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Departments of Laboratory Medicine and Pathobiology and Medicine (L.B., D.J.D.), Banting and Best Diabetes Centre, University Health Network, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada M56 2C4; and the Departments of Medicine and Physiology (T.J.K.), University of Alberta, Alberta, Canada T6G 2S2
Address all correspondence and requests for reprints to: Dr. Daniel J. Drucker, Toronto General Hospital, 101 College Street CCRW3–845, Toronto, Ontario Canada M5G 2C4. E-mail: d.drucker{at}utoronto.ca
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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GIP is a 42-amino acid peptide that is synthesized in intestinal K cells in the proximal jejunum and secreted primarily in response to the ingestion of glucose or fat (3, 4). In contrast, GLP-1 is a posttranslational product of the proglucagon gene (5) and is released from more distally located intestinal L cells in response to ingestion of glucose or a mixed meal (4, 6, 7, 8). Under conditions of elevated blood glucose concentrations, both GIP and GLP-1 stimulate insulin secretion and proinsulin gene transcription via specific receptors expressed on islet ß-cells (9, 10, 11).
The principle action of GIP seems to be the stimulation of glucose-dependent insulin secretion after enteral nutrient ingestion. Consistent with this hypothesis, GIP immunoneutralizing antisera or a GIP peptide antagonist reduced insulin secretion after oral glucose challenge in rats (12, 13). The biological importance of GIP as an incretin is further illustrated by GIP receptor -/- mice that exhibit defective glucose clearance after oral glucose loading; but normal fasting glucose and glycemic excursion, after ip glucose challenge (14). In contrast, GLP-1R-/- mice exhibit fasting hyperglycemia and abnormal glycemic excursion in response to both oral and ip glucose challenge (15).
Although results of studies in knockout mice may be used to infer specific physiological actions of GIP and GLP-1 for control of glucose homeostasis, disruption of incretin receptor signaling from birth may be associated with subtle developmental and adaptive changes that could modify the interpretation of physiological studies. For example, GLP-1R-/- mice exhibit abnormalities in the hypothalamic-pituitary-adrenal axis (16) and up-regulation of glucose-dependent GIP secretion and enhanced sensitivity to GIP action (17), complicating the interpretation of results ascribed simply to interruption of GLP-1R signaling in vivo. Accordingly, to control for potential confounding developmental or adaptive changes in incretin action observed in genetically modified mice, we have assessed the importance of GIP and GLP-1 for glycemic control in +/+ and GLP-1R-/- mice using antagonists of GLP-1 and GIP action in vivo.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Glucose tolerance tests and measurement of plasma insulin
levels
Oral glucose tolerance tests (OGTTs) or ip glucose tolerance
tests (IPGTTs) were carried out after an overnight fast (16–18 h). The
GLP-1 receptor antagonist
exendin(9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39)-NH2 (5 µg; California Peptide
Research Inc., Napa, CA) or PBS was administered ip 20 min before
glucose administration, after a fasting blood glucose measurement had
been obtained. Anti-GIP R antiserum was raised in rabbits against a
synthetic peptide containing an extracellular epitope of the GIP
receptor GQTTGELYQRWERYGWEC coupled to KLH. Immunopurified antibody
(GIPR Ab) specifically displaces 125I-GIP binding
with half-maximal displacement at approximately 1 µg/ml (data not
shown). In the rat, plasma levels of GIPR Ab peak approximately 4
h after ip injection and remain at this level for 2 days. When
delivered at a dose of 1 µg/g body weight, the insulinotropic action
of an exogenous bolus of GIP is completely abolished (data not shown).
Immunopurified antisera [1 µg/g body weight; GIPR Ab
(18)] or a rabbit 
-globulin control (1 µg/g body
weight; Jackson ImmunoResearch Laboratories, Inc., West
Grove, PA) was given ip at the onset of fasting, 16–18 h before the
glucose tolerance tests. For glucose tolerance tests, mice were given
1.5 mg glucose/g body weight orally through a gavage tube (OGTT) or via
injection into the peritoneal cavity (IPGTT). Blood was drawn from a
tail vein at 0, 10, 20, 30, 60, 90, and 120 min after glucose
administration; and blood glucose levels were measured by the glucose
oxidase method using a One Touch Basic Glucometer (Lifescan Ltd.,
Burnaby, British Columbia, Canada). Blood samples (100 µl) for
measurement of insulin secretion were removed from tail veins during
the 10- to 20-min time period after oral or ip glucose administration.
Plasma was assayed for insulin content using a rat insulin
enzyme-linked immunosorbent assay kit (Crystal Chem Inc.,
Chicago, IL) with mouse insulin as a standard.
