Section of Gastroenterology, Boston University School of Medicine, Boston, Massachusetts 02118
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ABSTRACT |
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Glucose-dependent insulinotropic polypeptide
(GIP) and glucagon-like peptide 1 (GLP-1) are potent insulinotropic
peptides released from the small intestine. To examine their relative
contribution to postprandial insulin release, a specific GIP antagonist
(ANTGIP) and a GLP-1 antagonist,
exendin-(939)-NH2, were infused
into rats after an intragastric glucose meal. In control rats, plasma glucose and insulin levels rose gradually during the first 20 min and
then decreased.
Exendin-(9
39)-NH2 administration
inhibited postprandial insulin secretion by 32% at 20 min and
concomitantly increased plasma glucose concentrations. In contrast,
ANTGIP treatment not only induced a 54% decrease in insulin secretion
but also a 15% reduction in plasma glucose levels 20 min after the
glucose meal. In vivo studies in rats demonstrated that glucose uptake in the upper small intestine was significantly inhibited by the ANTGIP,
an effect that might account for the decrease in plasma glucose levels
observed in ANTGIP-treated rats. When the two antagonists were
administered to rats concomitantly, no potentiating effect on either
insulin release or plasma glucose concentration was detected. Glucose
meal-stimulated GLP-1 release was not affected by ANTGIP
administration, whereas postprandial glucagon levels were diminished in
rats receiving
exendin-(9
39)-NH2. The results of these studies suggest that GIP and GLP-1 may share a common mechanism in stimulating pancreatic insulin release. Furthermore, the
GIP receptor appears to play a role in facilitating glucose uptake in
the small intestine.
glucose tolerance test; exendin; glucose-dependent insulinotropic polypeptide antagonist; glucagon
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INTRODUCTION |
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THE EXISTENCE of chemical stimulants of endocrine pancreatic function in the gastrointestinal tract has been suggested since the beginning of this century (19). Zunz and La Barre (30) proposed the term "incretin" as an insulin-stimulatory substance released from the small intestine after glucose-containing meals. Creutzfeldt (5) further expanded the incretin concept and defined it as an endocrine mediator produced in the gastrointestinal tract that was released by food and that stimulated pancreatic insulin secretion. Although several gastrointestinal regulatory peptides have been proposed as incretins, only glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) appear to fulfill the requirements to be considered physiological stimulants of postprandial insulin release (9, 15, 16, 18, 21).
Exendin-(939), a biologically active peptide isolated from
helodermatidae venom, has been shown to be a receptor-specific GLP-1
antagonist (29). Several groups have used this peptide to inhibit the
biological effects of GLP-1 and have shown that exendin significantly
reduced insulin release in response to a rat chow or a glucose meal
(17, 29). Recently, our laboratory developed a GIP-specific receptor
antagonist, GIP-(7
30)-NH2
(designated ANTGIP), and demonstrated that this antagonist inhibited
postprandial insulin release in chow-fed rats by 72% (27).
Although existing data suggest that both GIP and GLP-1 possess
significant insulinotropic properties, their relative physiological roles in stimulating insulin release are unknown. Furthermore, whether
GIP plays an indirect role on insulin secretion by simulating GLP-1
release, as suggested by some investigators (2, 17), or acts
independently on islet -cells is not clear. In the present report,
we have examined the effects of ANTGIP,
exendin-(9
39)-NH2, and a
combination of both antagonists on glucose meal-stimulated insulin
release in conscious rats. The effects of ANTGIP treatment on GLP-1
release and the influence of exendin-(9
39) and ANTGIP on postprandial
glucagon secretion were also investigated. Finally, the impact of
ANTGIP on glucose transport in the upper small intestine was explored
in vivo in rats.
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MATERIALS AND METHODS |
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Oral glucose tolerance test.
