 0.06%/6 h in adult female (17) and 0.38 ± 0.05/6 h
in adult male rats (18). Moreover, neogenesis of islets is occurring:
BrdU positive cells were found in the small ducts and budding of islets
from these ducts was seen at 13 days and later (data not shown). The
frequency of non-ß cell replication was too low for
quantification.
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). A multivariate analysis of the distribution of cells
by size (Fig. 5) shows a loss of the larger cells
(area> 80.2 µm2) at 17 days as compared with all the
other ages (chi square test P < 0.02). Such a change
in distribution was only evident at day 17.
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ß cell death
With propidium iodide and islet cell immunostaining, apoptotic ß
cells could be identified (Fig. 6); their condensed or
fragmented nuclei are readily discriminated from mitotic ß cells. At
all the neonatal ages examined the percentage of apoptotic ß cells
(Fig. 7) was high (1.51 ± 0.21% at day 2) as
compared with levels found in 3-month-old adult rats (0.37 ±
0.06%). At both 13 (3.5 ± 0.42%) and 17 days of age (3.08
± 0.12%) the percentage of apoptotic ß cells was significantly
increased compared with that of 2-day-old rats. Throughout the neonatal
period both exocrine and duct cells with fragmented or condensed nuclei
were also observed but these were not quantified.
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). The calculated net cell death is the difference
between the rate of change of the number of ß cells and the rate of
replication. Because neogenesis cannot be measured in cell number, net
cell death actually equals total cell death minus the new cells formed
through neogenesis or other processes that are not accounted for by
BrdU incorporation.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Kuang also predicted an increased occurrence of cell loss over this
time, but in the absence of morphological evidence of cell death, she
suggested that transdifferentiation occurred (13). In this latter
process, ß and cells would differentiate into other islet cells
and thus leave their respective mass compartments. Such an occurrence
would be consistent with the concept of islet endocrine cells passing
through a stage of expressing more than one islet hormone before final
differentiation into a specific islet cell type (20, 21, 22). While we have
no data addressing a loss of coexpression of islet hormones, Bouwens
et al. (8) could not find neonatal rat islet cells
differentiating from non-ß to ß cells. Our findings of the presence
of apoptotic ß cells by both light (immunostaining) and electron
microscopy (specific granule morphology) support the actual cell death
of ß cells.
The mass of ß cells is dependent on the number of cells and their mean cell size. A significant decrease in ß cell size was found at 17 days of age, but this decrease in cell size at only one time point hardly explains the flat curve of ß cell mass. The multivariate analysis of the distribution of ß cell population by size showed a significant difference when ß cells from 17 day old pancreas were compared with the other groups. There was a specific loss of the larger cells (>80.2 µm2) and an increase in the smaller ones (<49.5 µm2). The reason of this change remains unclear. One of the features of apoptosis is condensation of the cell and thus a reduction in its size. However, only those ß cells with normal nuclei were measured on electron micrographs, and therefore the reduction of cell size cannot be due to the larger number of apoptotic ß cells. Another possibility for this shift in the distribution curve is that replicating cells and/or newly differentiated cells are smaller. ß cell replication was, however, similarly high at all the ages examined with a trend to decrease with time, so it seems impossible that replicating cells could contribute to changes in cell size population at only one time point. It is not known whether ß cells newly differentiated from duct epithelium are smaller since no markers have been identified yet that could follow these cells. Unfortunately. the potential markers cytokeratin 19 and 20 are quickly lost in newly formed ß cells (8). Further investigations are needed to elucidate the relevance and relationship of this change in ß cell size to the development and metabolic function of the endocrine pancreas.
The contribution of replication and apoptosis to the overall stability of the ß cell mass can be estimated with our mathematical model (11). During the early phase (2–9 days), the number of cells dying is equal to about half of the number formed by replication. So only a slight increase in cell number will occur without the mass being significantly increased. During the middle phase (13–17 days), equal numbers of cells are dying as result from replication, so the number/mass does not increase at all. One should remember that we did observe neogenesis from 13 days onwards. The growth of mass begins to be significant by 24 days with a tripling of the number. Initially, this growth is due to increased neogenesis (so net cell death is now negative), but by 31 days is due to an increase in replication, very low cell death and possibly continued neogenesis.
