Regulation of glucose-dependent insulinotropic polypeptide
release by protein in the rat
M. Michael
Wolfe1,
Ka-Bing
Zhao2,
Kenneth D.
Glazier1,
Linda A.
Jarboe1, and
Chi-Chuan
Tseng1
2 Division of Gastroenterology, Beijing 301 Hospital,
Beijing 100853, People's Republic of China; and 1 Section of
Gastroenterology, Boston University School of Medicine and Boston
Medical Center, Boston, Massachusetts 02118
 |
ABSTRACT |
Glucose-dependent insulinotropic
polypeptide (GIP) release has been demonstrated predominantly after
ingestion of carbohydrate and fat. These studies were conducted to
determine the effects of protein on GIP expression in the rat. Whereas
no significant changes in duodenal mucosal GIP mRNA levels were
detected in response to peptone, the duodenal GIP concentration
increased from 8.4 ± 1.5 to 19.8 ± 3.2 ng GIP/mg protein at
120 min (P < 0.01). Plasma GIP levels also increased
from 95 ± 5.2 pg/ml to a peak of 289 ± 56.1 pg/ml at 120 min (P < 0.01). To determine whether the effects of
protein on GIP were due to stimulation of acid secretion, rats were
pretreated with 10 mg/kg omeprazole, after which mucosal and plasma GIP
concentrations were partially attenuated. To further examine the
effects of luminal acid, rats were administered intraduodenal 0.1 M HCl
for 120 min, which significantly enhanced GIP expression. These studies
indicate that nutrient protein provides a potent stimulus for GIP
expression in the rat, an effect that occurs at the posttranslational
level and may be mediated in part through the acid-stimulatory
properties of protein. The effects of acid on GIP are consistent with a
role for GIP as an enterogastrone in the rat.
gastric inhibitory polypeptide; nutrients; acid secretion; enterogastrone
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INTRODUCTION |
GLUCOSE-DEPENDENT
INSULINOTROPIC polypeptide (GIP), a 42-amino-acid regulatory
peptide, was first isolated from porcine small intestine and originally
named "gastric inhibitory polypeptide" on the basis of its ability
to inhibit acid secretion (3). Although the role of GIP as
a physiological inhibitor of acid secretion has been questioned
(16, 34), GIP has attained the status of an important
metabolic hormone by virtue of its ability to enhance insulin release
by pancreatic
-islet cells (8, 19, 20). It has thus
been suggested that the principal physiological function of GIP may be
its role in maintaining glucose homeostasis (5).
The release of GIP into circulation has been shown primarily after the
ingestion of two major nutrient stimuli, namely carbohydrate and fat
(5, 20). Although the release of GIP has been well characterized, few studies have examined the biosynthesis of this peptide. Our laboratory (27) previously cloned a rat GIP
cDNA from small intestine and demonstrated that a lipid-containing meal
stimulates duodenal GIP gene expression. We also have demonstrated that
glucose increases duodenal GIP gene expression, not only by enhancing
GIP release into the circulation but at the transcriptional level as
well (28). Studies examining GIP release after
various protein meals have yielded conflicting results. Although some investigators (7, 22) have been unable to detect a
stimulatory effect of protein on GIP release in humans, increases in
circulating GIP levels have been demonstrated in response to the
administration of individual amino acids (17, 25, 26).
Past studies in this laboratory (31), employing a
sensitive and specific RIA for measuring GIP, showed a 10-fold increase
in serum GIP concentrations 15 min after the intragastric infusion of
10% peptone in dogs. The effect of protein on GIP release in rodents
has not been examined previously.
In the present study, we have used the rat as a model to examine the
physiological regulation of GIP gene expression in the small intestine
by peptone, a protein hydrolysate. We have demonstrated that in
addition to carbohydrates and lipids, nutrient protein provides a
potent stimulus for GIP expression in the rat, an effect that occurs at
the posttranslational level and may be mediated in part through the
acid-stimulatory properties of protein.
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MATERIALS AND METHODS |
Animals and measurement of GIP by RIA.