Sprague-Dawley rats (250-300 g) purchased from Charles River
(Kingston, MA) were fasted overnight with access to water. Animals were
administered glucose (1 g/kg) by oral gavage as a 40% solution
(wt/vol). Blood samples were collected from the tail vein of conscious
unrestrained rats into heparinized capillary tubes at
time
0 and at 10, 20, 30, and 60 min after
the glucose meal. ANTGIP (5 µg/250 g body wt),
exendin-(939)-NH2 (3 µg/250 g
body wt, Bachem, Torrance, CA), or a combination of ANTGIP and
exendin-(9
39)-NH2 was given
intraperitoneally at time 0 after baseline blood samples were
obtained. The concentrations of ANTGIP and
exendin-(9
39)-NH2 were
determined by performing a dose-response curve for each peptide and by
selecting the lowest concentrations that exhibit maximal insulin
inhibitory effect. Control animals were injected with the same volume
of 0.9% NaCl. Blood samples were kept in ice-chilled tubes containing
250 kallikrein-inhibitor units of aprotinin and 0.1 mM diprotin A
(Sigma) and centrifuged at 4°C for 30 min, and the plasma was
stored at
20°C until analysis for glucose, insulin, or
peptides. Glucose levels were determined with hexokinase and
glucose-6-phosphate dehydrogenase (1). Insulin concentrations were
measured with a radioimmunoassay kit (Rat Insulin RIA Kit, Linco
Research, St. Charles, MO). Glucagon radioimmunoassays were performed
with the double-antibody method (Diagnostic Product, Los Angeles, CA).
Intra-assay variation was 15.7% with incubation of 35 pg of glucagon
and 4.1% with 564 pg glucagon. Interassay variation was 15.7% with
incubation of 37 pg glucagon and 5.7% with 534 pg glucagon. The lowest
detection limit for glucagon was 13 pg/ml (3.7 pM). No significant
cross-reactivity with any related peptide, such as GLP-1, GLP-2, GIP,
vasoactive intestinal polypeptide, or secretin was noted.
Plasma GLP-1 and GIP concentrations were measured with double-antibody
method according to the protocol of the manufacturer (Peninsula
Laboratories). The lowest detection limit for both GIP and
GLP-(7
36)-NH2 was 10 pg/ml. The GLP-1 assay detected only amidated GLP-1, and no cross-reaction with other related peptides was identified.
D-Glucose absorption in
vivo. D-Glucose
absorption from jejunum was measured in vivo in the rat according to
the method described by Hirsh et al. (14). Sprague-Dawley rats
(250-300 g) were fasted with access to water for 24 h to minimize
luminal contents during surgery. Rats were anesthetized with
intraperitoneal urethan (Sigma, 1.25 g/kg body wt) and were maintained
under anesthesia for the duration of the experiment. After laparotomy,
a 35-cm segment of jejunum starting 5 cm distal to the ligament of
Treitz was isolated, cleaned by gently flushing with 20 ml of warm
0.9% NaCl, and cannulated at both ends. Each segment was perfused
twice, first as a control and second as a test (after ANTGIP
administration) or a repeat control. The luminal perfusate, a
Krebs-bicarbonate saline solution containing 5 mmol/l
D-[14C]glucose
(Amersham, Arlington Heights, IL), and
3H-labeled polyethylene glycol
(PEG, NEN, Boston, MA) were used to correct for fluid movement into the
extracellular space. The solution was heated to 37°C and gassed
with 95% O2-5%
CO2 to maintain the pH at 7.4. The
perfusion system was single pass with a flow rate of 1.6 ml/min, with a
Harvard PHD 2000 pump (Harvard Apparatus, South Natick, MA). The
effluent from the luminal circuit was collected at 5-min intervals for
up to 30 min. After the first experiment, the segment was cleaned by
gently flushing with 20 ml of warm saline, at which time ANTGIP (20 µg/kg body wt) was injected subcutaneously before initiation of the
second infusion. After the second perfusion, the jejunal loops were
rinsed, ligated, and removed. The jejunal loop was then opened along
the mesenteric border, the mucosal lining was scraped off with a glass
slide, and the dry weight of each loop was determined. Radioactivity of
all samples was determined with a liquid scintillation counter (LS
6500, Beckman, Fullerton, CA). Glucose and PEG absorption from the
jejunum was calculated by changes in radioactivity of glucose and PEG
in the affluent and effluent solutions and expressed as micromoles per minute per gram dry weight. Intramucosal accumulation of
D-glucose in each animal was
calculated after correction for extracellular substrate (amount of
D-glucose absorbed amount of polyethylene glycol absorbed). The effect of ANTGIP
on glucose absorption was determined by comparing mucosal
D-glucose concentration between the first (no ANTGIP) and the second (with ANTGIP) experiment.