The lack of increase in ß cell number in face of both replication and differentiation potentially allows a selective deletion of some ß cells. Even though there is considerable evidence of functional heterogeneity of adult ß cells (23), nothing is known about the relation of this heterogeneity and the age of the ß cells. We do know that the maturation of the insulin response to glucose is seen in the postnatal period, but this occurs earlier, being between days 5 and 8 after birth (24). Recent data on apoptotic regulatory proteins have shown that bcl-2 is found in fetal islets but is no longer detected after birth (25), even though bcl-xL, bax, and bag-1 are expressed in adult islets (26). Perhaps there is a heterogeneity of expression of these proteins within ß cells that allows a differential response to apoptotic stimuli. At present the basis of the selective deletion in the endocrine pancreas is unknown.
In addition, the process of cell death can be influenced by the cell’s environment; for example, changes in hormones or growth factors can stimulate apoptosis. The large scale cell death in neonatal kidney was reduced by injections of epidermal growth factor (5), suggesting that limited amounts of survival factors trigger the loss of some cells. In the neonatal rat pancreas, there are marked changes in the message RNA levels of both IGF-I and IGF-II as well as transient appearances of IGFBP 1 and 2 between 14 and 21 days (27). Further studies are needed to examine if the IGFs serve as survival factors for the ß cells.
There may be important implications of cell deletion within the endocrine pancreas. One can speculate that a defective clearing of the apoptotic bodies in face of the substantial deletion of ß cells could lead to a presentation of ß cell antigens that could result in autoimmunity.
The present data show that the endocrine pancreas during the neonatal period is subject to substantial remodeling of the ß cell population and that apoptosis plays an important role in the final ß cell mass. A dysregulation of this process could be of great importance during this period of time when a fine balance between cell replication and cell death determines the development of the pancreatic ß cell mass.
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Acknowledgments |
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Footnotes |
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2 Recipient of Juvenile Diabetes Foundation Fellowship 393369.
3 Scholar of the Alberta Heritage Foundation for Medical Research, a
Scientist of the Medical Research Council of Canada and is supported by
an operating grant from the MRC (MT-10574).
Received August 15, 1996.
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L. Farilla, H. Hui, C. Bertolotto, E. Kang, A. Bulotta, U. Di Mario, and R. Perfetti Glucagon-Like Peptide-1 Promotes Islet Cell Growth and Inhibits Apoptosis in Zucker Diabetic Rats Endocrinology, November 1, 2002; 143(11): 4397 - 4408. [Abstract] [Full Text] [PDF]
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M. Lipsett and D. T. Finegood {beta}-Cell Neogenesis During Prolonged Hyperglycemia in Rats Diabetes, June 1, 2002; 51(6): 1834 - 1841. [Abstract] [Full Text] [PDF]
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J. Boloker, S. J. Gertz, and R. A. Simmons Gestational Diabetes Leads to the Development of Diabetes in Adulthood in the Rat Diabetes, May 1, 2002; 51(5): 1499 - 1506. [Abstract] [Full Text] [PDF]
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I. Rooman, J. Lardon, and L. Bouwens Gastrin Stimulates {beta}-Cell Neogenesis and Increases Islet Mass From Transdifferentiated but Not From Normal Exocrine Pancreas Tissue Diabetes, March 1, 2002; 51(3): 686 - 690. [Abstract] [Full Text] [PDF]
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I. Berkovich and S. Efrat Inducible and Reversible {beta}-Cell Autoimmunity and Hyperplasia in Transgenic Mice Expressing a Conditional Oncogene Diabetes, October 1, 2001; 50(10): 2260 - 2267. [Abstract] [Full Text]