Male Sprague-Dawley rats (250-350 g), purchased from Charles River
(Kingston, MA), were fasted overnight with access to water. After an
overnight fast, rats were anesthetized with pentobarbital sodium (60 mg/kg) and submitted to midline laparotomy. A small gastrotomy was
made, and Tygon tubing was passed through the mouth and into the
stomach; this tubing was ligated distal to the esophagogastric junction. The stomach was then perfused for 0, 60, 120, or 240 min with
solutions containing either 0.9% NaCl or peptone (protein hydrolysate,
pH 7.0) at a rate of 10 ml/h. In separate experiments, one group of
anesthetized rats was pretreated with 10 mg/kg omeprazole, a dose
previously shown to abolish acid output in the rat (11), before intragastric peptone perfusion for 120 min, and another group
was administered 0.1 M HCl by intraduodenal infusion for 120 min. The
rats were killed at various time points. The duodenum was removed and
cut longitudinally into two pieces; one half was used for RNA
extraction, as described below, and the other half was boiled in 2.0 M
acetic acid for 60 min. After boiling, the supernate was removed and
stored until assayed for GIP. The residual mucosa was then solubilized
in 1 M NaOH, and tissue protein was measured using a modification of
the method of Lowry et al. (15). Blood was obtained by
intracardiac puncture and centrifuged at 10,000 g for 10 min. Serum was separated and stored at
20°C until assayed for GIP.
GIP RIA of plasma samples and duodenal mucosal extracts was performed
using the double-antibody method, as described previously
(31).
RNA extraction.
Total RNA from small intestine was extracted using the acid-phenol
method of Chomczynski and Sacchi (6). Briefly, the tissue was homogenized in 4 M guanidinium isothiocyanate, 0.5% sarcosyl, 25 mM sodium citrate, pH 7.0, and 100 mM 2-mercaptoethanol. The homogenates were mixed with phenol, 2 M sodium acetate (pH 4.1), and
chloroform (800 µl/4.0 ml phenol) on a vortex for 30 s and iced
for 15 min. The homogenates were then centrifuged at 4°C for 15 min
at 4,350 g, and RNA in the aqueous phase was mixed with an
equal volume of chloroform. The aqueous phase was again extracted and
precipitated with an equal volume of isopropanol, after which samples
were washed with 70% ethanol and dried. RNA yields were examined by
spectrophotometric absorption at 260 and 280 nm, and total RNA was
measured by determining absorption at 260 nm (A260 of
1 = 40 µg of RNA/ml).
Northern blot hybridization analysis.
Northern blot hybridization analysis was done using stringent
conditions [at 42°C with 50% (vol/vol) formamide and 5× sodium saline citrate (SSC) (1× SSC is 0.15 M NaCl and 0.015 M sodium citrate, pH 7.0)]. Twenty micrograms of total RNA from small intestine were denatured in gel-running buffer (0.04 M MOPS, 10 mM sodium acetate, 0.5 mM EDTA, pH 7.5, 50% formamide, and 6% formaldehyde) (12). The RNA was then electrophoresed on a 1.5%
agarose-6% formaldehyde gel. The integrity of the extracted RNA was
determined by the visualization of 28S and 18S ribosomal RNA bands with
ethidium bromide staining. After electrophoresis at 10 V/cm, the RNA
was transferred from the gel to a Duralon ultraviolet filter by
capillary action, as described by the manufacturer (Stratagene).
Hybridization was then performed using a 394-bp BspM
I-Sal I fragment of the rat GIP cDNA that was radiolabeled
with [
-32P]dCTP, using the Klenow fragment of DNA
polymerase I and random oligonucleotides as primers (Promega). The
blots were prehybridized for 2 h at 42°C in 5× SSC, 10×
Denhardt's solution, 50% (vol/vol) formamide, 50 mM
NaPO4, 1% SDS (GIBCO-BRL), and 10 µg/ml herring sperm
DNA (Sigma Chemical, St. Louis, MO). The filters were then hybridized at 42°C for 16-24 h in 5× SSC, 1× Denhardt's
solution, 50% formamide, 20 mM NaPO4, 0.5% SDS, 20 µg/ml herring sperm DNA, and ~107 cpm of
probe/100-cm2 filter. After hybridization, blots were
washed once at room temperature in 1× SSC and 1% SDS for 15 min, once
at room temperature in 0.5× SSC and 0.5% SDS for 15 min, twice at
room temperature in 0.1× SSC and 0.1% SDS for 15 min, and once at
50°C in 0.1× SSC and 0.1% SDS for 30 min. Autoradiograms were
developed after exposure to X-ray film for 12-96 h at
70°C,
using a Cronex intensifying screen (DuPont). GIP mRNA and GAPDH mRNA
signals were quantified by laser densitometry and integration of the
autoradiographic images. The latter was used to correct for gel loading
(21, 28).
