1 Elliot P. Joslin Research Laboratories, Joslin Diabetes Center, and the Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215; and 2 Diabetes Research Laboratory, School of Kinesiology, Simon Fraser University, Burnaby, British Columbia, Canada V5A 1S6
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ABSTRACT |
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The effects of residual -cell mass and
glycemia on regeneration of endocrine pancreas after 90%
pancreatectomy were investigated. Streptozotocin or buffer alone was
injected into 4-wk-old male Lewis rats
(day
0). On
day
7, varying numbers of syngeneic islets were transplanted under the kidney capsule to achieve varying degrees
of glucose normalization. On day
14, a 90% pancreatectomy or sham
pancreatectomy was performed. On day
19, rats were killed and the pancreas
was fixed for quantitative morphometric determination of
-cell mass.
Focal areas of regenerating pancreas were observed in all animals that
underwent partial pancreatectomy. The percentage of remnant pancreas
classified as foci was unaffected by streptozotocin treatment or by
plasma glucose. Moderate to severe hyperglycemia did not promote
regeneration of the pancreatic
-cell mass; rather the total
endocrine cell mass was inversely related to the plasma glucose level
(r =
0.5,
P < 0.01). These data suggest that
the precursor population for both endocrine and exocrine tissue is not
susceptible to damage by streptozotocin and that local effects of
residual
-cell mass are not important to regeneration after a 90% pancreatectomy.
islets of Langerhans; precursor cells
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INTRODUCTION |
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SUBSTANTIAL REGENERATION of both exocrine and endocrine tissue occurs after a 90% partial pancreatectomy in the young adult rat (4, 7). Regeneration occurs through two pathways: 1) replication of preexisting differentiated exocrine and endocrine cells and 2) proliferation and differentiation of ductal epithelial cells to form new pancreatic lobules (2, 4, 7). The latter is seen as focal areas of regeneration that consist of duct-like "tubular complexes," or small ductules surrounded by loose connective tissue. Cells that immunostain for glucagon appear early in the development of these new lobules. As development progresses, cells that immunostain for insulin appear as new islets, as small aggregates of cells, and as single cells in ductules. In the final stages of regeneration, exocrine cells differentiate and form acini, the lumens of the terminal ductules decrease, and the normal morphology of a pancreatic lobe is assumed.
The origin of the tubular complexes has been a matter of
controversy. Some investigators suggest they arise from
dedifferentiation of acinar tissue (9, 10, 28), but there is also
strong evidence from our own laboratory to suggest that the ductular profiles can be the result of a regenerative process originating from
the ductal tree (2). We demonstrated that the regeneration begins with
increased proliferation of the common pancreatic duct at 24-36 h,
followed by increased proliferation of the main ducts at 36-48 h
and increased proliferation of small ducts at 48 h postpancreatectomy.
Areas of proliferating small ductules called focal areas of
regeneration have a high proliferative rate through 72 h. These data
also provide strong evidence to suggest that both the endocrine and
exocrine tissues of the focal areas arise from pluripotent precursor
cells. In support of the pluripotent precursor hypothesis are
demonstrations that -cell specific genes, such as GLUT-2 (18) and
the homeodomain transcription factor Pdx-1 (16), are expressed in
ductal epithelial cells of the developing embryo. Whether the precursor
cells of the normal adult animal have sufficient
-cell-specific
characteristics to be susceptible to the
-cell toxin streptozotocin
(STZ) has not been investigated.
Various hormones and growth factors have been shown to affect the
proliferation of the ductal epithelium and differentiation into
endocrine and exocrine cell types, including transforming growth factor
(TGF)- (1, 27), gastrin (26, 27), TGF-
(5, 21), epidermal growth
factor (1, 24), hepatocyte growth factor-scatter factor (17), and
insulin-like growth factor I (22). It is not known, however, whether
metabolic factors such as glucose play a role. Glucose is a well-known
stimulus for proliferation of preexisting
-cells (3), but its role in endocrine and/or exocrine cell neogenesis is unclear. Insulin is
also a well-known growth factor, and the mass of
-cells is thought
to have a trophic effect on the exocrine pancreas via a local islet
acinar portal circulation (19). Thus both glucose and insulin could
influence the magnitude of the regenerative response of endocrine
and/or exocrine tissue after partial pancreatectomy. The purpose of
this study was twofold: to determine if a massive depletion of
endogenous
-cells influences the regenerative response to a 90%
pancreatectomy and to determine the susceptibility of ductal precursor
cells to STZ.
