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From the Departments of Physiology and Medicine (J.T.L., B.D., T.J.K.), Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta, Canada T6G 2S2; and the Laboratory of Molecular Endocrinology (J.F.H.), Massachusetts General Hospital, Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts 02114
Address all correspondence and requests for reprints to: Timothy J. Kieffer, Ph.D., 370 Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta, Canada T6G 2S2. E-mail: tim.kieffer{at}ualberta.ca
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Abstract |
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35% lower at 10 min in GIPR Ab treated animals compared
with controls. As a result, the glucose excursion was greater in the
GIPR Ab treated group. Fasting plasma glucose levels were not altered
by GIPR Ab. We conclude that release of GIP following oral glucose may
act as an anticipatory signal to pancreatic ß-cells to promote rapid
release of insulin for glucose disposal. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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450
pM and 50–60 pM, respectively) GIP appears
to be more insulinotropic than GLP-1 (25).
Indeed, it has recently been suggested that the primary physiological
role of GLP-1 may be inhibition of upper gastrointestinal
motor and digestive functions rather then potentiation of meal-induced
insulin secretion (28). Recently, both GLP-1 and GIP receptors have been disrupted in mice (29, 30). Both models display glucose intolerance following oral glucose tolerance tests, firmly establishing the importance of both hormones in the maintenance of normal glucose homeostasis. However, it remains possible that the phenotype of these animals is modified in part by as of yet undetermined adaptive and developmental consequences to the chronic absence of incretin hormone action. For example, it has been recently reported that mice with a null mutation in the GLP-1 receptor have compensatory increases in GIP secretion and insulinotropic action (31). Therefore, it is possible that the glucose intolerance in GIP knockout mice is attenuated by an adaptive increase in release and/or insulinotropic action of GLP-1. To determine the effect of an acute ablation of the insulinotropic action of GIP, we developed a novel specific GIP receptor antagonist. Here we characterize the antagonist and report on its acute actions on glucose tolerance in rats.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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GIP receptor expression
Pancreatic islets were isolated by a modification of the method
described by Lacy and Kostianovsky (32) as previously
described (33) from male Sprague Dawley rats weighing
approximately 250 g. Islets were lysed in ice-cold RIPA buffer
[150 mM NaCl, 20 mM Tris-Cl pH 7.5, 1
mM EDTA, 1% Nonidet P-40, 1% deoxycholate, 0.1% SDS, 5
mM NaF, 1 mM phenylmethylsulfonyl fluoride, 1
mM DTT, and 1% protease inhibitor cocktail
(Sigma-Aldrich Canada Ltd., Oakville, ON)] 30 min at 4 C.
Lysates were spun at 12,000 x g for 5 min at 4 C, and
the resulting supernatants were assayed for total protein content using
the Bradford method. Protein was fractionated on 10% polyacrylamide
gels containing SDS and then transferred to Nitrocellulose membranes
(Micron Separations Inc., Westborough, MA). Nitrocellulose membranes
were then incubated with GIP receptor antiserum diluted 1:500 in 20
mM Tris, 73 mM NaCl, pH 7.6
with 5% nonfat milk and then washed in PBS-T (0.1%) buffer (137
mM NaCl, 2.7 mM KCl, 10
mM
Na2HPO4, 1.4
mM
KH2PO4, pH 7.5 and 0.1%
Tween-20). Visualization was achieved with a second antibody to rabbit
IgG coupled to horseradish peroxidase at 1:500 dilution (Amersham Pharmacia Biotech, Baie d’Urfé, Québec, Canada) and
then development with an enhanced chemiluminescence Western blotting
detection kit (Amersham Pharmacia Biotech).
For immunofluorescence studies, excised rat pancreases were embedded in OCT compound (Tissue-Tek; Miles Laboratories, Elkhart, IN). Cryosections of 7 µm were fixed in 4% paraformaldehyde for 10 min at room temperature and then double-stained with either preimmune or immune sera to the GIP receptor at 1:500 and for either insulin [guinea pig antiinsulin at 1:200 (Linco Research, Inc., St. Charles, MO)] or glucagon [mouse antiglucagon at 1:500 (a gift from Dr. G. W. Aponte, University of California-Berkeley]. Fluorescent secondary antisera coupled to Cy-3 or Cy-2 (iodocarbocyanine; Jackson ImmunoResearch Laboratories, Inc., West Grove, PA) were used at 1:2000 and 1:500, respectively. Images were captured on a Nikon epifluorescence microscope equipped with an Optronics TEC-470 CCD camera (Optronics Engineering, Goleta, CA) interfaced with IP-Lab Spectrum imaging software (Signal Analytics, Vienna, VA).
