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Cedars-Sinai Medical Center (R.P.), Division of Endocrinology, Los Angeles, California 90048; and Diabetes Section (J.Z., M.E.D., J.M.E.), Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224
Address all correspondence and requests for reprints to: J. M. Egan, M.D., Gerontology Research Center, National Institute on Aging, National Institutes of Health, Box 23, 5600 Nathan Shock Drive, Baltimore, Maryland 21224. E-mail: eganj{at}vax.grc.nia.nih.gov
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Abstract |
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 Top Abstract IntroductionMethods and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMethods and MethodsResultsDiscussionReferences |
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GLP-1 is a potent insulinotropic hormone (3), which binds to a specific cell surface receptor belonging to the secretin/glucagon superfamily of receptors coupled to heterotrimeric G proteins. The subsequent activation of adenylyl cyclase is believed to mediate the plethora of intracellular effects observed with GLP-1 treatment. The insulinotropic action of GLP-1 is preserved in patients with diabetes, even several years after diagnosis (4). This is similar to the situation in Wistar rats, which are glucose intolerant from 13 months of age. Also consistent with our animal model, when administered by sc injection for 48 h to subjects with type 2 diabetes whose fasting blood glucose was poorly controlled on diet and sulfonylurea therapy, GLP-1 lowered the fasting and postprandial glucose levels (5).
Recently, we demonstrated, in an insulinoma cell line, that GLP-1 enhanced the expression of the transcription factor pancreatic-duodenum homeobox-1 (PDX-1, variously known as IDX-1, STF-1, or IPF-1) (6). PDX-1 expression is essential for pancreogenesis, as demonstrated by the mouse homozygous knockout model and the recent human pdx-1 inactivating mutation, both of which exhibit pancreatic agenesis (7, 8). In the adult pancreas, PDX-1 regulates genes associated with pancreatic cell differentiation and maturation. These include the insulin, glucokinase, GLUT2, and amyloid precursor protein genes (9).
In this present report, we expanded on our previous research on Wistar rats by more fully characterizing the mechanism of actions of GLP-1, because GLP-1 and/or its agonists (10) may become accepted treatments for diabetes in humans. An up-regulation of PDX-1 could explain the effects we saw on insulin and GLUT2 gene expression, as well as the increase in intraislet insulin levels. Furthermore, if GLP-1 were recruiting new cells from precursor and/or differentiated ß-cells within the islets this would greatly increase the pool of existing insulin secreting cells and perhaps explain some of the long-term effects observed after exposure to GLP-1 (i.e. increase in intraislet insulin content). We considered that cell proliferation and the subsequent induction of insulin gene transcription would result from increased expression of homeobox protein(s) that regulates both islet cell mass and function. For both of these reasons, we investigated the effects of GLP-1-induced PDX-1 expression and new endocrine cell formation in our aging glucose-intolerant animals.
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Methods and Methods |
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TopAbstractIntroductionMethods and MethodsResultsDiscussionReferences |
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Animals
Twenty-two-month- and 6-month-old Wistar rats from the colony at
the National Institute on Aging, Gerontology Research Center
(Baltimore, MD) were implanted with Alzet microosmotic pumps
(Alza Corp., Palo Alto, CA) in the interscapular region
for 2 (for analysis of pdx-1 and insulin genes) or 5 days
(for the ip glucose tolerance test, immunocytochemistry, and protein
levels). A half-inch nick was made in the skin after the hair had been
shaved. A pocket was then made sc, into which the pump was slid. The
skin was closed with wound clips (Clay Adams Brand 9 mm, Sparks, MD).
In the treated group, GLP-1 was delivered at the rate of
1.5 pM/kg·min. This gives a plasma level of
GLP-1 of 125 ± 41 pM (normal
fasting levels are less than 10 pM)
(2). Ex, a competitive antagonist of GLP-1,
was infused at the rate of 15 pM/kg·min in the
relevant experiments. To prevent the insulintropic action of
GLP-1, a 10-fold higher concentration of Ex is required
(11).Three additional control groups were infused with
either normal saline, Ex (15 pM/kg·min), or the
noninsulinotropic GLP(1–36) (1.5 pM/kg·min).
All animals were fasted from 2300 h on the night before each
experiment.
Glucose tolerance testing
This was completed as outlined previously by us
(2). The pumps were removed 2 h before testing.
Pancreatic insulin content
Pancreata were rapidly excised and placed individually in 10 vol
of ice-cold 75% ethanol containing 1 M acetic acid and 0.1
M HCl. The tissue was homogenized with a
Brinkmann/KINEMATICA, Polytron PT3100
(Westbury, NY) using a setting of 7 for 15 sec x 3. Insulin
content was subsequently determined as before (1). An
aliquot of the above homogenate was centrifuged at 2,000 x
g for 5 min. The pellet and supernatant were lyophilized and
resolubilized in formic acid. The protein content was determined by the
Bradford method, and the amount of protein measured in both supernatant
and pellet were combined and used as the corrective factor for
determination of insulin levels (1).
