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Department of Cell Biology and Neuroanatomy, University of Minnesota Medical School, Minneapolis, Minnesota 55455
Address all correspondence and requests for reprints to: Robert L. Sorenson, Ph.D., Department of Cell Biology and Neuroanatomy, University of Minnesota Medical School, 4–144 Jackson Hall, 321 Church Street SE, Minneapolis, Minnesota 55455-0303. E-mail: soren{at}lenti.med
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Abstract |
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We found that insulin secretion measured over 24 h in culture and acute secretion measured over 1 h in response to high glucose were increased at least 2-fold by PRL treatment after 6 days in culture. Dexamethasone (DEX) treatment had a significant inhibitory effect on secretion in a dose-dependent manner at concentrations greater than 1 nM. At 100 nM, a concentration equivalent to the plasma corticosteroid level during late pregnancy, DEX inhibited secretion to below control levels. The addition of DEX (>1 nM) inhibited secretion from PRL-treated islets to levels similar to those produced by DEX treatment alone.
Bromodeoxyuridine (10 µM) staining for the final 24 h of a 6-day culture showed that PRL treatment increased cell proliferation 6-fold over the control level. DEX treatment alone (1–1000 nM) did not reduce cell division below the control level, but significantly inhibited the rate of division in PRL-treated islets.
YoYo-1, an ultrasensitive fluorescent nucleic acid stain, was added (1 µM; 8 h) to the medium after 1–3 days of culture to examine cell death. Islets examined under confocal microscopy showed that DEX treatment (100 nM) increased the number of cells with apoptotic nuclear morphologies. This was quantified by counting the number of YoYo-labeled nuclei per islet under conventional epifluorescence microscopy. The numbers of YoYo-1-positive nuclei per islet in control and PRL-treated islets were not different after 3 days of culture. However, DEX treatment increased YoYo-1 labeling 7-fold over that in controls. DEX also increased YoYo-1 labeling in PRL-treated islets 3-fold over the control level.
These data show that the increased plasma glucocorticoid levels found during the late stages of pregnancy could effectively reverse PRL-induced up-regulation of islet function by inhibiting insulin secretion and cell proliferation while increasing apoptosis.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Experiments, both in vitro and in vivo, examining the effects of homologous PL and PRL on islets indicate that hormones of lactogenic specificity induce the same changes in islets as those observed during pregnancy. These changes include 1) enhancement of glucose-stimulated insulin secretion with decreased glucose stimulation threshold (10, 11), 2) increased insulin synthesis (12), 3) increased glucose utilization and oxidation (3, 13), 4) increased glucose metabolism with elevated levels of glucokinase and glucose transporter 2 (3), and 5) increased cAMP metabolism (9). Furthermore, the changes observed in lactogen-treated islets require a similar length of time to occur as those observed in pregnancy. Based on these studies, it is apparent that lactogens (PL and/or PRL) are the key regulatory hormones for adaptation of islets to pregnancy.
Although, the up-regulatory changes that occur in islets during pregnancy are becoming increasingly well documented, there is little information about islet function during the return to nonpregnant conditions. During pregnancy in rats, up-regulation of islet function reaches peak levels on days 14–15. These levels slowly return to control levels by term (day 21) (7). Remarkably, this return to normal levels occurs in the presence of high concentrations of PL. This suggests that there are other inhibitory influences dominant in the later stages of pregnancy. Although autoregulation of lactogen receptors seems possible, it is unlikely, because prolonged stimulation of islets by lactogens in vivo and in vitro indicated that the effects of lactogenic activity on the up-regulation of islets can be maintained (10, 14). An alternative hypothesis is that a hormone that increases in concentration during the later stages of pregnancy mediates this down-regulation in the presence of elevated lactogen levels.
Measurements have shown that rat maternal plasma total and free corticosterone (CS) concentrations are increased by day 15 and continue to increase markedly until parturition (15, 16, 17). Interestingly, the increases in CS levels in maternal plasma correlate with the number of live fetuses during the final 3 days of gestation. During the final 5 days of gestation, the binding capacity of CS-binding globulin for CS remained unchanged in maternal plasma and fell dramatically in fetal plasma (15, 16). An increase in maternal plasma CS concentrations is a characteristic of the late stages of gestation.