GIPR Ab binding analysis
HEK 293 cells stably expressing either the GIP or
GLP-1 receptor (generously provided by T. Usdin, National
Institute of Mental Health, Bethesda, MD, and J. Gromada, Novo Nordisk A/S, University of Copenhagen, Denmark, respectively)
were cultured in DMEM (Life Technologies, Inc., Grand
Island, NY) containing 25 mM glucose supplemented with 100
U/ml penicillin, 100 µg/ml streptomycin, and 10% FBS at 37 C in
humidified 5% CO2-95% air. Cells were harvested
for receptor binding studies with trypsin-EDTA, resuspended in binding
buffer (138 mM NaCl, 5.6 mM KCl, 1.2
mM MgCl2, 2.6 mM
CaCl2, 10 mM HEPES, 1% BSA, 10
mM glucose, and 1% aprotinin), and aliquoted into
Eppendorf tubes (1 x 106
cells/800 µl). One hundred microliters of
125I-GLP-1
7–36NH2 or 125I-GIP
prepared as previously described (34) (30,000 cpm) and
100 µl of affinity purified GIPR Ab (0.01–50 µg/ml final
concentration) was added to the appropriate tubes and the samples were
rocked at room temperature for 30 min. Tubes were then centrifuged at
12,000 x g for 5 min, and the cell pellet was counted
in a 
-counter. Results are expressed as a % of the maximum specific
binding in the absence of GIPR Ab.
Measurements of intracellular cAMP were made on HEK 293 cells expressing the GIP receptor. Cells were plated into 24-well plates and cultured for 24–48 h before assay. At the time of assay, cells were transferred into DMEM + 0.1% BSA and incubated in triplicate with or without GIP (Peninsula Laboratories, Inc., Belmont, CA), GIP receptor antisera (1:100), or preimmune sera (1:100). After 5 min, cells were extracted in 0.5 ml ice-cold ethanol followed by freeze-thawing. Supernatants were then lyophilized, and cAMP quantity was determined by RIA using cAMP specific antisera (Biomedical Technologies, Inc., Stoughton, MA). The value for each well was determined in duplicate.
GIPR Ab kinetics
A sensitive ELISA was used to determine the half-life of GIPR Ab
in vivo. The GIP receptor peptide fragment used as an
antigen was coated at 1.0 µg/ml on Falcon microtiter plates
(Becton Dickinson and Co., Sparks, MD) in
carbonate-bicarbonate buffer, pH 9.6. A standard curve was then
constructed by incubating with a range of concentrations of GIPR Ab
(0.0001 to 10 µg/ml), followed by alkaline phosphatase conjugated
antirabbit secondary antisera at 1:1000 (Jackson ImmunoResearch Laboratories, Inc.) and development in 1 mg/ml disodium
p-nitrophenyl phosphate substrate (Sigma-Aldrich Corp.) in
10% diethanolamine buffer, pH 9.8. Formation of p-nitrophenyl was
monitored by absorbance at 405 nm.
Male Sprague Dawley rats (200 g) were given an ip injection of GIPR Ab (1 µg/g BW) and tail vein blood samples were collected over the next 4 days. Plasma samples were diluted 1:10 and 1:100 and assayed by ELISA as described above. OD values were converted to concentration of GIPR Ab off the standard curve.