Isolation of islets
Islets of Langerhans were isolated as described previously
(1, 2). Briefly, the whole pancreas was perfused with HBSS
containing 1.1% collagenase V, dissected into pieces of approximately
1 mm, and further digested with 0.75% collagenase V for 25 min. Islets
were hand-picked and used for Western blot analysis of PDX-1 and for
Northern blot analysis.
RNA extraction and Northern blot analysis
Northern blot analysis of total RNA extracted from isolated
islets and whole pancreata was performed as previously described
(1). RNA was transferred to nylon membranes, hybridized
with 32P-labeled insulin (a gift from Dr. S.
J. Giddings, Washington University, St. Louis, MO), PDX-1 (a gift from
Dr. C. V. E. Wright, Vanderbilt University Medical School,
Nashville, TN), or ß-actin complementary DNA probes. Membranes were
hybridized and washed as described previously (1).
Messenger RNA levels were quantified by densitometric analysis by
ImageQuant (Molecular Dynamics, Inc., Sunnyvale, CA) and
normalized for ß-actin.
Protein extraction for Western blotting from whole pancreas and
islets
Whole-cell protein extract was performed according to a
modification of the method of Schreiber et al.
(12). Fasted rats were killed; pancreata were removed and
weighed. The following process was performed at 4 C; all
solutions, tubes, and centrifuges were chilled to 4 C.
Phenylmethylsulfonyl fluoride (PMSF) and dithiothreitol (DTT) were
added to the buffers just before use. Minced tissue was brought to a
final vol of 30 ml with homogenization buffer containing 20
mM HEPES (pH 7.6), 25 mM
KCL, 0.15 mM spermine, 0.5
mM spermidine, 1 mM EDTA, 1
mM
Na3VO4, and 10% glycerol
and was homogenized using a motor-driven Teflon-glass homogenizer until
more than 90% of the cells were lysed. The homogenized tissue solution
was centrifuged at 1,500 x g (3,000 rpm) for 5 min and
washed with 10 ml cold PBS containing 1 mM
Na3VO4, 1
mM DTT, 0.5 mM PMSF,10
µg/ml aprotinin, and 20 µg/ml leupeptin, at 1500 x g
for 5 min. The pellet was resuspended in 100 µl of a cold hypertonic
buffer supplemented with 20 mM HEPES (pH7.9), 20
mM NaF, 1 mM
Na3VO4, 1
mM
Na4P2O7,
0.125 µM okadaic acid, 1
mM EDTA, 1 mM EGTA, 1
mM DTT, 0.5 mM PMSF, 1
µg/ml leupeptin, 1 µg/ml aprotinin, 0.42 M
NaCl, 20% glycerol, and 0.1%Triton X-100. The samples were
snap-frozen on dry ice and later thawed on wet ice for analysis. The
tubes were vigorously vortexed for 10 sec and rocked at 40 C for 30
min, to destroy any remaining whole cells, and centrifuged at 16,000
x g (14,000 rpm) for 20 min. Then the supernatant was
removed. Aliquots of the supernatant were used to quantify protein
content by the Bradford method. Protein (20 µg) was separated on SDS
4–12%-polyacrylamide gel, transferred to polyvinylidene difluoride
membrane, and probed with the anti-PDX-1 antibody (1:5000; a gift from
Dr. Joel Habener, Massachusetts General Hospital, Boston, MA). Blots
were developed using horseradish peroxidase-conjugated secondary
antibodies and the enhanced chemiluminescence detection system.
Islets from 22-month-old animals, treated with or without GLP-1 (six animals per condition), were washed with 1 ml cold PBS containing 1 mM Na3VO4, 1 mM DTT, 0.5 mM PMSF,10 µg/ml aprotinin ,and 20 µg/ml leupeptin, at 1500 x g (3000 rpm) for 5 min. The rest of the procedure is as outlined above. Autoradiographs were quantified using ImageQuant software (version 3.3) on a Molecular Dynamics, Inc. laser densitometer.
Immunohistochemistry
Pancreata were fixed in Bouin’s fixative and embedded in
paraffin. Five-micron sections were analyzed by an immunohistochemical
method with insulin (Linco Research, Inc., St. Charles,
MO) and proliferative cell nuclear antigen (PCNA) antisera (Roche Molecular Biochemicals, Indianapolis, IN), stained with
3,3'-diaminobenzidine, and costained with hematoxylin and eosin
(13).