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MATERIALS AND METHODS |
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Experimental animals. Male Lewis rats (Harlan Sprague Dawley, Indianapolis, IN) were used as both recipients and islet donors. Rats were housed in a temperature-controlled room with a 12:12-h light-dark cycle. All animals had continuous access to standard rat chow and water throughout the study. All procedures were approved by the institutional animal care committee.
After a few days of acclimation, rats (4 wk of age, ~100 g body wt) were randomly assigned to one of four experimental groups: 1) STZ treatment, islet transplant, and partial pancreatectomy (n = 19); 2) sham STZ, islet transplant, and partial pancreatectomy (n = 8); 3) STZ, islet transplant, and sham partial pancreatectomy (n = 5); and 4) STZ and partial pancreatectomy (n = 6). Young rats were used to facilitate the partial pancreatectomy procedure. Body weight and plasma glucose levels were recorded on days 0, 3, 7, 11, 14, 17, and 19, where day 0 is the day of the initial STZ administration.
STZ (Sigma, St. Louis, MO) was freshly dissolved in sodium citrate buffer (pH 4.5) at a concentration of 35 mg/ml. STZ was administered intraperitoneally as one (on day 0) or two (days 0 and 3) doses of 70-90 mg/kg. Citrate buffer alone was injected in controls (group 2). Animals not achieving hyperglycemia (plasma glucose >14 mM) after the first dose of STZ were administered a second dose on day 3. Plasma glucose was checked again on day 7, and only animals with a plasma glucose >14 mM were retained in the study. Plasma glucose determinations were made on tail vein blood samples with a Beckman Glucose Analyzer II.
Islets were isolated from donor rats (weighing 180-230 g) with previously described methods (14). Freshly isolated islets were transplanted under the kidney capsule of recipient rats on day 7 after the initial administration of STZ (14). To achieve different degrees of glucose normalization, variable numbers of 150-µm islet equivalents were used (group 1: 857 ± 87, range 127-1,526; group 2: 931 ± 98, range 704-1,526; group 3: 984 ± 113, range 704-1,217 islet equivalents; P = 0.72 for the difference among groups).
On day 14 after diabetes induction (7 days after the islet transplantation), rats in groups 1, 2, and 4 underwent a 90% partial pancreatectomy (4). Rats in group 3 underwent a sham partial pancreatectomy.
Immunocytochemistry. On
day
19 (5 days after the partial
pancreatectomy), the rats were killed with an overdose of amobarbital sodium and the pancreas or pancreatic remnant was excised, lightly blotted, weighed, and placed in Bouin's fixative. Paraffin sections (4-6 µm) of these tissues were immunoperoxidase stained for
non--endocrine cells with a cocktail of antibodies (anti-glucagon,
anti-somatostatin, and anti-pancreatic polypeptide antibodies; Ref. 14)
as previously described.
-Cells were identified in islets as the
endocrine cells not staining positive for glucagon, somatostatin, or
pancreatic polypeptide. Single
-cells or small clusters without
other endocrine cell types were not detected.
-cell mass was determined by point counting morphometry on these
immunoperoxidase-stained sections. Each section was counted systematically with a grid of 54 points (final magnification
×725). The numbers of points over
-cells, endocrine
non-
-cells, exocrine tissue, focal areas of regeneration (2), and
other tissue were counted.
-Cells and endocrine non-
-cells in
focal areas were counted separately from those surrounded by normal
exocrine tissue. The
-cell relative volume was calculated by
dividing the number of points over
-cells by the number of points
over the total tissue.
-Cell mass was determined by multiplying the
relative volume by the total weight of the pancreas.
Statistics. Statistics were performed with the Statistical Analysis System (version 6.10 for Windows, SAS Institute, Cary, NC). Differences among groups were determined with the general linear models procedure by one-way analysis of variance. Post hoc analysis for differences between specific groups was performed with Tukey's Studentized range test. Comparisons were deemed significant at the 0.05 level.
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RESULTS |
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Body weight. Body weights for each
group at baseline, after STZ treatment, islet transplantation, and 90%
partial pancreatectomy are given in Table
1. Body weight increased after STZ or
buffer injection, after islet transplantation, and after partial
pancreatectomy or sham operation in all four groups
(P < 0.05), except for
group 4 where there was a small but
significant weight loss after the partial pancreatectomy
(P = 0.04). Although there were small
differences in body weight among groups at the beginning of the study
and as a result of the STZ treatment
(P < 0.05), recovery after the transplant procedure resulted in no differences among groups before the
pancreatectomy.