There are many studies in the literature examining the effects of glucocorticoids on islet function. The effects are dependent upon two factors of major importance: the concentration of and length of exposure to glucocorticoid. Although many disparate results have been reported, the data are consistent in demonstrating that exposure to elevated concentrations of glucocorticoids results in an inhibition of insulin secretion (18, 19, 20). In contrast, in vitro studies examining the effects of long term exposure to near-physiological glucocorticoid concentrations demonstrate a slight stimulatory effect on secretion as well as ß-cell hyperplasia and hypertrophy (18, 21). However, exposure, either acute or chronic, to pathophysiological glucocorticoid concentrations results in a marked inhibition of insulin secretion (20, 22).
The aim of the present study was to examine whether dexamethasone (DEX) can counteract the ability of PRL to up-regulate islet function. A similar interaction has been reported in Nb2 lymphoma cells, in which PRL induces cell proliferation and DEX inhibits cell division and increases apoptosis, whereas the combination of PRL/DEX counteracts the effects of either hormone alone (23). The demonstration of a similar relationship in ß-cells would suggest that the increase in glucocorticoids in late pregnancy may have a role in the return of islet function toward the normal nonpregnant levels observed in later stages of gestation.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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For each experiment, the multiwell plates were incubated at 37 C in a humidified atmosphere of 95% air-5% CO2. The culture medium was changed every 24 h and stored at -20 C for subsequent assay. Insulin concentrations were determined by immunoassay (25) using rat insulin standards (Linco Research, Inc., St. Charles, MO).
The culture medium was supplemented with the desired hormones and test substance(s) as needed for each experiment. PRL was added as a concentrated sterile aqueous solution resulting in a final concentration of 500 ng/ml. We have previously demonstrated that this concentration of PRL is sufficient to produce the maximal effects on islet function induced by activation of the PRL receptor (7, 13, 26). The rat PRL (NIDDK rPRL B-8-SIAFP; 30 IU/mg) was obtained from the National Hormone and Pituitary Program of the NIDDK (Baltimore, MD). The concentration of CS in the serum of pregnant rats increases from 180 nM in controls to 1100 nM on day 16 of gestation, and up to 3800 nM by the end of gestation on day 21 (15, 16, 17, 18). Because DEX is approximately 30-fold more potent than CS (27), DEX (Sigma) was added as a 95% ethanol solution, resulting in a final concentration of 100 nM in most experiments. The final concentration of ethanol in the culture medium was less than 0.1%, and an equivalent amount of ethanol was added to the controls.
Determination of hormone effects on insulin secretion
The effects of the hormones on insulin secretion were examined
by measuring the insulin concentration in the culture medium from the
daily changes during the 6 days of treatment. After this treatment, the
acute response of the islets to glucose stimulation was also examined.
The islets were allowed to reach basal metabolic rates by preincubating
them for 1 h in a Krebs-Henseleit solution (KRB) containing 120
mM NaCl, 4.8 mM KCl, 2.6 mM
CaCl2, 1.18 mM
KH2PO4, 1.1 mM
MgSO4, 25 mM
NaHCO3, 10 mM HEPES, 0.1% BSA, and
2.8 mM glucose. After this preincubation, the islets were
stimulated for 1 h in KRB containing 2.8, 7.2, or 13.5
mM glucose. The insulin concentration of this medium was
measured. The islets were then washed with Hanks’ Balanced Salt
Solution (HBSS) and sonicated for 1 min in 1.0 ml RIA buffer. The
insulin concentration in these extracts was measured to determine the
total insulin content of the islets.
2-Bromo-5'-deoxyuridine (BrdU) immunocytochemistry
To estimate islet ß-cell proliferation, BrdU was added to the
culture medium to a final concentration of 10 µM for the
final 24 h of the 6-day culture period. The islets were then
washed in HBSS, fixed in 4% paraformaldehyde, and treated for 20 min
with 0.5 N HCl. Immunostaining was performed with a mouse
monoclonal anti-BrdU antibody (Caltag Laboratories, Inc.,
San Francisco, CA), and fluorescein isothiocyanate-conjugated goat
antimouse IgG (Jackson ImmunoResearch Laboratories, Inc.,
West Grove, PA) was used as a secondary antibody. To determine islet
ß-cell proliferation, the number of BrdU-labeled nuclei per islet was
counted by direct observation with conventional epifluorescence
microscopy. At least 35 islets were examined for each treatment group.
Slides were coded so that the evaluator was unaware of the treatment
groups. Details of this procedure for islet ß-cell studies have been
previously reported (14, 28).
Cytochemical staining for apoptotic nuclei
To estimate the rate of cell death in islet ß-cells, apoptotic
nuclei were identified using an ultrasensitive fluorescent nucleic acid
stain, YoYo-1 iodide (Molecular Probes, Inc., Eugene, OR).