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M. Skau, B. Pakkenberg, K. Buschard, and T. Bock Linear Correlation Between the Total Islet Mass and the Volume-Weighted Mean Islet Volume Diabetes, August 1, 2001; 50(8): 1763 - 1770. [Abstract] [Full Text] [PDF]
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C. Tourrel, D. Bailbe, M.-J. Meile, M. Kergoat, and B. Portha Glucagon-Like Peptide-1 and Exendin-4 Stimulate {beta}-Cell Neogenesis in Streptozotocin-Treated Newborn Rats Resulting in Persistently Improved Glucose Homeostasis at Adult Age Diabetes, July 1, 2001; 50(7): 1562 - 1570. [Abstract] [Full Text] [PDF]
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M. Federici, M. Hribal, L. Perego, M. Ranalli, Z. Caradonna, C. Perego, L. Usellini, R. Nano, P. Bonini, F. Bertuzzi, et al. High Glucose Causes Apoptosis in Cultured Human Pancreatic Islets of Langerhans: A Potential Role for Regulation of Specific Bcl Family Genes Toward an Apoptotic Cell Death Program Diabetes, June 1, 2001; 50(6): 1290 - 1301. [Abstract] [Full Text]
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N. Trivedi, J. Hollister-Lock, M. D. Lopez-Avalos, J. J. O’Neil, M. Keegan, S. Bonner-Weir, and G. C. Weir Increase in {beta}-Cell Mass in Transplanted Porcine Neonatal Pancreatic Cell Clusters Is Due to Proliferation of {beta}-Cells and Differentiation of Duct Cells Endocrinology, May 1, 2001; 142(5): 2115 - 2122. [Abstract] [Full Text]
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 A. GAROFANO, P. CZERNICHOW, and B. BRÉANT Impaired {beta}-cell regeneration in perinatally malnourished rats: a study with STZ FASEB J, December 1, 2000; 14(15): 2611 - 2617. [Abstract] [Full Text]
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S. Bonner-Weir Perspective: Postnatal Pancreatic {beta} Cell Growth Endocrinology, June 1, 2000; 141(6): 1926 - 1929. [Full Text] [PDF]
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D. J. Hill, B. Strutt, E. Arany, S. Zaina, S. Coukell, and C. F. Graham Increased and Persistent Circulating Insulin-Like Growth Factor II in Neonatal Transgenic Mice Suppresses Developmental Apoptosis in the Pancreatic Islets Endocrinology, March 1, 2000; 141(3): 1151 - 1157. [Abstract] [Full Text] [PDF]
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L. Wen, F. S. Wong, J. Tang, N.-Y. Chen, M. Altieri, C. David, R. Flavell, and R. Sherwin In Vivo Evidence for the Contribution of Human Histocompatibility Leukocyte Antigen (HLA)-DQ Molecules to the Development of Diabetes J. Exp. Med., January 3, 2000; 191(1): 97 - 104. [Abstract] [Full Text] [PDF]
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J. Petrik, B. Reusens, E. Arany, C. Remacle, C. Coelho, J. J. Hoet, and D. J. Hill A Low Protein Diet Alters the Balance of Islet Cell Replication and Apoptosis in the Fetal and Neonatal Rat and Is Associated with a Reduced Pancreatic Expression of Insulin-Like Growth Factor-II Endocrinology, October 1, 1999; 140(10): 4861 - 4873. [Abstract] [Full Text]
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J. Petrik, J. M. Pell, E. Arany, T. J. McDonald, W. L. Dean, W. Reik, and D. J. Hill Overexpression of Insulin-Like Growth Factor-II in Transgenic Mice Is Associated with Pancreatic Islet Cell Hyperplasia Endocrinology, May 1, 1999; 140(5): 2353 - 2363. [Abstract] [Full Text]
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J. Petrik, E. Arany, T. J. McDonald, and D. J. Hill Apoptosis in the Pancreatic Islet Cells of the Neonatal Rat Is Associated with a Reduced Expression of Insulin-Like Growth Factor II that May Act as a Survival Factor Endocrinology, June 1, 1998; 139(6): 2994 - 3004. [Abstract] [Full Text] [PDF]
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 H. Mutoh, F. J. Naya, M.-J. Tsai, and A. B. Leiter The basic helix-loop-helix protein BETA2 interacts with p300 to coordinate differentiation of secretin-expressing enteroendocrine cells Genes & Dev., March 15, 1998; 12(6): 820 - 830. [Abstract] [Full Text]
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