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Plasma glucose. Before STZ administration there was no difference in fed-state plasma glucose among groups of animals (Table 1). At 1 wk after STZ treatment, plasma glucose was significantly elevated in STZ-treated rats (to 22.6 ± 0.9 mM, P = 0.0001). Unexpectedly, there was also a small but significant rise in the plasma glucose level in rats receiving only citrate buffer (group 2, P = 0.003). Transplantion of islets under the kidney capsule resulted in a significant decrease in plasma glucose levels in diabetic rats (groups 1 and 3 combined: from 23.9 ± 0.8 to 15.0 ± 1.2 mM, P = 0.0001, range of decrement: 2.1-19.2 mM). Transplantation of islets into non-STZ-treated rats had no effect on their plasma glucose level (group 2, P = 0.10). There was also no change in the glucose level in rats not receiving a transplant (group 4, P = 0.14).
The plasma glucose remained stable after partial pancreatectomy in
groups (1,
2, and
3) that received a transplant before the surgical resection of the pancreas or sham partial pancreatectomy. In group
4 (rats without a transplant), plasma
glucose levels increased as a result of the pancreatectomy
(P = 0.001). Because the group
receiving islets after STZ injection (group
1) received a large range of islet
equivalents, there was a wide range in plasma glucose concentration
after partial pancreatectomy. Fed-state glucose levels in these animals
at the time they were killed ranged from 6.8 to 26.1 mM and were
inversely correlated with the number of islet equivalents transplanted
(r = 0.49,
P = 0.03).
Exocrine and endocrine cell mass.
There were no differences in the weight of the remnant pancreas among
groups at 5 days after partial pancreatectomy (Fig.
1). The average weight of the remnants was
21% of the weight of the pancreas in the group that received the sham
pancreatectomy. As expected, there were no areas characteristic of
pancreatic regeneration in group
3 (STZ and islet transplant, but no
partial pancreatectomy). In all other groups, focal regeneration was
observed regardless of whether the animals were pretreated with STZ or
not (Fig. 1). Focal areas of regeneration comprised 0.2-27.9% of
the pancreatic mass; this percentage did not differ among groups that
underwent pancreatectomy (Fig. 1).
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Endocrine tissue, both -cells and non-
-cells, identified by
positive staining for glucagon, somatostatin, and pancreatic polypeptide was found in the focal areas of regenerating tissue in 13 of the 25 animals that received STZ (52% total;
group
1: 10 of 19;
group
4: 3 of 6) and in four of eight
animals that were not pretreated with STZ (50%). As expected, the
total mass of non-
-cell endocrine tissue was significantly greater
in the animals not subjected to a partial pancreatectomy (Fig.
2). The non-
-cell mass of the
remnant pancreas was in proportion to the weight of the remaining
pancreas (Fig. 2). The pancreatic
-cell mass was significantly
reduced by the administration of STZ, as there was a significantly
lower
-cell mass in group
1 compared with
group 2 (Fig. 2). The
-cell mass in the
animals that received STZ was in proportion to the total weight of the
tissue.
-cell mass was significantly lower in the partial
pancreatectomy groups that received STZ compared with the
non-STZ-treated group (group
2: 0.31 ± 0.09 vs.
group
1: 0.11 ± 0.02 or
group
4: 0.06 ± 0.03%, P < 0.05).