The dye is impermeant to live cells and virtually nonfluorescent unless
intercalated into double stranded DNA. YoYo-1 (1 µM) was
added to the culture medium for the final 8 h of the culture
period. This length of time was necessary for complete staining through
the islet. Islets were then washed in HBSS and fixed in 4%
paraformaldehyde plus 0.01% glutaraldehyde. The number of YoYo-labeled
nuclei per islet was counted by direct observation with conventional
epifluorescence microscopy using standard fluorescein isothiocyanate
filters. At least 25 islets were examined for each treatment group.
Slides were coded so that the evaluator was unaware of the treatment
groups. Examination of YoYo-labeled nuclei was conducted through 3 days
of culture, after which the fluorescence in the DEX-treated islets was
too great for accurate quantitation.
To examine the morphology of necrotic nuclei stained with YoYo, islets were incubated at 43 C with 2% sodium azide for 8 h in the presence of 1 µM YoYo. Islets were then fixed, mounted on slides, and examined using laser scanning confocal microscopy. Images of immunostained islets were captured by MRC-1000 Confocal Imaging System (Bio-Rad Laboratories, Inc., Cambridge, MA) mounted on an Olympus Corp. BH-2 microscope equipped for epifluorescence (Lake Success, NY). This system allowed the three-dimensional structure of intact isolated islets to be represented without physical sectioning (29, 30).
Expression of data and statistical methods.
All results are expressed as the mean ± SEM.
Statistical differences among means were assessed with Student’s
t test for unpaired samples or ANOVA with Tukey’s test for
multiple comparisons. Each experiment was repeated more than three
times. Each treatment group within an experiment was replicated six
times.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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After 6 days of culture, insulin secretion from control islets was
1.3 ± 0.13 mU/islet·6 days. Insulin secretion from PRL-treated
islets was increased by 2.1-fold over the control level
(P = 0.005; n = 6) as reported previously (3, 13, 14, 28). DEX treatment had a significant inhibitory effect on secretion
in a dose-dependent manner at concentrations greater than 1
nM (P < 0.005; n = 6; Fig. 1
). Secretion from islets treated with
both PRL and DEX (>1 nM) was significantly lower
than that from PRL-treated islets (P < 0.004; n =
6), suggesting that DEX effectively blocks the stimulatory effect of
PRL on steady state insulin secretion.
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). Islets were then treated with a
concentration of DEX (100 nM) that is approximately
equivalent to the plasma CS concentration during pregnancy. The
inhibitory effect of 100 nM DEX on secretion was detected
after 1 day of treatment (P < 0.05; n = 6) and
continued through day 6. Similarly, secretion from islets treated with
both PRL and DEX (100 nM) was significantly lower
than that from PRL-treated islets after 1 day of culture
(P < 0.001; n = 6) and continued to be
significantly lower than that from PRL-treated islets through the 6
days of culture. These data indicate that the concentration of plasma
CS found during the late stages of pregnancy is sufficient to
effectively inhibit the stimulatory effect of PRL on insulin
secretion.
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).
Secretion was increased 2.7-, 2.8-, and 1.7-fold over the control
value, respectively (P = 0.03). As expected, secretion
from DEX-treated islets (100 nM) was
significantly lower than that from control islets in response to
glucose concentrations above 2.8 mM
(P = 0.04; n = 4). Secretion from islets treated
with PRL plus DEX at glucose concentrations above 2.8
mM was significantly lower than that from
PRL-treated islets (P < 0.01). These data show that
DEX effectively inhibits the up-regulatory effects of PRL on secretion
and indirectly suggest that DEX inhibits the up-regulatory effects of
PRL on glucose signaling or metabolism.
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In control islets, the insulin content was 0.73 ± 0.13 mU/islet (n = 4). The insulin contents in islets treated with PRL, DEX (100 nM), and the combination of PRL and DEX (100 nM) were 0.92 ± 0.09, 0.53 ± 0.11, and 0.75 ± 0.11 mU/islet (n = 4), respectively. The insulin contents in the treatment groups were not different from that in the control group. This suggests that the inhibitory effect of DEX on secretion is not a consequence of a measurable decrease in insulin content.