Statistical analysis.
Results are expressed as means ± SE of 4-6 separate
experiments. Data was analyzed using two-way ANOVA (BMDP Statistical
Software, Los Angeles, CA) for concentration and time and Student's
t-test. Significance was assigned if P
0.05.
 |
RESULTS |
Effects of peptone on GIP expression.
No significant changes in plasma or duodenal mucosal GIP levels or
duodenal GIP mRNA concentrations were detected during the intragastric
infusion of 0.9% NaCl (data not shown). Initial dose-ranging experiments examining the effects of 6%, 8%, and 10% peptone
solutions demonstrated that intragastric infusion of the 10% solution
produced the greatest and most consistent increase in plasma GIP levels compared with a control (0.9% NaCl) infusion (Fig.
1). Thus a 10% solution was the
concentration of peptone used throughout subsequent studies. The basal
plasma GIP level was 95 ± 5.2 pg/ml and increased to a maximum
concentration of 289 ± 56.1 pg/ml at 120 min (Fig.
2, P < 0.01). GIP levels
in duodenal mucosal extracts also increased in response to intragastric
peptone infusion from a basal concentration of 8.4 ± 1.5 ng
GIP/mg protein to a peak of 19.8 ± 3.2 ng GIP/mg protein at 120 min (Fig. 3, P < 0.02). In contrast, the intragastric perfusion of peptone did not
significantly alter steady-state duodenal GIP mRNA levels compared with
rats perfused with 0.9% NaCl. GIP mRNA levels (expressed as a ratio of
GIP mRNA to GAPDH mRNA) in fasting rats were 0.55 ± 0.04 and remained unchanged in peptone-fed rats throughout the entire 4-h experimental period (Fig. 4).

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Fig. 1.
Integrated plasma glucose-dependent insulinotropic
polypeptide (GIP) response to graded doses of peptone administered by
intragastric infusion. Meals were infused over a 4-h period, and plasma
GIP levels were measured at baseline and at 30, 60, 120, and 240 min.
Data are expressed as means ± SE in
ng · min · ml 1 of 4-6 experiments.
* P < 0.01 compared with control (0.9% NaCl).
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Fig. 2.
Plasma GIP concentration in rats after the intragastric
infusion of 10% peptone. Data are expressed as means ± SE in
pg/ml of 4-6 measurements at each time point.
* P < 0.01. ** P < 0.05.
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Fig. 3.
Duodenal mucosal GIP concentration in rats after the
intragastric infusion of 10% peptone. Data are expressed as means ± SE in ng GIP/mg protein of 4-6 measurements at each time point.
* P < 0.01. ** P < 0.02.
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Fig. 4.
Steady-state levels of duodenal GIP mRNA in rats after
the intragastric infusion of 10% peptone. GIP mRNA concentration is
expressed as the mean ± SE ratio of GIP mRNA to GAPDH mRNA (to
correct for gel loading). Each time point represents measurements from
4-6 rats for each group.
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Role of gastric acid in regulation of GIP expression.
To determine whether the effects of protein on GIP were due to
stimulation of gastric acid secretion, rats were pretreated with 10 mg/kg omeprazole for 120 min. After the administration of omeprazole,
peptone-stimulated duodenal mucosal and plasma GIP concentrations were
diminished. At 120 min, the duodenal mucosal GIP level decreased by
~55% in omeprazole-treated rats from 19.7 ± 3.2 to 8.9 ± 2.4 ng GIP/mg tissue protein (P < 0.02), a value not
different from the basal concentration (Fig.
5A). The plasma GIP
concentration after intragastric infusion of 10% peptone was 688 ± 142 pg/ml at 120 min, which was partially attenuated (~30% decrease) by pretreatment with omeprazole to 485 ± 120 pg/ml
(Fig. 5B). To further examine the effects of luminal acid,
anesthetized rats were administered 0.1 M HCl by intraduodenal infusion
for 120 min. In response to duodenal acidification, although only a
modest, but significant, increase in circulating GIP levels was seen
after the intraduodenal infusion of 0.1 M HCl, a marked and progressive
increase in mucosal concentrations of GIP was detected (Fig.