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Role of STZ treatment and hyperglycemia in
regeneration. Although focal areas of pancreatic
regeneration were found in all of the animals that underwent a partial
pancreatectomy, there were no differences among
groups
1, 2,
and 4 in the weight of the remnant
pancreas, the mass of the focal area, or the mass of the non--cell
endocrine tissue. This lack of difference was present despite a
significant difference in the
-cell mass of the remnant in those
animals that received STZ treatment (groups 1 and
4) compared with those animals that
were not pretreated with STZ (group
2). There was also no relationship
between the mass of the focal area and the degree of hyperglycemia in
animals receiving both STZ and a partial pancreatectomy (data not
shown). Similarly, the mass of endocrine tissue in the focal regions
was not related to the plasma glucose level
(P = 0.63, data not shown). There was
also no difference in the prevailing plasma glucose level between the
17 animals with positive non-
-hormone staining in focal areas of
regeneration compared with the 16 animals without non-
-hormone
staining in foci, but there was a significant difference in the mass of
the focal regions between animals with and without endocrine tissue in
the focal areas (Table 2). Although the
prevailing plasma glucose level was different in
groups
1, 2,
and 4 (Table 1), there was no
difference in the plasma glucose level between rats with positive
non-
-hormone staining in focal areas of regeneration compared with
rats without non-
-hormone staining in foci when group was considered
a factor (2-way ANOVA; P = 0.77). The difference in the mass of the focal regions between animals with and without endocrine tissue in the focal areas remained significant when group was
considered a factor (2-way ANOVA; P = 0.0002).
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The mass of endocrine tissue in the entire remnant was inversely
proportional to the post-partial pancreatectomy plasma glucose level
(Fig. 3, r = 0.50, P = 0.01). Although
groups
1 and
4 had identical pancreatectomy
procedures, group
4 had much higher plasma glucose
levels and significantly less endocrine cell mass in the remnant
pancreas than normoglycemic group
1 animals that were treated with STZ
(plasma glucose >26 mM: 0.29 ± 0.10 vs. plasma glucose <9.6 mM:
0.96 ± 0.23 mg, P < 0.05). Because of the large variation in plasma glucose levels among
the rats in group
1, there was insufficient power to
detect a difference in either
-cell or non-
-endocrine cell mass
between groups
1 and
4 (Fig. 2).
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DISCUSSION |
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The effects of a 90% partial pancreatectomy on pancreatic regeneration
have been well described (2, 4, 7). Increased proliferation is
initially seen in the common pancreatic duct, then subsequently in
smaller ducts, followed by increased proliferation in the ducts in
focal areas of the regenerating tissue. This suggests that the ductal
tree expands by proliferation from the common pancreatic duct outward,
making new lobes of the ductal tree, and that the tubular complexes,
which are characteristic of the focal areas of regeneration, arise from
ductal precursors. Also in support of the ductular origin of the
regenerating tissue is the demonstration by Bouwens et al. (6) that
cytokeratins, which are specifically expressed in ductal cells but not
acinar cells of the normal rat pancreas, are also expressed in cells in
the focal areas of regeneration after partial pancreatectomy. The
possibility that the ductal precursors are pluripotent is suggested by
the observation of cells with various endocrine and hepatocyte markers
in ducts and regenerating islets of interferon- transgenic mice (12)
and the presence of both exocrine and endocrine cells in the focal
areas of regeneration after pancreatectomy (2). Embryologically, ductal
progenitor cells are known to express various proteins that are
relatively specific to the
-cell, such as GLUT-2 (18), Pdx-1 (16),
and glutamic acid decarboxylase (12).
In this study, we demonstrate that treatment with the -cell toxin
STZ sufficient to induce diabetes does not inhibit pancreatic regeneration after a 90% partial pancreatectomy. Both endocrine and
exocrine cell types were found in focal areas of regeneration, and
there were no qualitative or quantitative differences in regeneration between animals pretreated with STZ and those that were not given STZ.
These data suggest that the precursor cell population is not
susceptible to damage by STZ. This lack of susceptibility may be due to
the fact that the cells do not express sufficient
-cell
characteristics, e.g., the expression of GLUT-2 is too low, or they
lack other essential characteristics that make the mature
-cell
particularly susceptible to toxins such as STZ or alloxan (13). Our
results are consistent with the recent reports by Movassat et al. (15)
and by Wang and colleagues (25). Wang et al. found that treatment of
newborn rats with 100 µg/g of STZ dramatically reduced the number of
-cells in islets but had little effect on the number of
-cells
found in aggregates of less than six endocrine cells. Presumably, these
small aggregates are neogenic and are derived from differentiation of a
precursor cell population. The lack of an effect of STZ on these
aggregates suggests that this may be a less differentiated, immature
-cell population or that they arose after the STZ was administered.