Effects of PRL and DEX on islet cell division
To examine the effects of PRL, DEX, and the combination of PRL and
DEX on islet cell proliferation, BrdU was added to the culture medium
to a final concentration of 10 µM during the final
24 h of the 6-day culture period. The islets were then
immunohistochemically stained for BrdU, and the number of labeled
nuclei per islet was counted (Fig. 4). In
control islets, the number of BrdU-labeled nuclei per islet was
15.4 ± 5.9 (n = 6). The number of BrdU-labeled nuclei per
islet in PRL-treated islets was 6.4-fold greater than the control value
(P = 0.01; n = 6). This corresponds to approximate
labeling indexes of less than 2% for control islets and 12% for the
PRL-treated islets, assuming that there are 800-1000 cells/islet as
previously reported (14). This large increase in islet cell division by
PRL is comparable to that observed in our previous studies (7, 14, 28, 31).
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Laser scanning confocal microscopy examination demonstrated that greater than 90% of the BrdU-labeled nuclei in PRL-treated and control rat islets were observed in ß-cells with insulin immunoreactivity (14). Therefore, the present data suggest that the inhibitory effect of DEX on cell division is involved in the return of islet ß-cell numbers and insulin secretion to normal levels.
Effects of PRL and DEX on islet cell death
Confocal microscopic examination of islet nuclei during cell
death. For the investigation of cell death, islets were stained
with YoYo, an ultrasensitive fluorescent nucleic acid stain that is
impermeant to live cells. Before this stain was used for examination of
the effects of DEX on islets, the morphology of necrotic nuclei in
intact islets stained with YoYo was investigated. Islets were incubated
at 43 C and exposed to sodium azide for 8 h in the presence of
YoYo. The islets were then fixed, mounted, and imaged using confocal
microscopy. Throughout the islet, necrotic nuclei labeled with YoYo
appeared intact with typical nuclear morphology and homogeneously
fluorescent with very low background staining (Fig. 5B).
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, C–F). Four different
morphologies were observed: 1) the condensation of chromatin into a
small sphere (Fig. 5C); 2) the margination of the condensed chromatin
toward the nuclear membrane (Fig. 5D); 3) the chromatin filling the
cellular space, suggesting the breakdown of the nuclear membrane (Fig. 5E); and 4) the chromatin exuding out of the cell, suggesting the
breakdown of the cell membrane (Fig. 5F). These morphologies were
previously described as being stages of apoptosis (32, 33, 34).
Lower magnification confocal imaging demonstrates the effect of DEX on
YoYo labeling in treated islets. The number of YoYo-labeled nuclei per
islet was very low and not noticeably different in control and
PRL-treated islets (Fig. 6, upper
left and right panels). In contrast, DEX treatment
resulted in a large number of YoYo-labeled nuclei (Fig. 6, lower
left panel). The number of labeled nuclei in the PRL- plus
DEX-treated islets was similar to that in controls (Fig. 6, lower
right panel).
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). The number of YoYo-labeled
nuclei in PRL-treated islets was not different from that in controls
throughout the 3-day culture period. As expected, labeling in
DEX-treated islets (100 nM) was significantly greater than
that in control islets. The number of labeled nuclei increased to
14.0 ± 1.0, 25.1 ± 1.0, and 49.1 ± 4.9 after 24, 48,
and 72 h of culture (P = 0.01; n = 3). YoYo
labeling in islets treated with PRL plus DEX (100
nM) was greater than that in PRL-treated and
control islets after 24, 48, and 72 h (P = 0.01;
n = 3). These data show that DEX is effective in increasing the
number of apoptotic cells in an islet, and furthermore, that DEX is
effective during PRL treatment. Moreover, these data suggest that the
increased plasma CS levels found during the late stages of pregnancy
could effectively increase the rate of cell death, which would lead to
the return of islet cell numbers to normal levels.
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). Note that labeling of islets treated
with DEX (100 nM) was significantly greater than
that of Prg-treated islets (P = 0.05). Furthermore, in
the presence of PRL, DEX increased the number of labeled nuclei per
islet above that in islets treated with PRL alone (P <
0.05), but not to the level with DEX alone (P < 0.05).
In contrast, Prg in the presence of PRL increased the number of labeled
nuclei above that with PRL treatment alone (P < 0.05)
to a level not different from that with Prg alone. Interestingly, these
data show that although Prg alone is not as effective in inducing
apoptosis as DEX, in the presence of PRL the number of YoYo-labeled
nuclei per islet is not different from that with DEX. These data
suggest that DEX and Prg together may contribute to counteract the
stimulatory effects of elevated lactogens during the latter stages of
pregnancy.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In the present study we show that DEX had an inhibitory effect on insulin secretion in a dose-dependent manner at concentrations greater than 1 nM and was effective after 1 day of treatment. The addition of DEX inhibited the up-regulatory effects of PRL on islets, returning secretion, steady state and acute, to control levels. We found that DEX had no effect on total insulin content, suggesting that the DEX-induced inhibition of secretion is not due to a decrease in insulin stores. We further show that DEX treatment strongly inhibited the PRL-induced up-regulation of cell division, returning them to control levels. In addition, DEX increased the amount of islet cell death (apoptosis) in both control and PRL-treated islets. These results demonstrate the ability of glucocorticoid (at concentrations equivalent to those in maternal plasma during late stages of pregnancy) to reverse PRL-induced up-regulated islet function by inhibiting insulin secretion and islet cell division and returning islet cell numbers to control levels. However, further studies are needed to determine whether similar results are observed with conditions that more closely resemble the temporal evolution of hormonal changes during pregnancy.