Statistics. Results are expressed as means ± SE. Statistical analysis was performed with ANOVA and Student's t-test. P values <0.05 were considered to be statistically significant.
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RESULTS |
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Dose-response curves of ANTGIP and
exendin-(939)-NH2 on insulin
release. The effect of ANTGIP and
exendin-(9
39)-NH2 on plasma insulin concentrations after a glucose meal was examined at 20 min when
maximal inhibition occurred. ANTGIP and
exendin-(9
39)-NH2 dose
dependently inhibited glucose-induced insulin secretion with maximal
inhibition achieved at 5 and 3 µg/250 g body wt, respectively (Fig.
1, A and
B). No further decrease in insulin
levels was observed when higher doses of ANTGIP and
exendin-(9
39)-NH2 were
administered. Hence, these concentrations of ANTGIP (5 µg/250 g body
wt) and exendin-(9
39)-NH2 (3 µg/250 g body wt) were chosen for the following oral glucose
tolerance test studies.
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Plasma glucose concentrations. After
intragastric glucose administration, the mean plasma glucose levels in
control rats increased from 82.5 ± 3.5 to 174.4 ± 3.6 mg/dl at
20 min and then plateaued (Fig. 2). The
administration of
exendin-(939)-NH2 produced a significant increase in plasma glucose concentration during the first
20 min (glucose concentration of 186.2 ± 2.4 mg/dl at 20 min). In
contrast, rats receiving either ANTGIP alone or the combination of
ANTGIP and exendin-(9
39)-NH2
exhibited lower glucose levels than control rats during the first 20 min, with concentrations of 148.7 ± 2.5 and 145.2 ± 4.0 mg/dl,
respectively, at 20 min (Fig. 2; P < 0.05 compared with control). No differences in plasma glucose
concentrations were detected between 30 and 60 min. As seen in Fig. 2,
the plasma glucose concentrations of rats injected with ANTGIP or the
combination of ANTGIP and
exendin-(9
39)-NH2 were similar
at all the time points examined.
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Plasma insulin concentrations. In
response to intragastric glucose administration, plasma insulin
concentrations increased from a fasting level of 0.87 ± 0.16 to
2.75 ± 0.35 ng/ml at 20 min and then gradually decreased (Fig.
3). The administration of
exendin-(939)-NH2, ANTGIP, or
the combination of
exendin-(9
39)-NH2 and ANTGIP
significantly decreased plasma insulin levels by 32, 54, and 49%,
respectively, at 20 min (insulin concentrations of 1.87 ± 0.20, 1.27 ± 0.40, and 1.38 ± 0.45 ng/ml, respectively, P < 0.05 compared with control). No
significant differences were detected at 30 and 60 min after glucose
administration (Fig. 3).
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Plasma glucagon levels. Plasma
glucagon concentrations were measured at 20 min, at which time the
highest glucose levels were observed. In response to an oral glucose
meal, plasma glucagon concentrations decreased from a fasting level of
181 ± 7 to 154 ± 5 pg/ml at 20 min (Fig.
4). ANTGIP administration did not affect postprandial glucagon levels significantly, whereas
exendin-(939)-NH2 injection
significantly decreased glucagon levels to 138 ± 2 pg/ml at 20 min
(P < 0.05, compared with control
rats; Fig. 4). Plasma glucagon concentrations in rats receiving both
exendin-(9
39)-NH2 and ANTGIP did
not differ from those of control rats.
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Plasma
GLP-1-(736)-NH2
concentrations. Fasting plasma
GLP-1-(7
36)-NH2 levels were
nearly identical in normal control and in ANTGIP-injected rats and
ranged from 18 to 22 pg/ml (Fig. 5). In
response to intragastric glucose infusion, plasma
GLP-1-(7
36)-NH2 levels in
control rats increased significantly at 10 min and peaked at 30 min
with concentration of 83 ± 5 pg/ml.