6). Likewise, after 120 min of 0.1 M HCl
duodenal perfusion, the ratio of duodenal mucosal GIP mRNA to GAPDH
mRNA increased by ~124%, from 1.44 ± 0.12 to 3.22 ± 0.36 (P < 0.001) (Fig. 7).

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Fig. 5.
Two-hour duodenal mucosal (A) and plasma
(B) GIP concentrations in rats given 10% peptone by
intragastric infusion in the presence or absence of pretreatment with
intraperitoneal omeprazole (10 mg/kg). Data are expressed as means ± SE in pg/ml (A) or ng GIP/mg tissue protein
(B) from 10 rats at each time point. * P < 0.02. ** P < 0.01.
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Fig. 6.
Duodenal mucosal (A) and plasma (B)
GIP concentrations in rats administered 0.1 M HCl by intraduodenal
infusion. Data are expressed as means ± SE (% of control) from 6 rats at each time point. * P < 0.05 and
** P < 0.01 compared with basal values.
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Fig. 7.
Two-hour steady-state levels of duodenal GIP mRNA in rats
administered 0.1 M HCl by intraduodenal infusion. Values are expressed
as means ± SE of the ratio of GIP mRNA to GAPDH mRNA to correct
for gel loading. Each time point represents measurements from 6 rats.
* P < 0.001 compared with basal values.
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DISCUSSION |
The release of GIP into the circulation has been demonstrated
primarily after the ingestion of two major nutrient stimuli, namely
carbohydrate and fat (5, 20). However, the release of GIP
in response to oral glucose differs in both magnitude and timing from
that which follows fat ingestion. After glucose ingestion, GIP release
is rapid, preceding insulin release, and reaches a peak in peripheral
venous blood in ~15 min, returning to basal values by 180 min
(5). In early studies, Andersen et al. (1) examined the effect of GIP on insulin release after oral glucose feeding in normal subjects using the glucose clamp technique. Andersen
et al. (1) found that the stimulation of insulin secretion by GIP released after glucose required hyperglycemia. Therefore, the
insulinotropic action of GIP requires a threshold concentration of
blood glucose, below which GIP is not insulinotropic (1, 4). After the ingestion of 100 ml of a triglyceride suspension, the peripheral blood GIP response does not reach a peak until 120-150 min and does not return to baseline by 180 min
(2). Furthermore, the amount of GIP released in response
to fat is greater than that which follows glucose ingestion
(2).
GIP release into the circulation has previously been demonstrated in
humans (7, 25, 26) and dogs (17) after the
administration of leucine and other amino acid solutions. However, GIP
release has not been reported in humans in response to various protein meals, including steak (7) and steamed cod
(22). In addition to glucose- and fat-stimulated GIP
release, we (31) previously demonstrated the release of
GIP after a protein meal in dogs. These studies showed a 10-fold
increase in serum GIP concentration 15 min after the intragastric
infusion of 10% peptone in dogs. A small, but significant, increase in
serum glucose concentrations was detected 90 min after the peptone
meal, which occurred long after circulating GIP levels had returned to
baseline. No changes in serum insulin concentration were detected
throughout the duration of the 90-min blood collection period. The
mechanisms by which amino acids and protein stimulate GIP release have
not previously been examined.
The gastric phase of acid secretion accounts for ~50% of the total
acid secretory response to a meal and occurs as a result of both
chemical and physical factors (33). In addition to antral distension, which involves both short intramural nerve fibers and
vago-vagal pathways, gastric acid secretion is stimulated by increases
in intraluminal pH and by certain substances contained in food,
principally protein, primarily via gastrin-mediated events (33). It has been shown that although intact proteins are
poor stimulants of gastrin release and gastric acid secretion, peptic hydrolysates of the same proteins and individual amino acids are potent
secretagogues (9, 13, 14). Digested protein in the duodenum also enhances acid secretion, and this duodenal phase constitutes ~5% of the total acid secretory response to a meal. To
explore the possibility that the peptone-stimulated GIP release in the
present study was due to the stimulation of gastric acid secretion,
acid output was abolished by pretreatment with omeprazole. After
treatment with omeprazole, peptone-stimulated mucosal and plasma GIP
concentrations were significantly attenuated (Fig. 5). Furthermore,
duodenal acidification produced significant stimulatory effects on
mucosal and circulating GIP concentrations (Fig. 6), consistent with
the hypothesis that GIP release was mediated principally through the
acid-stimulatory properties of hydrolyzed protein.