The inhibition of insulin secretion from islets by DEX alone is consistent with the findings of previous studies (19, 20, 35, 36, 37). The mechanism by which this occurs is not completely understood. This decrease in glucose-stimulated insulin secretion could not be attributed to decreases in insulin content (20, 22, 35, 37, 39). It does not appear to involve a defect in the recognition of glucose, because no changes in the rate of glucose oxidation, NADPH production, or intracellular Ca2+ concentrations have been observed (20, 35, 39). These observations are surprising considering that a decrease in the expression of the glucose transporter 2 (Glut-2) (37, 40) and the sulfonylurea receptor 1 (SUR1) component of the ATP-sensitive K+ channel of the ß-cells (41) has also been reported. Moreover, this defect is not restricted to glucose, because an impairment of insulin secretion in response to arginine, tolbutamide, or high concentrations of K+ after DEX treatment is also observed (20, 39). These inhibitory effects of DEX can be reversed by incubation with (Bu)2cAMP or phorbol ester (20, 38). This suggests that the potentiation pathways that regulate the rate of insulin secretion, for example cAMP/protein kinase A and phospholipase C/protein kinase C pathways, can compensate for the actions of DEX. This is further supported by an impairment in the activation of phospholipase C, protein kinase C, and mobilization of intracellular Ca2+ stores in response to acetylcholine after DEX treatment (20). Overall, it appears that DEX acts at a distal site by decreasing the efficacy of Ca2+ on the secretory response by interfering with the potentiation pathways (42).
In contrast, a major factor in the up-regulation of islet function by PRL appears to be an increased recognition of glucose. We have shown that the increased insulin secretion from PRL-treated islets corresponds to an elevation in glucose metabolism resulting from an increase in glucokinase activity (3). Furthermore, no changes in cAMP production or its effectiveness on the secretion of insulin granules have been observed for comparable rates of glucose metabolism in control and PRL-treated islets (9). This suggests that DEX can counteract the effects of PRL on insulin secretion because it interferes with more distal sites of the stimulus-secretory process. This implies that the increase in glucose metabolism and thereby the potentiation pathways induced by PRL is not sufficient to overcome the effects of DEX.
The concentration of Prg in the maternal plasma of the rat is important in initiation of both parturition and lactation. Although elevated during late gestation, maternal Prg levels fall to low levels before birth. In contrast, maternal corticosteroid concentrations increase late in gestation and decrease rapidly after birth (43). A previous study has shown that Prg is involved in counteracting the influence of lactogenic hormones during the later stages of pregnancy (28). Prg had a major impact on the effect of PRL on insulin secretion and islet cell division in a time-dependent manner. This study showed that up-regulation of islets progress under the influence of lactogenic stimulus, and Prg acts to counteract the effects of lactogens. During gestation, the increase in Prg peaks earlier than that in glucocorticoids, then decreases rapidly, whereas glucocorticoid levels remain high until parturition (43). It seems likely that Prg and DEX act together to return up-regulated islet function to normal levels by parturition.
Table 1 summarizes the effects of
pregnancy or PRL on the up-regulation of islet function and the effects
of DEX on the counterregulation of islet function. Pregnancy increases
insulin secretion and cell division 8- to 9-fold over the control value
by day 15. This increase returns to control levels before term (day
20). Similar to midpregnancy, PRL treatment of islets in
vitro increases insulin secretion and ß-cell proliferation 3- to
5-fold over control values. In a manner similar to late pregnancy, the
addition of DEX or Prg to PRL-treated islets in vitro causes
a decrease in insulin secretion and islet cell proliferation to control
levels. In addition, DEX or Prg can induce islet cell death in the
presence of PRL. These data, using this in vitro model of
islets during pregnancy, suggest that the combined effects of DEX and
Prg on islet function may provide an important inhibitory mechanism for
the return of islets to control levels at the end of pregnancy.
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Footnotes |
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Received August 11, 1999.
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