Glucose tolerance tests
Male Sprague Dawley rats (250–300 g) (Biological Sciences
Animal Services, University of Alberta, Edmonton, Alberta, Canada)
received either 1.0 µg/g BW GIPR Ab or 1.0 µg/g BW rabbit
-globulin in PBS (Jackson ImmunoResearch Laboratories, Inc.) by ip injection, approximately 21 h before glucose
tolerance testing. All studies were performed following an overnight
fast. For iv glucose tolerance tests, rats were anesthetized by ip
injection of 50 mg/kg BW sodium pentobarbital (Somnotol; MTC
Pharmaceuticals, Cambridge, Ontario, Canada) and the right jugular vein
was cannulated with PE 90 polyethlylene tubing (Becton Dickinson and Co.) for infusions. Experiments were performed 20–30 min
after implantation of the infusion catheter. Body temperature was
maintained throughout experiments by use of heating pads. Rats were
infused with either glucose alone (2.8 mmol/kg), glucose plus 60 pmol
porcine GIP (American Peptide Co., Sunnyvale, CA), or
glucose plus 60 pmol GLP-1 7–36NH2
(Peninsula Laboratories, Inc.). Blood samples were
collected from the tail vein into heparinized capillary tubes at time 0
and at 5, 10, 20, 30, and 60 min following infusions. The samples were
immediately transferred into microcentrifuge tubes on ice, centrifuged
at 12,000 x g (4 C) for 5 min and the plasma was then
stored at -20 C until assays were performed.
For oral glucose tolerance tests conscious, unrestrained rats that had received either GIPR Ab or control rabbit IgG injections were allowed to acclimate under a heat lamp for 20 to 30 min before the experiments. Glucose (1 g/kg BW) was administered orally as a 50% solution by gavage. Blood samples were collected at time 0 and at 10, 20, 30, 60, 90, and 120 min following oral glucose and were prepared as above for assays.
Assays
Plasma glucose was determined using a colorimetric enzymatic
assay kit (Sigma, St. Louis, MO) scaled down for use in
96-well microtiter plates. Plasma insulin concentrations were measured
with a RIA kit (rat insulin RIA kit, Linco Research, Inc.,
St. Charles, MO).
Data analysis
For the iv glucose tolerance test experiments, incremental area
under the curve (AUC) was calculated using the trapezoidal rule from
5–30 min after the glucose infusion. This calculation is the sum of
the products of the mean plasma glucose concentrations for each time
period multiplied by the number of minutes in each time period, minus
the product of the basal plasma glucose concentration multiplied by the
total number of minutes. All values are presented as means ±
SEM. Unpaired Student’s t tests were used to
identify differences between treatment groups.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). In contrast, no product was detected
in an extract prepared from HEK 293 cells overexpressing the highly
homologous GLP-1 receptor. In a total cell extract from
rat islets a major product was detected with an apparent molecular
weight of 65K (Fig. 1). The difference in product size between the
extracts may reflect different posttranslational processing of the GIP
receptor.
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). In contrast, no specific
immunoreactivity was detected with the preimmune sera.
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). Half-maximal displacement was
achieved with approximately 1 µg/ml. No significant displacement of
125I-GLP-1 nor
125Iglucagon binding to INS-1 cells was observed
(data not shown).
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).
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).
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).
Coinfusion of a 60 pmol bolus of GIP increased peak insulin levels by
approximately 2-fold and reduced the glucose AUC by approximately 15%
in control animals receiving IgG. In the animals treated with GIPR Ab,
this insulinotropic effect of GIP was completely ameliorated (864
± 83 vs. 1521 ± 161 pM;
P < 0.01) and the AUC was significantly greater than
in the IgG-treated group (271 ± 14 vs. 233 ± 9
mM x min; P < 0.05). In control
animals receiving IgG, coinfusion of a 60 pmol bolus of
GLP-1 increased peak insulin levels nearly 3-fold and
reduced the glucose AUC by approximately 15%. Treatment with GIPR Ab
had no significant effect on the insulinotropic action of
GLP-1 (1864 ± 500 vs. 2488 ± 321
pM) or glucose AUC (241 ± 7 vs.
228 ± 14 mM x min).
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).