After a meal, the secretion of acid is modulated by a negative feedback
mechanism in which both antral and duodenal acidification inhibits the
further release of gastrin and, subsequently, acid secretion. Previous
studies (18, 23, 24, 30) have shown that somatostatin
derived from antral D cells inhibits the release of gastrin via
paracrine mechanisms and inhibits acid secretion both indirectly by its
effects on gastrin expression and by local inhibitory mechanisms in the
gastric corpus and fundus. In addition to these local factors in the
stomach, various regulatory peptides emanating from the small
intestine, including GIP, have been proposed as enterogastrones,
factors that provide additional physiological feedback inhibition of
gastric acid secretion. Using antibodies to bind endogenous GIP, we
(29) previously demonstrated the capacity of GIP to
decrease meal-stimulated gastric acid secretion in dogs, an effect that
appeared to be due to its inhibitory effects on gastrin release.
Subsequent experiments in our laboratory (12), using rat
antral mucosa in short-term culture, indicated that the inhibitory
effects of GIP on gastrin release appeared to be mediated through the
stimulation of neighboring somatostatin-containing D cells in the antrum.
In the present studies, duodenal acidification produced significant
stimulatory effects on mucosal and circulating GIP concentrations (Fig.
6). However, in contrast to previous studies in our laboratory (27, 28), in which both glucose and lipid meals increased duodenal mucosal GIP mRNA concentrations, steady-state GIP mRNA levels
remained unchanged in peptone-fed rats. These observations are
consistent with a role for GIP as a physiological enterogastrone in the
rat. Under these circumstances, the response to intraduodenal acid
would be expected to produce an immediate response, with GIP release
into the circulation and possibly an increase in mucosal levels
occurring rapidly. Moreover, the release of GIP into the circulation
did not reach peak levels until 120 min, which is significantly later
than the increase observed after a glucose meal (28).
Although not examined in the present study, this relative delay in GIP
release may be attributed in part to the buffering effects of the
peptone meal, which normally has a pH of 7.0 (31). After
infusion of the peptone meal, although acid secretion would increase
rapidly, the meal itself would maintain the intragastric pH at an
elevated level, until endogenous gastric acid overwhelms the buffering
capacity of peptone. Thus, under such circumstances, a decrease in
intraduodenal pH, and consequently GIP release, would not occur
immediately, but rather would be delayed. Acid also stimulates the
immediate release of mucosal and pancreatic bicarbonate, and
neutralization of the acidic contents ensues promptly and persists for
extended periods of time (10). As a result, the stimulus
for continued GIP biosynthesis would not be present and mRNA levels
could be expected to remain constant. In support of this hypothesis,
the continuous duodenal infusion of 0.1 M HCl does produce a marked
increase in mucosal GIP mRNA levels (Fig. 7).
In conclusion, the present studies indicate that in addition to lipids
and carbohydrates, nutrient protein provides a potent stimulus for GIP
expression in the rat, an effect that occurs at the posttranslational
level and may be mediated in part through the acid-stimulatory
properties of protein. Although the precise physiological relationship
between GIP and gastric function has not been fully elucidated, it is
possible that GIP may act synergistically with other candidate
enterogastrones, such as secretin, enteroglucagon, and peptide YY, to
inhibit antral gastrin release and acid secretion under physiological
conditions (33). Further study will be necessary to fully
characterize these complex interactions.
 |
ACKNOWLEDGEMENTS |
This study was supported by National Institute of Diabetes and
Digestive and Kidney Diseases Grant RO1-DK-53158.
 |
FOOTNOTES |
Address for reprint requests and other correspondence: M. Michael Wolfe, Section of Gastroenterology, Boston Medical Center, 650 Albany St., Boston, MA 02118 (E-mail:
michael.wolfe{at}bmc.org).
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.
Received 17 December 1999; accepted in final form 29 March 2000.
 |
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Am J Physiol Gastrointest Liver Physiol 279(3):G561-G566
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