ß-cell mass and counting of PCNA-positive cells
ß-cell mass was determined by point counting in the manner of
Pick et al. (14) at a final magnification of
x420. Measurements were performed on an Optiphot-2 microscope
(Nikon, Melville, NY) and the images were collected on a
Sony CCD camera (Dage MTI, Michigan City, IN) and projected to a Sony
color monitor with a 96-point transparent (Arkright transparency film,
Johnson, RI) overlay used for point counting. The number of points over
ß-cells was counted, ß-cells being those staining with the insulin
antiserum. Approximately 200 fields per pancreas were acquired. The
percentage of PCNA-positive cells (cells with brown nuclei) was
determined by systematically scanning each slide at a final
magnification of x400. Every cell on a slide was also counted. The
number of positive nuclei was expressed as a percentage of the total
number scanned.
Statistical analysis
The data are expressed as mean ± SEM. Data
were analyzed using the nonpaired Student’s t test;
P < 0.05 was judged significant.
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Results |
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TopAbstractIntroductionMethods and MethodsResultsDiscussionReferences |
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).
This was associated with a significant increase in total pancreatic
weight (P < 0.02) and insulin content
(P < 0.001) (Table 1).
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); levels were 50% lower in the older
rats, relative to young untreated controls. Treatment with
GLP-1 over 48 h resulted in a statistically
significant (P < 0.05) increase in pdx-1
and insulin mRNA levels in both age groups. Despite the lower basal
levels seen in the older rats, the increase in mRNA for both insulin
and pdx-1 after treatment was comparable to that seen in the
young rats.
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, compared with Fig. 2a, where saline
alone was given). Concomitant administration of Ex with
GLP-1 specifically inhibited the induction of
pdx-1 (Fig. 2c) in the whole pancreas. pdx-1 was
down-regulated by the infusion of Ex (Fig. 2d) and inactive GLP(1–36)
(Fig. 2e) alone (P < 0.05). A longer
GLP-1 infusion (5 days) led to a further increase in
pdx-1 expression (Fig. 2f), suggesting no down-regulation of
the biological actions of GLP-1 occurred within this time
frame. pdx-1 expression in the adult rodent is confined to
mature terminally differentiated insulin- and somatostatin-producing
cells (15).
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, a and b represents
PDX-1 protein from two control pancreata, one young (a) and one old
(b). The protein levels were 32% lower in the old animals, compared
with young (P < 0.05, n = 4).
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) and 6 old
treated (Fig 3f) animals showed a 6-fold increase in PDX-1 levels with
treatment. The amount of PDX-1 per 20 µg of total protein was 2-fold
greater in extracts from islets than in those from the whole
pancreas.
GLP-1 induces cell proliferation in the pancreas
Pancreatic sections from the rats infused for 48 h with
GLP-1 were immunostained for PCNA. PCNA is identical to
cyclin and to the auxiliary protein of DNA polymerase-
and is
marker of proliferative activity. Numerous positive nuclei were
observed in the ductal epithelium wall as well as in acinar tissue,
suggesting that those cells were induced to multiply by progressing
from the early to the late G1 phase of the cell cycle (Fig. 4). Very few PCNA-positive nuclei were
observed within the islets of Langerhans. Although the labeling index
of all three pancreatic components (ductal, acinar, and endocrine)
increased, the relative number of ductal cells induced toward cell
mitosis was higher than the other pancreatic cell types. Small- to
medium-size pancreatic ducts exhibited up to 80% positivity for PCNA.
Investigation of staining in the smaller ducts revealed PCNA positivity
in the entire ductal epithelium wall, and the presence of mitotic
figures was noted. Large pancreatic ducts were also responsive to the
GLP-1-dependent proliferative stimulus: an average of 4–6
cells in large ducts were PCNA-positive (Fig. 4d). Numerous
PCNA-positive nuclei were also detected within acinar tissue. PCNA was
positive in 16.6 ± 3.1% acinar cells from
GLP-1-treated animals vs. 6.2 ± 1.3%
acinar cells from control animals(P < 0.01). Although
isolated PCNA-positive acinar cells were present in all sections
analyzed, more frequently these were present in aggregates of a few
cells. They were commonly, but not exclusively, localized in close
proximity to small- to medium-size ducts. In some cases a bridge of
extracellular matrix and a few sparse fibroblast-like cells physically
connected PCNA-positive cell aggregates with a nearby pancreatic duct.
Finally, the occasional PCNA-stained cell was observed in the main
ducts and in scattered cells within connective tissue. The extent of
PCNA staining had decreased after 3 days and was no longer present by
the fifth day of treatment.
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).