GLP-1-(7
36)-NH2 levels remained
unaltered by the administration of ANTGIP throughout the entire
experimental period (Fig. 5).
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Effects of ANTGIP on
D-glucose absorption in
vivo. To examine whether ANTGIP affected glucose
transport in the small intestine, D-glucose absorption from the
rat jejunum was measured in vivo. In control experiments during which
both the first and second perfusions were performed in the absence of
ANTGIP, D-glucose uptake was not
significantly different (data not shown). In response to
D-glucose infusion, plasma GIP
level increased from 0.82 ± 0.25 ng/ml at basal state to 1.48 ± 0.13 ng/ml at the end of the first 30-min infusion
(P < 0.05). When ANTGIP was
administered before the second perfusion period,
D-glucose absorption was
significantly decreased from 4.15 ± 0.66 in the control rats to
2.70 ± 0.52 µmol · min1 · g
dry wt
1 (P < 0.05;
n = 6) at 20 min (Fig.
6). The total area under the curve (AUC)
for the first 20 min after perfusion was calculated in all animals.
These data are presented in the inset
to Fig. 6 and showed that the intestinal accumulation of
D-glucose decreased by
30% from 42 ± 5 in control rats to 28 ± 4 mmol · 20 min
1 · g
dry wt in ANTGIP-treated rats (P < 0.05; Fig. 6, inset).
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DISCUSSION |
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As stated in the previous paragraphs, although both GIP and GLP-1
possess insulinotropic properties, their relative physiological roles
in regulating postprandial insulin release have not been well defined.
Wang et al. (29) demonstrated that exendin reduced postprandial insulin
release to a rat chow by 48%. Our laboratory has recently shown that
after a rat chow meal insulin release was decreased by 72% in animals
receiving the GIP antagonist ANTGIP (27). In the present report, we
demonstrated that
exendin-(939)-NH2 and ANTGIP
administration before enteral glucose infusion reduced insulin release
by 32 and 54% at 20 min, respectively. Together, these data suggest
that approximately one-half of meal-stimulated insulin secretion is due
to the incretin activities of GIP and GLP-1. Furthermore, because no
additive effect was observed in animals receiving both
exendin-(9
39)-NH2 and ANTGIP
when compared with either receptor antagonist alone, it would appear
that the insulin-stimulatory properties of GIP and GLP-1 may be
mediated, at least in part, through a common pathway. These results
support recent observations by Pederson et al. (24), who demonstrated similar GIP- and GLP-1-mediated insulin secretion in wild-type and
GLP-1-receptor knockout mice. Furthermore, enhanced GIP secretion and
insulinotropic action in the GLP-1 receptor knockout mice are also
consistent with the notion that GIP and GLP-1 may share an identical
signaling pathway in the
-cell (24). Our current conclusions are,
however, based on a glucose meal. Previous studies (3, 25) have shown
that the release of GIP into the circulation after a meal depended on
two major nutrient stimuli, carbohydrate and fat. Thomas et al. (26)
reported that an amino acid mixture containing arginine, histidine,
isoleucine, leucine, lysine, and threonine also provided a potent
stimulus for GIP release. In contrast, few studies have examined
nutrient-stimulated GLP-1 release. Nevertheless, oral glucose,
arginine, or mixed meal administration has been demonstrated to enhance
GLP-1 release (6, 10, 12). Further studies with other nutrients will be
necessary to determine whether these effects observed in the present
study are glucose specific.
Recently, several studies have shown that GIP stimulates GLP-1 release
in rats (2, 13), as well as in isolated canine intestinal L cells (8).