Insulin levels 10 min after oral glucose were reduced by approximately
35% by GIPR Ab (245 ± 29 vs. 355 ± 42
pM; P < 0.05). This was
accompanied by an increase in the glucose excursion compared with the
IgG-treated control group. In controls, glucose levels declined after
the 20 min sampling point. In contrast, glucose levels remained
elevated in GIP receptor antibody treated animals until the 30 min
sampling point (12.9 ± 0.5 vs. 11.4 ± 0.3
mM; P < 0.05).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Antiserum was generated to a specific epitope in the extracellular
region of the rat GIP receptor. In extracts from rat pancreatic islets,
this antiserum detected a product of the approximate size predicted for
the GIP receptor. GIP receptor immunoreactivity was located throughout
islets, including both ß- and 
-cells, as expected from previous
reports which identified both messenger RNA and binding sites on these
cell types (45, 46). These findings support the concept
that the insulinotropic and glucagonotropic actions of GIP
(47) are mediated through direct actions of GIP on ß-
and -cells, respectively. Purified GIP receptor antibody (GIPR Ab)
bound to the GIP receptor with high affinity and thereby prevented GIP
from activating the receptor, both in vitro and in
vivo. Notably, GIPR Ab did not bind to the related receptors for
GLP-1 and glucagon. This GIP receptor antagonist was
remarkably stable in vivo, with half-maximal levels
following a single ip injection remaining after 4 days.
Pretreatment of rats with GIPR Ab significantly attenuated the insulin response to oral glucose resulting in a greater glucose excursion. These findings confirm the importance of GIP in the rapid ß-cell response to glucose. However, the rather modest effect of acute ablation of the GIP signal illustrates the remarkable redundancy of the enteroinsular axis. For example, the autonomic nervous system has recently been shown to play a crucial role in glucose- and meal-induced insulin release (48, 49). Glucose itself is also a potent insulin secretagogue. Thus, with these additional pathways remaining intact following blockage of GIP action, sufficient insulin was still released from ß-cells to adequately absorb the glucose challenge, albeit with suboptimal kinetics. It is also possible that delayed glucose absorption from the gut in rats pretreated with GIPR Ab reduced the severity of the glucose intolerance following disruption of the insulinotropic activity of GIP. GIP, but not GLP-1, increases jejunal basolateral glucose transport activity (50, 51). Consistent with these findings, treatment with a GIP peptide antagonist reduced absorption of glucose from the small intestine of rats (40).
The effect of acute GIP antagonism was not as marked as was observed in GIP receptor knockout mice (30). Mice with disrupted expression of the GIP receptor exhibit severe glucose intolerance. Peak plasma glucose values were approximately 30% higher than control mice following an oral glucose challenge (compared with 13% in our study). This apparent difference in findings may be explained by the fact that Miyawaki et al. (30) used a glucose challenge that was double the dose we used in this study, thereby perhaps making the result of absent GIP signaling more evident.
Significant differences are beginning to emerge between the roles of GIP and GLP-1 in the maintenance of normal glucose homeostasis. Neither acute nor chronic impairment of GIP action seems to alter fasting plasma glucose levels, as expected for a hormone acting in the classical incretin fashion. In contrast, glucose intolerance in mice with a disrupted GLP-1 receptor is frequently accompanied by fasting hyperglycemia (29). Perhaps even more surprising is the observation that mice with a null mutation in the GLP-1 receptor also exhibit abnormally elevated levels of blood glucose following ip glucose challenge where glucose bypasses the enteroinsular axis entirely (29). This observation was not made in mice with a disrupted GIP receptor (30). When compared with control mice, disrupted incretin hormone action would not be expected to impair clearance of a glucose challenge that bypasses the gut as both GIP and GLP-1 are released in response to luminal, but not iv, glucose (9, 27, 52, 53). Therefore, while GIP appears to act as an acute insulinotropic hormone in order that ß-cells may anticipate the absorption of glucose from the gut, GLP-1 signaling appears to be additionally important for the maintenance of normoglycemia, irrespective of the site of glucose entry into the circulation. This ability to promote glucose disposal makes GLP-1 a candidate therapeutic for the treatment of the abnormal glucose homeostasis associated with diabetes mellitus (7).
In summary, GIP receptors are present on rat pancreatic ß-cells where GIP is insulinotropic. Acute disruption of GIP action has no effect on fasting glucose levels but delays the insulin response to oral glucose and thereby increases the plasma glucose excursion. Therefore, GIP release from the upper intestine in response to the ingestion of nutrients (e.g. glucose) may act as an anticipatory signal to the ß-cells to ensure insulin is rapidly released as glucose is absorbed from the gut.
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Footnotes |
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2 CDA and Alberta Heritage Foundation for Medical Research
Scholar.
Received May 25, 2000.
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References |
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- and ß-cell
responses to GIP infusion in normal man. Am J Physiol
237:E185–E191
-cells of the rat endocrine pancreas. Diabetes 46:785–791[Abstract]
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