In contrast, sections from GLP-1-treated animals exhibit
insulin staining in small clusters and ducts as well as in the mature
islets (Fig. 5, b–e). These insulin-positive cell clusters were
obvious by 5 days (Fig. 5, b and c), but occasional insulin-positive
cells could be seen in ducts as early as 3 days. Within the exocrine
parenchyma, a few cell aggregates containing insulin also
appear. The number of insulin-positive cells present in the epithelial
wall of pancreatic ducts was inversely related to the diameter of the
duct itself. In the very small ducts, such as in Fig. 5e, most of the
cells were insulin-positive. Insulin-positive one- or two-cell pairs
were also seen in large-sized ducts (Fig. 5, b and d). Very frequently
in the treated animals, individual or paired insulin-positive cells
were seen in the acinar regions (Fig. 5, b and c). The mass of the
ß-cells was also significantly increased by GLP-1
infusion (7.2 ± 0.58 vs. 4.88 ± 0.38 mg, treated
vs. control, respectively, P = 0.02).
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Discussion |
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TopAbstractIntroductionMethods and MethodsResultsDiscussionReferences |
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PDX-1 is important for pancreatic development because pdx-1 nullizygosity results in failure of the pancreas to develop in both mice and a human (7, 8). There is recent evidence of an association between missense mutations of pdx-1 and type 2 diabetes (18, 19). It is known that ß-cell function continues to deteriorate with age in this condition (20). Although it has not been investigated, it may be that ß-cell mass and PDX-1 expression are reduced in type 2 diabetes, analogous to what is seen here in the glucose-intolerant aging rat. It is feasible that chronic GLP-1 treatment may retard, or even prevent, this deterioration of the ß-cell.
PDX-1 serves a second function in adult life as it regulates genes that are specific to the ß-cell. Specifically, it transactivates the promoter regions of the insulin, glucokinase, GLUT2, and amyloid precursor protein genes (9, 21). We have previously demonstrated that GLP-1 infusion, in vivo, increases not only insulin gene expression but also glucokinase and GLUT2 expression in young and old animals. These facts, together with the data here, allow us to form an outline of the pathway whereby GLP-1 causes an up-regulation of insulin mRNA and protein. GLP-1 up-regulates PDX-1 expression, which in turn, up-regulates insulin, GLUT2, and glucokinase genes. The macroscopic manifestation of these events is seen in the improved glucose tolerance. The evidence suggests this effect is directly mediated through the GLP-1 receptor, because there is no increase in PDX-1 or insulin expression when GLP-1 is infused in the presence of the antagonist Ex (present data and 2). Treatment with the inactive insulinotropic form of GLP-1, GLP-1(1–36), did not replicate the effects of GLP-1. There is a decrease in mRNA levels of PDX-1, relative to saline-treated controls, when both Ex and GLP-1(1–36) were administered in isolation. Possible explanations are that Ex is inhibiting the action of endogenous GLP-1 and that the inactive GLP-1(1–36) is abrogating the synthesis of GLP-1.
GLP-1 caused an increase in the proliferative capacity of acinar and duct cells. Our hypothesis is that pdx-1 expression is subsequently induced with consequent differentiation of some of these proliferating cells to endocrine cells. This is substantiated by the finding that PDX-1 protein is increased not only in islets but in the whole pancreas (this paper and 22). If PDX-1 were increased in islets alone (and because islets compose only 0.5–1% of the total pancreatic mass), we would be unlikely to appreciate the increase in protein extracted from the whole pancreas as analyzed by Western blot. On the other hand, the expression of PDX-1 in nonislet cells is unlikely to be, per se, sufficient to cause differentiation of all PDX-1-positive cells into endocrine cells. Other differentiation factors are known to be necessary for the full differentiation of the endocrine pancreas (9). The presence of other differentiation factors and/or perhaps specific topography within the pancreatic parenchyma (i.e. proximity with ductal structures and/or mature islets) may allow some PDX-1-positive cells to progress toward a fully differentiated ß-cell phenotype This may explain the discrepancy reported in the present study between GLP-1-dependent increase in PDX-1 and insulin transcripts. PDX-1 is necessary for the process that leads to the differentiation into ß-cell, whereas insulin testifies that the process has reached full completion.
The capacity of GLP-1 treatment to induce PDX-1 and ß-cell neogenesis in old animals is of importance in the context of type 2 diabetes. In this report and our previous one (2), the improvement in glucose tolerance can, at least in part, be ascribed to an increase in ß-cell mass. At the point we carried out the glucose tolerance testing, the source of exogenous GLP-1 was removed 2 h previously; thus, GLP-1 levels in plasma were below the detection limit (2). Improved glucose tolerance cannot, therefore, be ascribed to a direct incretin effect. As type 2 diabetes occurs in the older age group, this is the population that is likely to receive a GLP-1 type compound in the future. Our data, therefore, are pertinent to the clinical application of GLP-1.
Received March 20, 2000.
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