The authors of these studies proposed that GIP might exert only a
"permissive action" on the -cell via direct stimulation of
GLP-1 secretion. Studies in human subjects have, however, failed to
confirm these findings (20), and the present studies demonstrating that
the GIP antagonist exhibited more profound inhibition of insulin
secretion than the GLP-1 antagonist are also inconsistent with this
conclusion. Our current study suggests that the incretin function of
GIP may be mediated through both a direct effect on islet
-cells and
the indirect stimulation of GLP-1 release. The latter effect does not
appear to involve receptor-mediated processes, because postprandial
GLP-1 secretion was not affected by the administration of GIP-receptor
antagonist. In the current study, the fasting plasma amidated GLP-1
levels were compatible to those reported by Ørskov et al. (22). In response to a glucose meal, amidated GLP-1 rose significantly, but its
concentrations were lower than those after a regular meal observed by
Ørskov et al. (25 vs. 41 pM; Ref. 22). Although plasma
glycine-extended GLP-1 and GLP-1-(7
37) levels are not measured in
this study, it is unlikely that these peptides are relevant to our
conclusions because the majority of circulated GLP-1 after meal is the
amidated form (22). Whether GIP antagonist affects the release of
nonamidated GLP-1 requires additional investigation.
The increase in postprandial plasma glucose levels after the
administration of
exendin-(939)-NH2 is consistent
with findings from previous reports (17, 29) and appears to account for the reduction in postprandial glucagon release in exendin-treated rats.
Previous reports have shown that GIP exhibited stimulatory effects on
glucagon secretion in the rats, whereas GLP-1 inhibited glucagon
release (11, 18). These effects were, however, shown to depend on the
ambient glucose concentration (18, 23). In the perfused rat pancreas,
GIP-stimulated glucagon secretion was observed only in the presence of
glucose levels of 5 mmol/l or lower, and no effect was found at higher
glucose concentrations (18). In our study, the plasma glucagon
concentration in rats given both
exendin-(9
39)-NH2 and
ANTGIP was significantly higher than that of exendin-treated
rats, consistent with above observations that plasma glucose
concentration plays a more physiologically pertinent role than GLP-1 or
GIP in modulating postprandial glucagon release. Although the precise
mechanism for exendin-induced hyperglycemia has not been elucidated,
this effect may be attributed to a reduction of the insulin response
(17) or to a decrease in glucose utilization in peripheral tissues (7).
Although not determined in the current study, Cheeseman and Tseng (4)
have recently demonstrated that GLP-1 has no effect on
D-glucose uptake in the jejunum.
In contrast to exendin, ANTGIP administration in the present
studies significantly decreased both insulin and glucose levels after a
glucose meal. The latter appears to be due, at least in part, to the
inhibition of glucose uptake in the small intestine, as demonstrated in
our in vivo studies.
The ability of the GIP-receptor antagonist to inhibit glucose uptake
suggests that this function is receptor mediated, a notion further
supported by the localization of the GIP receptor to the small
intestinal mucosa by in situ hybridization (28). Moreover, our results
are also consistent with the observations of Cheeseman and Tseng (4),
who reported that the infusion of GIP, but not GLP-1, resulted in
significant increases in carrier-mediated glucose uptake in the rat
jejunum. In the current study, the concomitant administration of ANTGIP
and exendin-(939)-NH2 reduced
plasma glucose levels to those seen in ANTGIP-treated rats, which
indicates that the GIP receptor plays an important role in regulating
glucose transport in the upper small intestine. Further studies will be required to determine whether additional mechanisms, such as effects on
peripheral glucose utilization, are involved in exerting the physiological properties attributed to GIP.
In summary, the current report demonstrates that both GIP and GLP-1
play an essential role in regulating postprandial insulin secretion and
that their incretin effects account for 50% of insulin release after
a glucose meal. Furthermore, the incretin properties of GIP and GLP-1
may be mediated, in part, through common mechanisms. Finally, as GIP
antagonism inhibits glucose uptake in the small intestine, a similar
approach may prove useful in improving postprandial hyperglycemia
commonly seen in diabetic patients, as well as in treating disorders
characterized by obesity.
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ACKNOWLEDGEMENTS |
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The authors thank Dr. Timothy J. Kieffer for assistance during the course of these studies.
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FOOTNOTES |
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This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants DK-52186 to C.-C. Tseng and DK-53158 to M. M. Wolfe.
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: C. C. Tseng, Section of Gastroenterology, Boston Univ. School of Medicine, Boston, MA 02118 (E-mail: chichuan.tseng{at}bmc.org).
Received 6 November 1998; accepted in final form 23 February 1999.
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