Chronic exposure to incretin antagonists
For chronic studies, all mice were given free access to standard
rodent chow and water. Wild-type CD1 and GLP-1 receptor
-/- mice were given ip injections of either PBS or 5 µg of
exendin(9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39) in 8% gelatin. Injections were commenced at 0500
h, and each animal was given an ip injection of the appropriate test
substance every 4 h, with the last injection given 3 h before
death, for a total of 15 h of treatment. Blood glucose levels were
measured, animals were killed, and blood was obtained by cardiac
puncture. Plasma was collected for analysis of insulin levels (as
described above). The pancreas was removed from each animal. One
portion was used for RNA isolation and Northern blot analysis.
The remaining portion of the pancreas was homogenized twice in 5 ml of
extraction medium [1 N HCl containing 5% (vol/vol) formic
acid, 1% (vol/vol) trifluoroacetic acid, and 1% (wt/vol) NaCl] at 4
C. Peptides and small proteins were adsorbed from extracts by passage
through a C18 silica cartridge (Waters Associates,
Milford, MA). Adsorbed peptides were eluted with 4 ml of 80% (vol/vol)
isopropanol containing 0.1% (vol/vol) trifluoroacetic acid. Pancreatic
insulin levels were measured using a rat insulin enzyme-linked
immunosorbent assay kit (Crystal Chem Inc.), with mouse insulin
as a standard. Total protein levels in extracts were determined using
the Bradford method (19) with dye reagent (Bio-Rad Laboratories, Inc., Hercules, CA). For chronic studies with GIPR
Ab, wild-type CD1 and GLP-1 receptor -/- mice were given
ip injections of either rabbit -globulin or 1 µg/g body weight of
purified GIPR Ab. Only a single injection of GIPR Ab was required,
because the antibody is stable in plasma for several days (18). At
18 h after administration of GIPR Ab or -globulin control, mice
were anesthetized with CO2 and exsanguinated by
cardiac puncture. Blood glucose, plasma insulin, and pancreatic insulin
content were determined as described above.
RNA isolation and Northern blot analysis
After chronic exposure to PBS, exendin(9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39), rabbit
-globulin, or GIPR Ab, mice were anesthetized with
CO2, and pancreases were removed immediately for
RNA extraction by the acid-guanidinium isothiocyanate method
(20). Total RNA (10 µg) was electrophoresed in a 1%
(wt/vol) formaldehyde-agarose gel and transferred to a nylon membrane
(Nytran Plus; Schleicher & Schuell, Inc., Keene, NH). For
Northern blot analysis, the blot was hybridized to
32P-labeled random-primed complementary
DNA probes corresponding to rat proglucagon, rat insulin, or 18S
rRNA.
Statistics
Results are expressed as means ± SEM.
Statistical significance was calculated by ANOVA and
Student’s t test using INSTAT 1.12 (GraphPad Software, Inc., San Diego, CA). A P value <
0.05 was considered to be statistically significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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;
P < 0.05 for saline vs.
exendin(9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39)-treated mice]. Surprisingly, plasma insulin levels were
not significantly different, after oral glucose loading, in saline
vs. exendin(9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39)-treated mice (Fig. 1B).
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). Furthermore, the levels of
glucose-stimulated circulating insulin were significantly reduced in
exendin(9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39)-treated mice (Fig. 2B; P < 0.05;
0.58 ± 0.02 vs. 0.47 ± 0.02 ng/ml in
saline-vs. exendin(9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39)-treated mice, respectively).
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, A and B), demonstrating the
specificity of exendin(9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39) for GLP-1R receptor-mediated glucose
clearance at the dose employed here in vivo.
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; 13.1
± 0.6 vs. 10.8 ±0.5 mM in GIPR
Ab-treated vs. control +/+ mice, respectively,
P < 0.05). The increase in blood glucose was
associated with a small but nonsignificant increase in plasma insulin
(Fig. 4B). In contrast, treatment of GLP-1R-/- mice with GIPR Ab
produced a significant increase in blood glucose (Fig. 5A; 10.4 ± 0.8 vs.
8.3 ± 0.5 mM in GIPR Ab vs.
control-treated mice, P < 0.05) and a significant reduction in
levels of glucose-stimulated insulin (Fig. 5B, P <
0.05; 0.31 ± 0.03 vs. 0.46 ± 0.05 ng/ml for mice
receiving GIPR Ab vs. rabbit -globulin,
respectively).
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The results of these experiments demonstrated that acute antagonism of
GLP-1 or GIP action produces differential effects on
glycemic excursion after oral vs. ip glucose loading.