Our second hypothesis was that metabolic factors would affect the
regenerative response after pancreatectomy. Glucose is a well-known
stimulus for proliferation of preexisting -cells, such as during a
continuous infusion of 50% glucose in vivo (3) or exposure of isolated
islets or
-cells in vitro (8, 23). Hyperglycemia may also play a
role in stimulating
-cell replication after neonatal STZ
administration (15). After a partial pancreatectomy, marked
-cell
regeneration occurs in the presence of moderate hyperglycemia, but the
relative influence of this hyperglycemia on new
-cells arising from
ductal precursors vs. those arising from preexisting
-cells is
uncertain. In the present experiments, however, there was no
correlation between the fed plasma glucose level and the mass of the
focal areas of regeneration, which suggests that glucose has no effect
on ductal proliferation. Additionally, the plasma glucose levels in
animals with endocrine cells in foci and those without endocrine cells
in foci were not different (Table 2). These results suggest that
glucose itself is not a stimulus for either exocrine or endocrine
differentiation after pancreatic resection.
Insulin is a well-known trophic agent that acts on many cell types,
including pancreatic exocrine cells. Atrophy of the exocrine pancreas
is a characteristic of established type I diabetes mellitus, where few
-cells remain (19). Although the atrophy is thought to be due to the
disappearance of insulin, Rahier et al. (20) found no correlation
between the weight of the pancreas and the age at onset or the duration
of diabetes. We had hypothesized that pancreatic regeneration after a
90% partial pancreatectomy would be impaired by reduction of the
preexisting
-cell mass. In contrast to our expectation, a reduction
of the
-cell mass >70% by pretreatment with STZ had no effect on
regeneration of either endocrine or exocrine tissue in the remnant
pancreas. These data suggest that locally exerted trophic effects of
insulin are not important during regeneration after pancreatic
resection. However, because insulin was supplied systemically by the
islets transplanted under the kidney capsule, these data cannot exclude a trophic effect of circulating insulin.
In contrast to our observations that suggest that STZ did not affect
the precursor population is the report by Gu et al. (11). They injected
500 mg/kg (in 2 doses) of STZ into transgenic mice expressing
interferon- in their pancreatic
-cells. In this model of ongoing
islet cell regeneration, the high dose of STZ inhibited replication of
pancreatic duct cells, suggesting that the ducts are at least partially
susceptible to the deleterious effects of STZ. Whether the difference
between their observations and ours is due to the difference in animal
models, the three- to fourfold higher dose of STZ used by Gu et al., or
the prevailing glucose level is unclear. Despite the effect of STZ on
duct cell replication, Gu et al. concluded that duct cell proliferation is not enhanced by hyperglycemia and that islet regeneration is not
dependent on the existing
-cell mass. These observations in the
interferon-
transgenic mouse model are consistent with our
observations of pancreatic regeneration after a 90% pancreatectomy.
The finding that focal areas with endocrine cells in the foci are threefold larger than those without endocrine cells in the foci is probably a reflection of the dynamics of focal area development. Presumably, not all of the focal areas were initiated at exactly the same time, so taking samples at a single point in time will result in focal areas of different "ages." Both the size and the appearance of endocrine tissue probably indicate that the focal area is older or more "mature" (see Fig. 3 in Ref. 2).
In summary, our results suggest that the precursor population that
contributes to regeneration of both endocrine and exocrine tissue after
a 90% pancreatectomy is not susceptible to the -cell toxin STZ.
Locally exerted trophic effects of insulin secreted by the pancreatic
remnant are also quantitatively unimportant to pancreatic regeneration.
The effects of hyperglycemia, however, may be complex. There is no
evidence that hyperglycemia enhances the formation of new endocrine
cells from ductal precursor cells. The possibility that moderate
hyperglycemia has a trophic influence on preexisting
-cells in the
form of hypertrophy or replication has not been excluded, but severe
hyperglycemia, or something associated with it, appears to inhibit the
development of the endocrine cell mass.
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ACKNOWLEDGEMENTS |
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We wish to thank Jennifer Hollister, Petra Reitz, and Dr. Yoshiji Ogawa for technical assistance.
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FOOTNOTES |
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This work was supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases (DK-44523) and the Medical Research Council of Canada (MT-10574). D. T. Finegood is a medical scientist of the Medical Research Council of Canada.
A preliminary version of this work was published in abstract form in Diabetes 44, Suppl. 1: 247A, 1995.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: D. T. Finegood, Diabetes Research Laboratory, School of Kinesiology, Simon Fraser Univ., Burnaby, British Columbia, Canada V5A 1S6 (E-mail: finegood{at}sfu.ca).
Received 31 July 1998; accepted in final form 26 January 1999.
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