Because both GLP-1 and GIP have been postulated to
regulate glycemia, in part through effects on insulin biosynthesis at
the level of insulin gene transcription (9, 10, 11), we
examined the effects of administering either exendin(9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39) or GIPR Ab
on glucose control, over a more prolonged 18-h time period. Repeated
administration of exendin(9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39) to +/+ mice produced a significant
elevation in blood glucose (Fig. 6A, P < 0.05; 7.1 ± 0.4 vs. 8.8 ±
0.4 mM for saline vs.
exendin(9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39)-treated mice) and a significant reduction in the levels
of plasma insulin (Fig. 6B, P < 0.05; 2.4 ± 0.1
vs. 1.7 ± 0.2 ng/ml for saline vs.
exendin(9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39)-treated mice). Comparable treatment of GLP-1R-/- mice
with repeated injections of exendin(9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39) had no effect on either
blood glucose or plasma insulin (Fig. 6, C and D). In contrast to
changes in glucose and insulin in mice treated with repeated
administration of exendin(9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39), no significant perturbation of blood
glucose or plasma insulin levels was observed in +/+ or GLP-1R-/-
mice, 18 h after administration of GIPR Ab (Fig. 7, A–D)
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, A and C) or pancreatic insulin content
(Fig. 8) were detected, after repeated
treatment with exendin(9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39), in either +/+ or GLP-1R-/- mice.
Similarly, no significant changes in the levels of proinsulin RNA or
insulin content were detected in the pancreas of mice treated with GIPR
Ab (Figs. 9, B and C; and 8B).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The importance of nonincretin effects of GLP-1 are further exemplified by experiments in mice with genetic disruption of GLP-1R signaling. Consistent with the concept of GLP-1 functioning as an incretin, GLP-1R-/- mice exhibit defective glucose-stimulated insulin secretion and increased glycemic excursion after oral glucose challenge, even if only one GLP-1 receptor allele is disrupted (15, 32). Studies of islet function demonstrate defects in basal islet cAMP and glucose-stimulated calcium signaling in GLP-1 R-/- islets (33). The importance of basal GLP-1R signaling for ß-cell function may partly explain why GLP-1R-/- mice also exhibit mild fasting hyperglycemia and abnormal glucose excursion after ip glucose challenge (15), conditions that would not be associated with increases in levels of circulating GLP-1. Although the phenotype of impaired glucose tolerance in GLP-1R-/- mice can be mild and variable, analysis of large numbers of knockout mice of different ages demonstrates statistically significant impairment of glucose homeostasis in the fasting state and after oral and ip glucose challenge (15, 32, 34).
Interpretation of the modest impairment of glucose tolerance after genetic GLP-1R disruption is complicated by the observation that GIP secretion and GIP-stimulated insulin secretion are up-regulated in GLP-1R-/- mice, suggesting that compensatory enhancement of GIP action partially modifies the phenotype of GLP-1 deficiency in vivo (17). Furthermore, it remains possible that potential developmental effects of GLP-1R deficiency might also modify islet and ß-cell development and responsivity, hence the abnormalities in ß-cell function and glucoregulation detected in GLP-1R-/- mice may not necessarily be directly correlated with acute disruption of GLP-1 action in vivo.
Accordingly, to eliminate confounding variables introduced by the potential contribution of developmental and adaptive changes in physiological regulatory systems, we reexamined the importance of GLP-1 and GIP action for both incretin and nonincretin-mediated control of glycemia in wild-type mice. Our data clearly show that inhibition of GLP-1 activity during ip glucose challenge produces abnormal glycemic excursion in +/+ mice, associated with a significant reduction in plasma insulin. Because nonenteral glucose challenge would not be expected to stimulate GLP-1 secretion, our findings strongly suggest that basal levels of circulating GLP-1 are essential for glycemic control, both in the fasting state and after glucose challenge, independent of the mode of glucose entry.
Further evidence supporting the importance of basal GLP-1 signaling for glucoregulation derives from studies using exendin(9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39) in both humans and baboons. Administration of exendin(9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39) produced significant elevations in fasting levels of both glucose and glucagon, suggesting that even basal GLP-1 signaling during the fasting state exerts a tonic inhibitory effect on glucagon secretion (35, 36, 37). The finding that glucagon secretion is under tonic inhibitory control by GLP-1 signaling is consistent with our observation that glucose levels rise in exendin(9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39)-treated mice, without an obligatory increase in the levels of circulating insulin. Additional evidence for the importance of basal GLP-1 signaling derives from studies demonstrating that exendin(9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39) is an inverse agonist of the ß-cell GLP-1 receptor and that constitutive activity of the GLP-1 receptor, even in the absence of bound ligand, is important for maintaining basal levels of cAMP and for sustaining pancreatic ß-cells in a glucose-competent state (33, 38).
In contrast to the importance of GLP-1 for glucose regulation and ß-cell function in the fasting state, our current data strongly suggest that the role of GIP in glucose control is considerably more restricted, principally functioning as an incretin in the postabsorptive state. Disruption of GIP action during oral glucose challenge produced a significant increase in glycemic excursion in both +/+ and GLP-1R-/- mice, in association with a diminution of glucose-stimulated insulin secretion. In contrast, administration of GIPR Ab did not effect fasting glucose or glycemic excursion after ip glucose loading, even in mice with loss of GLP-1 function.
Although the incretin function of GIP is well established (3, 4, 12), a role for GIP in the control of ß-cell function in the fasting state is less clearly defined. Infusion of GIP produced a dose-dependent increase in plasma insulin, in fasted rats, that was attenuated by coinfusion of a GIP peptide antagonist (39). Although the GIP peptide antagonist ANTGIP diminished glucose-stimulated insulin secretion in rats, the effect of ANTGIP on blood glucose or insulin secretion, in the fasting state or after ip glucose challenge, was not reported (13). Although we cannot be absolutely certain that the limitations of the immunoneutralizing GIPR Ab may affect our experimental results, the finding that GIP is primarily important for glucose clearance, after enteral (but not ip) glucose loading, is consistent with data from GIP receptor -/- mice. These mice exhibit normal fasting glucose, and the glycemic response to ip glucose challenge is comparable and normal in the presence or absence of GIP receptor signaling (14). These findings are entirely consistent with our data showing no effect of GIPR Ab on fasting glucose or ip glucose clearance in mice in vivo. Taken together, the cumulative evidence strongly suggests that the glucoregulatory actions of GIP on the ß-cell are restricted to the potentiation of glucose-stimulated insulin secretion after enteral nutrient absorption.
The results of several studies have suggested an important role for GLP-1 in the regulation of insulin gene expression and insulin biosynthesis. Incubation of islet cell lines, with GLP-1 or exendin-4, increases proinsulin mRNA via activation of insulin gene transcription (9, 10). Similarly, GIP increases insulin mRNA and insulin content in islet cells, via induction of insulin promoter activity and insulin gene expression (11, 40). Despite the putative importance of GLP-1 and GIP for insulin gene expression and insulin biosynthesis, we did not detect changes in pancreatic insulin content or insulin RNA in +/+ mice treated with either exendin(9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39) or GIPR Ab. Furthermore, we found minimal to no changes in pancreatic insulin mRNA and insulin content in GLP-1R-/- mice (17, 32, 41). These findings, taken together with our data using exendin(9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39) or GIPR Ab, strongly suggest that GLP-1 and GIP are not essential for insulin gene expression and insulin biosynthesis in mice in vivo.
In summary, our studies demonstrate that GLP-1 is essential for glucose-stimulated insulin secretion in mice, independent of the mode of glucose entry. Although several investigators have suggested that the predominant effect of GLP-1 on glucose control resides at the level of gastric emptying (42, 43), our data clearly indicate an essential role for GLP-1 in glucoregulation independent of nutrient entry via the gastrointestinal tract. In contrast, GIP plays a more restricted role in glucose homeostasis, with GIP actions restricted to the classical incretin function of potentiating nutrient-stimulated insulin secretion. The wider spectrum of GLP-1 actions on gastric emptying, ß-cell function, glucagon secretion, food intake, and islet growth suggest that GLP-1 is likely to exhibit more potential, compared with GIP, as a therapeutic agent for the treatment of diabetes.
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Acknowledgments |
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Footnotes |
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2 Supported by a doctoral research award from the Medical Research
Council of Canada.
3 A CDA and Alberta Heritage Foundation for Medical Research
Scholar.
4 A Senior Scientist of the Medical Research Council of Canada.
Received May 4, 2000.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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 E. E. Daniel, M. Anvari, J. E. T. Fox-Threlkeld, and T. J. McDonald Local, exendin-(939)-insensitive, site of action of GLP-1 in canine ileum Am J Physiol Gastrointest Liver Physiol, September 1, 2002; 283(3): G595 - G602. [Abstract] [Full Text] [PDF]
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 M. Nian, J. Gu, D. M. Irwin, and D. J. Drucker Human glucagon gene promoter sequences regulating tissue-specific versus nutrient-regulated gene expression Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2002; 282(1): R173 - R183. [Abstract] [Full Text] [PDF]
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D. J. Drucker Minireview: The Glucagon-Like Peptides Endocrinology, February 1, 2001; 142(2): 521 - 527. [Abstract] [Full Text] [PDF]
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